Hepatitis B Virus Intrauterine Transmission Research Articles

Altered TLR7 Expression-Mediated Immune Modulation Is Supportive of Persistent Replication and Intrauterine Transmission of HBV.

Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.

Intrauterine Infection and Mother-to-Child Transmission of Hepatitis B Virus: Route and Molecular Mechanism

In high prevalence settings, mother-to-child transmission is responsible for more than 50% of chronic Hepatitis B Virus (HBV) infections with 1–9% of newborns of HBV-carrying mothers acquiring HBV in early life. Little is known about the routes and cellular mechanisms by which HBV intrauterine transmission occurs. Clinical studies indicate that placental trophoblasts can be infected with HBV. In vitro studies using primary trophoblast and cell lines support this hypothesis. Several cellular parameters, including the differentiation state of the trophoblasts, cytokine secretion, and the surface molecules involved in virus entry, may influence the receptivity of trophoblastic cells to HBV. In HBV-infected trophoblastic cells, a reduction of apoptosis and increased production of antiviral cytokines has been observed, presumably via an HBx antigen-Akt or TLRs-MyD88-NF-kB pathway. Trophoblast HBV infection occurrence involves complex pathological processes with little currently known of the related mechanisms within infected cells. Whilst much focus has been on the placental routes of infection, through trophoblasts in particular, other routes have also been suggested. In this article, we review the models for HBV mother-to-child transmission and discuss the possible mechanisms of HBV intrauterine transmission with particular emphasis upon the involvement of placental trophoblast infection.

Relationship between mutations of HBV basal core promoter region in HBsAg-positive mothers and intrauterine transmission

Objective: To analyze the relationship between maternal mutations in basal core promoter region of hepatitis B virus (HBV) genotype C and intrauterine transmission. Methods: We collected information on general demographic characteristics and process of delivery among 399 pairs of consecutive HBsAg-positive mothers and their neonates, from the Third People's Hospital of Taiyuan in Shanxi province, China. Fluorescence quantitative polymerase chain reaction (FQ-PCR) and Electro-chemiluminescence immuno-assay (ECLIA) kits were used to detect both maternal and neonatal HBV DNA and serological markers in the peripheral blood. From 113 mothers with HBV DNA load ≥10(6) IU/ml, we selected 22 mothers whose neonates were with intrauterine transmission and randomly selected the same number of mothers whose neonates were without intrauterine transmission, as controls. The whole-length HBV DNA were extracted, amplified, cloned, sequenced and genotyped. Finally, a total of 39 mothers with genotype C of HBV were selected for mutation analysis. Results: Thirty-nine cases of genotype C (88.63%) were finally included in the study, with 19 cases in the intrauterine transmission group and 20 cases as controls. Rates of A1762T/G1764A double mutations were significantly different between the intrauterine transmission group and the control group (7.53% vs. 27.72%, P<0.001). Results from the multivariate analysis showed that the A1762T/G1764A double mutations had reduced the risk of intrauterine transmission (aOR=0.065, 95%CI: 0.006-0.746, P=0.028). Maternal A1762T/G1764A double mutations appeared to be possibly associated with neonatal HBeAg (P=0.050). Conclusion: A1762T/G1764A double mutations of HBV DNA from the genotype C of those HBsAg-positive mothers could reduced the risk of HBV intrauterine transmission during pregnancy.

Role of TLR 9 expression in maternal peripheral blood and placenta in intrauterine transmission of HBV

