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1.  Effect of elective cesarean section on the risk of mother-to-child transmission of hepatitis B virus 
Many clinicians and hepatitis B virus (HBV)-infected pregnant women prefer elective caesarean section (ECS) to prevent mother-to-child transmission of HBV, since some studies found higher transmission of HBV in infants born by vaginal delivery (VD) than by cesarean section. However, other studies showed that ECS does not reduce the risk of being infected with HBV in infants. In this study, we aimed to clarify whether ECS may reduce the risk of mother-to-child transmission of HBV.
Totally 546 children (1–7-year-old) born to 544 HBsAg-positive mothers from 15 cities and rural areas across Jiangsu Province, China, were enrolled. Of these children, 137 (2 pairs of twins) were born to HBeAg-positive mothers; 285 were delivered by ECS and 261 others by VD (one pair of twin in each group). HBV serologic markers were tested by enzyme or microparticle immunoassay.
The maternal and gestational ages, maternal HBeAg-positive rates, and children’s ages, gender ratios, hepatitis B vaccine coverage and administrations of HBIG were comparable between ECS and VD groups (all p >0.05). The overall prevalence of HBsAg in the 546 children was 2.4%, with 2.5% (7/285) and 2.3% (6/261) in those born by ECS and VD respectively (p = 0.904). Further comparison of chronic HBV infection in the 137 children of HBeAg-positive mothers showed that the HBsAg-positive rates in ECS and VD groups were 10.3% (7/68) and 8.7% (6/69) respectively (p = 0.750), while the mothers had similar HBV DNA levels (2.38 × 106 vs. 2.35 × 106 IU/ml, p = 0.586). Additionally, the overall rate of anti-HBs ≥10 mIU/ml in the children was 71.6%, with 72.3% and 70.9% in those born by ECS and VD respectively (p = 0.717).
With the recommended immunoprophylaxis against hepatitis B, ECS does not reduce the risk of mother-to-child transmission of HBV. Therefore, ECS should not be used in HBsAg-positive pregnant women to prevent mother-to-child transmission of HBV.
PMCID: PMC3664615  PMID: 23706093
Hepatitis B virus; Mother-to-child transmission; Vaginal delivery; Caesarean section
2.  Active-passive Immunization Effectiveness Against Hepatitis B Virus in Children Born to HBsAg Positive Mothers in Amol, North of Iran 
Oman Medical Journal  2011;26(6):399-403.
HBV infection is a contagious disease that may transmit vertically from mothers to their neonates or horizontally by blood products and body secretions. Over 50% of Iranian carriers have contracted the infection perinatally, making this the most likely route of transmission of HBV in Iran. This study assesses the serologic markers of HBV in children born to HBsAg positive mothers who received HBIG and 3 doses of HBV vaccine.
To evaluate the effectiveness of vaccination against HBV, a study was conducted on 95 Children, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received Hepatitis B Immune Globulin and HBV vaccines during 2004-2008. All children were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc).
Among an estimated 30000 pregnant women during the five year study, about 130 (0.42%) were HBV carriers. Ninety-five children from these mothers were enrolled in this study. Only one child (1.1%) was HBsAg positive, while 88.4% of children were Anti-HBs Positive. Eleven children (11.6%) were exposed to HBV as shown by the presence of anti-HBc. A significant difference was observed between the children’s age and Anti-HBs (p=0.0001).
Passive-active immunoprophylaxis of high risk babies was highly efficacious in preventing perinatal transmission of the HBV carrier state. Also, evaluation of serologic markers in HBV infected people is important for designing the strategies for disease control.
PMCID: PMC3251203  PMID: 22253947
Children; HBsAg positive mothers; Hepatitis B Vaccine; Hepatitis B Immunoglobulin; Anti-HBc; Anti-HBs
3.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
PMCID: PMC4280122  PMID: 25549238
4.  Breastfeeding Is Not a Risk Factor for Mother-to-Child Transmission of Hepatitis B Virus 
PLoS ONE  2013;8(1):e55303.
Many clinicians do not encourage breastfeeding in hepatitis B virus (HBV) carriers, since HBV DNA can be detected in breast milk and breast lesions may increase exposure of infants to HBV. The aim of this study was to determine whether breastfeeding may add risk for perinatal HBV transmission.