Objective: To explore the role of TLR 9 in intrauterine transmission of hepatitis B virus (HBV) through blood pathway and placenta. Methods: Epidemiological investigation was carried out in 290 HBsAg positive parturients and 45 normal parturients (control group) in Northwest Women and Children Hospital of Shaanxi Province. Enzyme-linked immunosorbent assay (ELISA) was used to detect five serological makers of hepatitis B and TLR 9 levels in peripheral blood of pregnant women and newborns. HBV DNA was detected by real-time fluorescence quantitative PCR. Detection of TLR 9 expression in placenta by immunohistochemical method. A case-control study was conducted to analyze the difference of TLR 9 levels in placenta and peripheral blood of HBsAg- positive pregnant women with intrauterine transmission of HBV. Results: The incidence of dominant HBV infection (DBI), occult HBV infection (OBI) and intrauterine transmission of HBV were 9.28% (27/291), 40.21% (117/291) and 49.48% (144/291) respectively. (1) The level of TLR 9 in peripheral blood of HBsAg-positive parturients, non-HBV intrauterine transmission (NBIT) group and OBI group were significantly lower than that of control group (P<0.001). The level of TLR 9 in DBI group was significantly higher than those in NBIT group and OBI group (P=0.000). (2) The TLR 9 level in HBeAg-negative group was significantly lower than that in HBeAg-positive parturients in OBI group (P=0.01). (3) With the increased severity of intrauterine transmission of HBV in each HBV DNA load group, the TLR 9 level in maternal peripheral blood increased significantly (P<0.05). (4) With the increased severity of intrauterine transmission of HBV, the levels of TLR 9 increased significantly in antiviral therapy, immunoglobulin injection and non-hepatitis B vaccine groups (P<0.05). (5) The expression of TLR 9 in placenta tissues with DBI group was significantly higher than that in OBI group and NBIT group (P<0.05). Conclusions: HBV can inhibit the secretion of TLR 9 in parturient to some extent, but HBeAg can stimulate the secretion of TLR 9. However, with the increased severity of intrauterine transmission of HBV, the level of TLR 9 in parturients is increased by intra-group cross-differentiation. Therefore, TLR 9 is not an independent marker for screening and grouping, but it can be used as an reference indicator for the monitoring and management of HBsAg-positive parturients.

Relationship between Maternal PBMC HBV cccDNA and HBV Serological Markers and its Effect on HBV Intrauterine Transmission

ObjectiveTo investigate the relationship between maternal peripheral blood mononuclear cells (PBMC) hepatitis B virus (HBV) covalenty closed circular deoxyribonucleic acid (cccDNA) and other HBV serological markers and its effects on HBV intrauterine transmission. MethodsWe enrolled 290 newborns and their hepatitis B surface antigen (HBsAg) positive mothers. HBV cccDNA in PBMC and HBV DNA in serum were detected by a real-time PCR-TaqMan probe while HBV serological markers were detected with an electrochemiluminescence immunoassay. ResultsThere was a positive correlation between the levels of PBMC HBV cccDNA and serum HBV DNA and HBeAg (r = 0.436 and 0.403, P < 0.001). The detection rate of pattern A [‘HBsAg (+), HBeAg (+), and anti-HBc (+)’] was significantly higher in the PBMC HBV cccDNA positive group than in the control group (χ2 = 48.48, P < 0.001). There was a significant association between HBV intrauterine transmission and PBMC HBV cccDNA (χ2 = 9.28, P = 0.002). In the presence of serum HBV DNA, HBeAg, and PBMC HBV cccDNA, the risk of HBV intrauterine transmission was three times higher (OR = 3.69, 95% CI: 1.30-10.42) than that observed in their absence. The risk of HBV intrauterine transmission was the greatest (OR = 5.89, 95% CI: 2.35-14.72) when both PBMC HBV cccDNA and pattern A were present. A Bayesian network model showed that maternal PBMC HBV cccDNA was directly related to HBV intrauterine transmission. ConclusionPBMC HBV cccDNA may be a direct risk factor for HBV intrauterine transmission. Our study suggests that serological markers could be combined with PBMC-related markers in prenatal testing.

Incidence and Risk Factors of Intrauterine Transmission Among Pregnant Women With Chronic Hepatitis B Virus Infection.

To identify the potential risk factors of hepatitis B virus (HBV) intrauterine transmission and predict the incidence of HBV intrauterine transmission among hepatitis B surface antigen-positive pregnant women with diverse viral load. The intrauterine transmission of HBV significantly contributes to the persistence of a high number of patients infected with HBV. However, its risk factors remain unclear. A prospective study was performed on hepatitis B surface antigen-positive pregnant women who delivered from June 2012 to December 2016 at Wuhan Medical Care Center for Women and Children, Wuhan, China. In total, 1200 women paired with 1219 infants were enrolled. In total, 11 (0.9%) infants were identified with intrauterine transmission. We observed that all infants with intrauterine transmission were born to hepatitis B e antigen-positive mothers who had serum HBV DNA levels >7 log10 copies/mL. Our study suggested that the HBV DNA levels (for each log10 copies/mL increase, odds ratio=5.43; 95% confidence interval, 1.31-22.43; P=0.019) had independent effects on HBV intrauterine transmission in a multivariate logistic regression model. Moreover, cesarean section (odds ratio=0.18; 95% confidence interval, 0.04-0.74; P=0.018) was associated with a reduced risk of HBV intrauterine transmission. The predictive rates of intrauterine transmission were 0.06%, 0.50%, 2.81%, 8.89% in infants with maternal HBV DNA levels of 10, 10, 10, 10 copies/mL, respectively. Our data confirmed that increasing maternal viral load has the ability to predict intrauterine HBV transmission. Vaginal delivery increased risk of HBV transmission in infants compared with cesarean section. Further studies are warranted to clarify the possible mechanism underlying these associations.

Impact of HBV replication in peripheral blood mononuclear cell on HBV intrauterine transmission.

This study determined the effect of hepatitis B virus (HBV) replication in peripheral blood mononuclear cell (PBMC) from HBsAg-positive mothers on HBV intrauterine transmission. A total of 150 HBsAg-positive mothers and their neonates were recruited in this study. Within 24 h after birth, HBV serological markers, serum HBV DNA, PBMC HBV relaxed circular DNA (rcDNA), and covalently closed circular DNA (cccDNA) were measured in the HBsAg-positive mothers and their neonates before passive-active immune prophylaxis. The relationship between HBV replication in PBMC and HBV intrauterine transmission was examined through Chisquare test and logistic regression. The rate of HBV intrauterine transmission was 8.00% (12/150) in the 150 neonates born to HBsAg-positive mothers. The positivities of PBMC HBV rcDNA and cccDNA in the HBsAg-positive mothers were 36.67% (55/150) and 10% (15/150), respectively. Maternal PBMC HBV cccDNA was a risk factor of HBV intrauterine transmission (OR = 6.003, 95% CI: 1.249-28.855). Maternal serum HBeAg was a risk factor of PBMC HBV rcDNA (OR = 3.896, 95% CI: 1.929-7.876) and PBMC HBV cccDNA (OR = 3.74, 95% CI: 1.186-11.793) in the HBsAg-positive mothers. Administration of hepatitis B immune globulin was a protective factor of PBMC HBV cccDNA (OR = 0.312, 95%CI: 0.102-0.954) during pregnancy. The positivity of PBMC HBV rcDNA was related to that of cccDNA in the HBsAg-positive mothers (χ 2= 5.087, P = 0.024). This study suggests that PBMC is a reservoir of HBV and an extrahepatic site for virus replication and plays a critical role in HBV intrauterine transmission.

Involvement of viperin in prevention of intrauterine transmission of hepatitis B virus.

The aim of this study was to explore the role of viperin in the prevention of intrauterine infection of hepatitis B virus (HBV). Placental samples were collected from seven HBV-positive pregnant women with their infants infected via intrauterine transmission (infected group), 30 HBV-positive women with non-infected infants (non-infected group), and 30 HBV-negative women (controls). The expression of viperin in placenta was analyzed with immunohistochemistry and Western blotting. The expression of viperin of placental trophoblast cell line Swan71 was determined after exposed to HBV. Viperin was localized to syncytiotrophoblast, and there was a significant difference in placental viperin levels among control, non-infected group and infected group (F = 12.824, p < 0.001). The expression of viperin was significantly higher in non-infected group than in control (p = 0.019) and in infected group (p < 0.001), and viperin expression was significantly lower in infected group than in control (p = 0.001). The exposure to HBV significantly increased the expression of viperin in Swan 71 (p < 0.001). Exposure to HBV up-regulates viperin expression in vivo and in vitro in placental trophoblast, and lack of this up-regulation is associated with intrauterine transmission of HBV.