Methodology/Principal Findings
Totally 546 children (1–7-year-old) of 544 HBV-infected mothers were investigated, with 397 breastfed and 149 formula-fed; 137 were born to HBeAg-positive mothers. All children had been vaccinated against hepatitis B but only 53.3% received hepatitis B immune globulin (HBIG). The overall prevalence of HBsAg+, HBsAg−/anti-HBc+, and anti-HBs (≥10 mIU/ml) in children was 2.4%, 3.1%, and 71.6% respectively. The HBsAg prevalence in breast- and formula-fed children was 1.5% and 4.7% respectively (P = 0.063); the difference was likely due to the higher mothers' HBeAg-positive rate in formula-fed group (formula-fed 49.0% vs. breastfed 15.9%, P<0.001). Further logistic regression analyses showed that breastfeeding was not associated with the HBV infection in the children, adjusting for the effect of maternal HBeAg status and other factors different between the two groups.
Under the recommended prophylaxis, breastfeeding is not a risk factor for mother-to-child transmission of HBV. Therefore, clinicians should encourage HBV-infected mothers to breastfeed their infants.
PMCID: PMC3557270  PMID: 23383145
5.  Individualized management of pregnant women with high hepatitis B virus DNA levels 
World Journal of Gastroenterology : WJG  2014;20(34):12056-12061.
Hepatitis B is a major health concern in the Asia-Pacific region, and is endemic in China, Southeast Asia, and Africa. Chronic hepatitis B virus (HBV) infection may cause hepatic cirrhosis and liver cancer. It is estimated that there are more than 350 million chronic HBV carriers worldwide, of whom approximately one quarter will die of chronic hepatitis B-related liver diseases. HBV is transmitted horizontally through blood and blood products or by sexual transmission, and vertically from mother to infant. Perinatal infection is the predominant mode of transmission in countries with a high prevalence of hepatitis B surface antigen (HBsAg) carriage, and perinatal transmission leads to high rates of chronic infection. Therefore, it is important to prevent the mother-to-child transmission (MTCT) of HBV. Research has shown that pregnant women with high HBV DNA levels have an increased risk of MTCT. However, most of the obstetrics guidelines do not make a distinction between pregnant women with high HBV DNA levels and those who are HBsAg positive only. This review addresses the management of pregnant women with high levels of HBV viremia, in terms of antiviral therapy, use of hepatitis B immunoglobulin (HBIG), the combined application of hepatitis B vaccine and HBIG, choice of delivery mode and feeding practices.
PMCID: PMC4161794  PMID: 25232243
Hepatitis B virus; Hepatitis B virus DNA; High level; Management; Pregnancy
6.  Weight-Based Policy of Hepatitis B Vaccination in Very Low Birth Weight Infants in Taiwan: A Retrospective Cross-Sectional Study 
PLoS ONE  2014;9(3):e92271.
The current recommendation of giving the first dose of hepatitis B vaccine to very low birth weight (VLBW) infants at 30 days of chronologic age usually is not practical, because most VLBW infants are not medically stable at that age. We use an alternative body-weight-based protocol, and evaluate its efficacy in an endemic area under a universal immunization program.
The immunogenicity of the current hepatitis B vaccination strategy in 155 VLBW preterm infants was evaluated at age 2 to 13 years, with parental consent. All of the infants were born between 1995 and 2006, and received their first dose of hepatitis B vaccine when they reached 2,000–2,200 g, irrespective of chronological age. Hepatitis B immunoglobulin (HBIG) was given at birth to infants born to HBsAg(+)/HBeAg(+) mothers.
All 155 of the recruited children were HBsAg and anti-HBc negative. The anti-HBs seropositivity rate (geometric mean titer) was 84.1% (146.5 mIU/mL) for children under 3 years, 73.5% (68.8 mIU/mL) for 4- to 7-year-olds, 27.7% (55.4 mIU/mL) for 8- to 11-year-olds and 20% (6.0 mIU/mL) for children ≥12 years of age. More than 90% of these children received the first vaccination after 30 days of age, half (51%) at 60 to 90 days, and 29 children (18.6%) after 90 days of age. Of the 26 infants born to HBsAg(+) mothers, 6/6 infants of HBeAg(+) mothers received HBIG at birth, and 12/20 infants of HBeAg(−) mothers received HBIG. None of the 26 infants became infected.