Genetic variant in CXCL13 gene is associated with susceptibility to intrauterine infection of hepatitis B virus.

Intrauterine infection of hepatitis B virus (HBV), which accounts for the majority of mother-to-child transmission, is one of the main reasons for the failure of combined immunoprophylaxis against the transmission. Recent studies have identified that genetic background might influence the susceptibility to intrauterine infection of HBV. We conducted this study to investigate the associations between 10 genetic variants in 9 genes (SLC10A1, HLA-DP, HLA-C, CXCR5, CXCL13, TLR3, TLR4, TLR9 and UBE2L3) of mothers and their neonates and HBV intrauterine infection. A significantly decreased risk of HBV intrauterine transmission were found among mothers who carried the rs355687 CT genotypes in CXCL13 gene compared to those with CC genotypes (OR = 0.25, 95% CI, 0.08–0.82, P = 0.022); and a marginally significantly decreased risk was also observed under the dominant model (OR = 0.34, 95% CI, 0.11–1.01, P = 0.052). Besides, neonatal rs3130542 in HLA-C gene was found to be marginally significantly associated with decreased risk of HBV intrauterine infection under the additive model (OR = 0.55, 95% CI, 0.29–1.04, P = 0.064). However, we found no evidence of associations between the remaining 8 SNPs and risk of HBV intrauterine infection among mothers and their neonates. In conclusion, this study suggested that genetic variant in CXCL13 gene was associated with susceptibility to intrauterine infection of HBV.

The safety of telbivudine in preventing mother-to-infant transmission of hepatitis B virus in pregnant women after discontinuation

To determine the efficacy and safety of telbivudine for blocking intrauterine transmission of hepatitis B virus (HBV) in pregnant women with high-load HBV DNA. Women in general good health and pragnant were enrolled for study between the ages of 20 to 40 year-old, with a diagnosis of HBV infection with high-load HBV DNA level (≥1*10(6) IU/ml). According to each participant's willingness, the women were divided into a telbivudine treatment group (82 women) and an untreated control group (75 women). The telbivudine treatment was initiated at gestation week 26 as oral dosing of 600 mg/d and continued until 1 month after the birth.Women in the control group had not gotten any antiviral drug treatment. All of the women delivered by cesarean section, and all of the neonates were administered the standard passive immunization therapy, which consisted of a hepatitis B immunoglobulin (200 IU) injection given within 12 hours of birth and an injection of hepatitis B vaccine (20 µg) at birth and at postnatal month 1 and 6. None of the mother's performed breastfeeding. The telbivudine-treated women showed a significant decrease in HBV DNA levels prior to delivery, as well as significantly decreased prenatal HBV DNA levels (>2 logl0). Efficiency of the telbivudine treatment was 100%. Immediately prior to delivery, 16 (19.5%) of the women in the telbivudine treatment group showed negative HBV DNA status, as opposed to the untreated control group in which no women showed negative status. The telbivudine treatment group had no case of maternal or fetal adverse reaction or of congenital malformation. Use of telbivudine antiviral therapy during late pregnancy in women with high-load HBV DNA can significantly reduce level of HBV DNA in maternal peripheral blood, block HBV intrauterine transmission, and provide good short-term efficacy, with good tolerability and safety.

Evaluation of neonatal Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in HBV intrauterine transmission susceptibility.

To investigate whether single nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 3 and 9 affect the susceptibility of hepatitis B virus (HBV) intrauterine transmission, we genotyped 399 neonates for TLR3 (c.1377C/T) [rs3775290] and TLR9 (G2848A) [rs352140] using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A femoral venous blood sample was obtained from these subjects. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were measured using chemiluminescence immunoassay kits and hepatitis B virus DNA (HBV DNA) levels were determined by fluorescence quantitative PCR assay. Our results showed that when adjusting for maternal HBeAg, maternal HBV DNA and mode of delivery, allele 'T' for SNP c.1377C/T was significantly associated with HBV intrauterine transmission susceptibility [adjusted OR (aOR) 0.55, 95% confidence interval (CI) 0.34-0.91, P = 0.020] and the TT genotype decreased the risk of HBV intrauterine transmission (aOR 0.28, 95% CI 0.09-0.91, P = 0.033). Allele 'A' for SNP G2848A was significantly associated with HBV intrauterine transmission susceptibility (aOR 0.62, 95% CI 0.39-1.00, P = 0.048) and the GA genotype protected neonates from HBV intrauterine transmission (aOR 0.45, 95% CI 0.22-0.93, P = 0.031). The TLR3 (c.1377C/T) and TLR9 (G2848A) polymorphisms may be relevant for HBV intrauterine transmission susceptibility, although the reduction in risk to HBV intrauterine transmission is modest and the biological mechanism of the observed association merits further investigation.

Potential roles of placental human beta-defensin-3 and apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G in prevention of intrauterine transmission of hepatitis B virus.

Approximately 5% of newborns were infected by hepatitis B virus (HBV) via intrauterine transmission and this is the main reason for high prevalence of HBV in endemic regions. However, the mechanisms by which intrauterine transmission is avoided in most cases remain elusive and placental natural anti-microbial factors may play a role in the prevention of HBV intrauterine transmission. The expression levels of human β-defensin-3 (HBD-3), apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G (A3G) and mannose binding lectin (MBL) were determined in the placenta of 30 HBV-seronegative pregnant women (controls), 7 HBV-seropositive pregnant women with infants infected via intrauterine transmission (infected group) and 30 HBV-seropositive pregnant women with non-infected infants (non-infected group). The expression of HBD-3, A3G, and MBL of placental trophoblast cell line Swan71 was determined after exposed to HBV. There were significant differences in placental HBD-3 and A3G levels among three groups, but the expression of MBL did not significantly differ. The expressions of HBD-3 and A3G were higher in non-infected group than controls and infected group, but not significantly different between infected group and controls. The exposure to HBV increased significantly the expression of HBD-3, A3G, and MBL by Swan 71. It may be concluded HBV up-regulates HBD-3 and A3G expression in vivo and in vitro in placental trophoblast and lack of this up-regulation is possibly associated with intrauterine transmission of HBV.

Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis.

BECKGROUND: Evaluate the efficacy and safety of telbivudine during the 2nd and 3rd trimester of pregnancy in intrauterine transmission of hepatitis B virus (HBV). Based on the principle of Cochrane systematic reviews, a database was constructed from Medline, EMBASE, Cochrane Library, the US National Science Digital Library (NSDL), the China Biological Medicine Database (CBM-disc), and contact with Chinese experts in the field from November 2006 to February 2013. The Critical Appraisal Skills Programme (CASP) of Oxford, Cochrane Collaboration's tool, and Review Manager Version 5.0 (Rev-Man 5.0) for assessing the quality of clinical trials, risk of bias, and statistical analysis was used. We analyzed the effects and safety of telbivudine treatment on intrauterine mother-to-child transmission (MTCT) of HBV from HBsAg and HBV-DNA positive mothers. All newborns received an immune prophylaxis schedule consisting of simultaneous hepatitis B virus vaccine and hepatitis B immunoglobulin (HBIG) postpartum. Of 32 studies, 7 studies fulfilled the inclusion criteria in the study. Either the Mantel-Haenszel or Inverse Variance fixed-effects model or Mantel-Haenszel or Inverse Variance random-effects model was applied for all analyses indicated by odds ratio (OR) and 95% confidence interval (CI). The meta-analysis based on new onset of HBsAg seropositivity of infants at 6-12 months postpartum revealed that the control group had an intrauterine transmission rate of 8.25-42.31%. This rate was reduced to 0-14.29% in the telbivudine treatment group (OR 0.09, 95% CI 0.04-0.22, including seven trials, p < 0.001). The rates of intrauterine transmission based on new onset of HBV DNA seropositivity of infants at 6-12 months postpartum were 8.25-19.23% in the control group and 0 - 3.57% in the treatment group (OR 0.07, 95% CI 0.02-0.22, p < 0.001, including only five trials, since two trials had no data on HBV DNA in infants). With the exception of CK elevations, adverse effect frequencies were similar in both groups. Telbivudine is an effective and safe drug for preventing intrauterine transmission of HBV.