Delaying hepatitis B vaccinations in VLBW preterm infants until they reach a weight of 2,000 g, with the administration of HBIG at birth for infants of HBsAg(+) mothers provided adequate immunogenicity and protection in a highly endemic area. Weight-based policy of hepatitis B vaccination is an effective and practical alternative strategy for VLBW infants.
PMCID: PMC3956928  PMID: 24638122
7.  Rare Detection of Occult Hepatitis B Virus Infection in Children of Mothers with Positive Hepatitis B Surface Antigen 
PLoS ONE  2014;9(11):e112803.
The prevalence of occult Hepatitis B virus (HBV) infection in children was considerably varied from 0.1–64% in different reports. In this study we aimed to investigate the prevalence of occult HBV infection among the children born to mothers with positive hepatitis B surface antigen (HBsAg) in Jiangsu, China. Serum samples were collected from 210 children of 207 mothers with positive HBsAg. HBV serological markers were detected by ELISA and HBV DNA was detected by nested PCR. Homology comparison of HBV sequences recovered from the child and mother was used to define the infection. Three children (1.43%) were positive for HBsAg, in whom the HBV pre S and S gene sequence in each child was identical to that in her mother. Of the 207 HBsAg-negative children, nine displayed HBV DNA positive by two nested PCR assays using primers derived from S and C genes. However, the sequence alignment showed that the sequences in each child were considerably different from those in his/her mother. Therefore, the sequences amplified from the children were very likely resultant from the cross-contaminations. Furthermore, the nine children with ‘positive HBV DNA’ were all negative for anti-HBc, and one had anti-HBs 3.42 mIU/ml and eight others had anti-HBs from 72 to >1000 mIU/ml, indicating that the nine children were less likely infected with HBV. Therefore, none of the 207 HBsAg-negative children of HBV-infected mothers was found to have occult HBV infection. We conclude that the prevalence of occult HBV infection in vaccinated children born to HBsAg positive mothers should be extremely low. We recommend that homology comparison of sequences recovered from the child and mother be used to define the occult HBV infection in children born to HBV infected mothers.
PMCID: PMC4226608  PMID: 25383543
8.  Cellular immunity in children with successful immunoprophylactic treatment for mother-to-child transmission of hepatitis B virus 
BMC Infectious Diseases  2010;10:103.
The administration of hepatitis B immunoglobulin followed by hepatitis B vaccine can result in a protective efficacy of almost 90% in mother-to-child transmission of hepatitis B virus (HBV). However, little is known about immunity against HBV infection in children after immunoprophylactic treatment. We tried to assess the association between T-cell responses and viremia in children after successful prophylactic treatment.
Thirteen children and their 8 HBV carrier mothers (8 families), who were positive for human leukocyte antigen (HLA)-A24, were enrolled in this study. All of the 13 children received immunoprophylactic treatment and became negative for hepatitis B surface antigen (HBsAg) after birth. HBV-specific cytotoxic T lymphocyte (CTL) responses were evaluated using IFNγ - enzyme-linked immunosorbent spot (ELISPOT) and major histocompatibility complex class I peptide pentamer assays. Serum HBV DNA was measured by real-time PCR.
Significant HBV-specific T-cell responses were detected in 2 (15%) of the 13 children by ELISPOT. However, the frequency of HLA-A24-HBV-specific CTLs was very low in both HBV carrier mothers and children using pentamers. Of the 13 children, 4 (31%) were positive for serum HBV DNA. However, the levels of serum HBV DNA were 100 copies/ml or less. One of the 2 children in whom significant HBV-specific CTL responses were detectable was positive for serum HBV DNA.
HBV core and polymerase-specific T-cell responses were detected and a low-dose viremia was observed in children after successful immunoprophylaxis treatment. Although the presence of viremia was not related to HBV-specific T-cell responses, CTLs might play a role in the control of HBV infection in children born to HBsAg-positive mothers after immunoprophylactic treatment.
PMCID: PMC2879245  PMID: 20423521
9.  Strategy for vaccination against hepatitis B in areas with high endemicity: focus on Korea. 
Gut  1996;38(Suppl 2):S63-S66.