Potential Role of Mannose-Binding Lectin in Intrauterine Transmission of Hepatitis B Virus

Intrauterine transmission of hepatitis B virus (HBV) is the main cause of the high prevalence of HBV in endemic areas; however, the mechanisms underlying intrauterine transmission of HBV remain unknown. To explore the role of mannose-binding lectin (MBL), a pattern recognition molecule of the innate immune system, in intrauterine transmission of HBV, we determined MBL levels using an enzyme-linked immunosorbent assay (ELISA) in cord serum of 7 intrauterine-infected neonates and 30 non-infected neonates born to HBV-positive mothers, and 30 control neonates born to HBV-negative mothers. We observed significant differences in cord serum MBL levels among the three groups (P < 0.001). Non-infected neonates had significantly higher MBL levels than controls (P < 0.001), and intrauterine-infected neonates had significantly lower serum MBL levels than non-infected neonates (P < 0.001). However, serum MBL levels were not significantly different between intrauterine-infected neonates and controls (P = 0.800). Our results indicate that maternal HBV infection induces an increase in fetal MBL levels and the absence of this increase is possibly associated with intrauterine transmission of HBV, suggesting that MBL plays a role in intrauterine transmission of HBV.

Risk factors of HBV intrauterine transmission among HBsAg‐positive pregnant women

Little is known about the risk factors associated with hepatitis B virus (HBV) intrauterine transmission among HBsAg-positive mothers. We conducted a study in Taiyuan, China, including 1133 HBsAg-positive mothers and their babies. A total of 101 neonates had HBsAg and/or HBV DNA positive with an intrauterine transmission rate of 8.9%. Maternal menstrual irregularity (OR=4.95, 95% CI: 1.71, 14.33) and severe nausea during the first trimester (OR=1.86, 95% CI: 1.11, 3.09) were associated with an increased risk of intrauterine transmission, while caesarean delivery (OR=0.32, 95% CI: 0.20, 0.51) was associated with a decreased risk after adjusting for potential confounders. Maternal HBeAg positive was a strong independent predictor for intrauterine transmission (OR=2.56, 95% CI: 1.54, 4.27). A positive association between maternal HBV DNA levels and intrauterine transmission was suggested. Maternal HBIG administration during pregnancy, family history of HBV infection and premature rupture of membranes was not associated with the risk of intrauterine transmission. The study confirmed that maternal HBeAg positive was a risk factor and caesarean delivery was a protective factor for intrauterine transmission. The new findings associated with menstrual irregularity and severe nausea during the first trimester warrant further investigation.

A preliminary study on the molecular evolution of the two routes of intrauterine transmission of HBV

Intrauterine transmission of hepatitis B virus (HBV) is one of the main reasons for the failure of vaccination and plays an important role in areas with high HBV prevalence. In the present study, the quasispecies isolated from eight pairs of HBsAg-positive mothers and their neonates, who were infected with HBV by intrauterine transmission, were selected as study subjects. Phylogenetic trees of the HBV strains of each pair of mother and neonate were constructed, the topological structures were compared, and the distance between and within the quasispecies was calculated. The eight phylogenetic trees included four types. In the first type, the maternal and neonatal sequences clustered into one clade. In the second type, the sequences of the mothers and neonates formed separate monophyletic clusters, and the two clades were sister groups. In the third type, the strains of mother were the ancestors of the neonatal strains. In the fourth type, the strains of the mothers clustered with only some of the sequences of the neonate, and the other strains of the neonate formed another monophyletic group. Combined with the genetic distance, possible transmission routes of the eight cases are proposed.

Hepatitis B immunoglobulin injection in pregnancy to interrupt hepatitis B virus mother-to-child transmission—a meta-analysis

To evaluate the efficacy and safety of using hepatitis B immunoglobulin (HBIG) during pregnancy to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT). We systematically reviewed the effect of HBIG in decreasing HBV MTCT from randomized controlled trials (RCTs) carried out between January 1990 and December 2008, in English and Chinese languages. Multiple databases were searched, and experts in this field were contacted. The methodological quality of each RCT was assessed by the Jadad score. We abstracted data on HBV intrauterine infection, MTCT, treatment methods, newborn immune prophylaxis methods, and adverse effects. A Mantel-Haenszel random-effects model was employed for all analyses using odds ratios (OR) and 95% confidence intervals (95% CI). Five thousand nine hundred newborns of asymptomatic hepatitis B surface antigen (HBsAg)-seropositive mothers from 37 qualified RCTs were included. Compared with the control group, newborns in the HBIG group had a lower intrauterine infection rate (indicated by HBsAg as OR 0.22, 95% CI [0.17, 0.29], from 32 RCTs; indicated by HBV DNA as OR 0.15, 95% CI [0.07, 0.30], from 13 RCTs; p<0.01 for both) and a higher protection rate (indicated by hepatitis B surface antibody (HBsAb) as OR 11.79, 95% CI [4.69, 29.61], from 15 RCTs; p<0.01). The same trend was found in MTCT by the time of 9-12 months after birth, indicated by HBsAg (OR 0.33, 95% CI [0.21, 0.51], from nine RCTs; p<0.01) and HBsAb (OR 2.49, 95% CI [1.55, 4.01], from 11 RCTs; p<0.01). HBIG appears to be safe, but a few RCTs have reported adverse events. Multiple injections of HBIG in HBV carrier mothers with a high degree of infectiousness in late pregnancy, effectively and safely prevent HBV intrauterine transmission.

Maternal hepatitis B virus (HBV) DNA positivity and sexual intercourse are associated with HBV intrauterine transmission in China: A prospective case–control study

Hepatitis B virus (HBV) intrauterine transmission from infected mothers contributes significantly to the persistence of the high number of HBV carriers. The aim of this study was to identify potential risk factors for HBV intrauterine transmission. A case-control study was performed on pregnant women tested positive for HBsAg at Shaanxi Maternal and Neonatal Health Hospital, Xi'an, China, from September 2002 to October 2004. Serum samples were taken from infected women and their newborn infants and used for the detection of HBsAg. A structured standard questionnaire was used to collect demographic, medical and maternal data, and maternal HBV DNA, HBeAg, anti-hepatitis C virus and anti-hepatitis D virus were also assessed. Ten neonates validated as having HBV intrauterine transmission were selected as cases and others as controls. The univariate analysis indicated that maternal HBeAg positivity (odds ratio [OR] = 5.96, 95% confidence interval [CI]: 1.61-22.12), HBV DNA positivity (OR = 12.09, 95% CI: 2.97-40.17) and sexual intercourse in the second trimester (OR = 9.15, 95% CI: 1.08-202.99) were significantly associated with an increased risk for HBV intrauterine transmission, whereas contraceptive measures before pregnancy (OR = 0.21, 95%CI: 0.04-0.99) were associated with a decreased risk. The multivariate analysis, however, identified maternal HBV DNA positivity (OR = 19.18, 95%: CI: 3.26-118.73) and sexual intercourse in the second trimester (OR = 1.29, 95%: CI: 1.00-1.66) as the only independent risk factors for HBV intrauterine transmission. The risk of HBV intrauterine transmission increased with increased frequency of sexual intercourse. Therefore, it is concluded that maternal HBV DNA positivity and sexual intercourse in the second trimester are independent risk factors for HBV intrauterine transmission.