Hepatitis B vaccination strategies may vary from country to country depending on hepatitis B virus (HBV) endemicity, predominant modes of infection, age of infection, and health care resources. In areas with high endemicity like Korea, transmission of virus from carrier mothers to infants during the perinatal period, and from other horizontal sources to infants and children, account for most cases of HBV infection. The consequences of HBV infection at an early age are serious, as more than 70% remain chronic carriers of the virus. These chronic carriers are the principal source of infection for other susceptible people, and are themselves at high risk of developing other serious diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Theoretically, therefore, routine infant immunisation supplemented with prenatal screening of pregnant women for HBsAg or HBeAg and mass immunisation of children is the appropriate strategy for control of hepatitis B in these countries. To prevent primary liver cancer associated with HBV infection, however, immunisation of adults at high risk would also be prudent. Mandatory vaccination of all neonates is recommended in highly endemic areas, together with hepatitis B immune globulin in babies born to HBsAg carrier mothers.
PMCID: PMC1398045  PMID: 8786058
10.  Analysis of residual perinatal transmission of hepatitis B virus (HBV) and of genetic variants in human immunodeficiency virus and HBV co-infected women and their offspring 
Despite implementation of universal infant hepatitis B (HB) vaccination, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) still occurs. Limited data are available on the residual MTCT of HBV in human immunodeficiency virus (HIV)-HBV co-infected women.
We assessed the prevalence of HBV infection among HIV-infected pregnant women and the rate of residual MTCT of HBV from HIV-HBV co-infected women and analyzed the viral determinants in mothers and their HBV-infected children.
Study design
HIV-1 infected pregnant women enrolled in two nationwide perinatal HIV prevention trials in Thailand were screened for HB surface antigen (HBsAg) and tested for HBeAg and HBV DNA load. Infants born to HBsAg-positive women had HBsAg and HBV DNA tested at 4–6 months. HBV diversity within each HBV-infected mother-infant pair was analyzed by direct sequencing of amplified HBsAg-encoding gene and cloning of amplified products.
Among 3,312 HIV-1 infected pregnant women, 245 (7.4%) were HBsAg-positive, of whom 125 were HBeAg-positive. Of 230 evaluable infants born to HBsAg-positive women, 11 (4.8%) were found HBsAg and HBV DNA positive at 4–6 months; 8 were born to HBeAg-positive mothers. HBV genetic analysis was performed in 9 mother-infant pairs and showed that 5 infants were infected with maternal HBV variants harboring mutations within the HBsAg “a” determinant, and four were infected with wild-type HBV present in highly viremic mothers.
HBV-MTCT still occurs when women have high HBV DNA load and/or are infected with HBV variants. Additional interventions targeting highly viremic women are thus needed to reduce further HBV-MTCT.
PMCID: PMC3872003  PMID: 23916828
HBs antigen variants; Hepatitis B vaccine failure; HIV pregnant women; mother-to-child transmission; Thailand
11.  Chronic hepatitis B in pregnancy: unique challenges and opportunities 
Chronic hepatitis B (CHB) affects 350 million individuals worldwide. Perinatal transmission leads to high rates of chronic infection and complications, including cirrhosis and hepatocellular carcinoma. It is important to recognize and appropriately treat CHB in pregnancy, thereby reducing the risk of neonatal transmission and HBV-associated morbidity and mortality. Screening for CHB is recommended in all pregnant mothers as is universal vaccination of infants with hepatitis B virus (HBV) vaccine with or without hepatitis B immunoglobulin (HBIG). This has resulted in a lower incidence of HBsAg seropositivity and HCC in regions where universal infant vaccination has been endorsed. Mode of delivery and breastfeeding do not appear to affect HBV transmission rates based on available data. Overall, CHB does not increase perinatal maternal-fetal mortality. Administration of oral antiviral therapy during the third trimester to HBsAg-positive mothers with HBV DNA≥7 log IU/mL may be useful in preventing breakthrough infection. Treatment may be considered earlier in pregnancy for persistently active liver disease shown by high ALT, HBV DNA levels and/or significant hepatic fibrosis. Lamivudine, tenofovir and telbivudine are safe and effective and are the agents of choice in pregnancy. However, further clinical studies are necessary to elucidate the role of antiviral therapy in the pregnant HBV carrier.
PMCID: PMC3304622  PMID: 21494071
Hepatitis B; Pregnancy; Prevention; Transmission; Antivirals
12.  The effects of telbivudine in late pregnancy to prevent intrauterine transmission of the hepatitis B virus: a systematic review and meta-analysis 
Virology Journal  2012;9:185.
Chronic hepatitis B virus (HBV) infection poses a serious public health problem in many parts of the world. Presently, even with proper joint immunoprophylaxis, approximately 10-15% of newborns from HBV carrier mothers suffer from HBV infection through intrauterine transmission. One of the risk factors is the level of maternal viraemia. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV. A few studies have evaluated the efficacy of telbivudine in preventing intrauterine HBV infection during late pregnancy. So we conducted this meta-analysis to arrive at an evidence-based conclusion. We searched Medline/PubMed, EMBASE, Cochrane Library, Web of Knowledge and China Biological Medicine Database from January 1990 to December 2011. Relative risks (RR) of the seropositivity rates for hepatitis B surface antigen (HBsAg) and HBV DNA in newborns and infants were studied. Mean differences (MD) in maternal HBV DNA levels were reviewed. Finally two randomised controlled trials (RCTs) and four non-randomised controlled trials (NRCTs) were left for analysis which included 576 mothers in total, of whom 306 received telbivudine treatment and 270 did not receive any drug. All newborns received hepatitis B vaccine (HBVac) and hepatitis B immunoglobulin (HBIG) after birth. The seropositivity rate for HBsAg or HBV DNA was significantly lower in the telbivudine group, both at birth and at 6–12 months follow up. Meanwhile, maternal HBV DNA levels prior to delivery were significantly lower in the telbivudine group. In addition, the frequency of serum creatine kinase (CK) elevation was similar in the two groups. Our meta-analysis provides preliminary evidence that telbivudine application in late pregnancy is effective in the interruption of intrauterine HBV infection, with no significant adverse effects or complications. More high quality, well-designed, double-blinded, randomised controlled and large size clinical trials are needed for further investigation and more convincing results in the future.
PMCID: PMC3494585  PMID: 22947333
Hepatitis B virus; Telbivudine; Intrauterine transmission; Pregnanc
13.  The association between maternal hepatitis B e antigen status, as a proxy for perinatal transmission, and the risk of hepatitis B e antigenaemia in Gambian children 
BMC Public Health  2014;14:532.
Early age at infection with hepatitis B virus (HBV) increases the risk of chronic HBV infection. In addition early age at infection may further increase the risk of persistent viral replication beyond its effect on chronicity. The effects of perinatal and early postnatal transmission on the risk of prolonged hepatitis B e antigenaemia in children with chronic HBV infection are not well documented in Africa. We examine these associations using maternal HBV sero-status and the number of HBV-positive older siblings as proxy measures for perinatal and early postnatal transmission, respectively.
Hepatitis B e antigen (HBeAg)-positive mothers were identified in six population-based HBV sero-surveys conducted in The Gambia between 1986 and 1990. For every HBeAg-positive mother, a hepatitis B surface antigen (HBsAg)-positive HBeAg-negative mother and HBsAg-negative mother were randomly selected from the population surveyed. These mothers and their family members were tested for HBV sero-markers in a subsequent survey conducted between 1991 and 1993.
Thirty-eight HBeAg positive mothers and the same number of HBsAg-positive HBeAg-negative mothers and HBsAg-negative mothers participated in the study. Sixty-nine percent of their children also participated. There was a non-significant positive association between HBeAg prevalence in children and the number of HBeAg-positive older siblings (64.1%, 69.2% and 83.3% in children with 0, 1 and ≥2 HBeAg-positive older siblings, respectively). After adjusting for confounders, having an HBeAg-positive mother was a risk factor for HBeAg positivity in children carrying HBsAg (adjusted OR 4.5, 95% CI: 1.0-19.5, p = 0.04), whilst the number of HBeAg-positive older siblings was not.
Maternal HBeAg was associated with positive HBeAg in children with chronic HBV infection. This suggests that interrupting mother-to-infant transmission in sub-Saharan Africa might help reduce the burden of liver disease. A timely dose of HBV vaccine within 24 hours of birth, as recommended by WHO, should be implemented in sub-Saharan Africa.
PMCID: PMC4066313  PMID: 24885392
Hepatitis B; Hepatitis B e antigens; Infectious disease transmission; Vertical; Age factors; Africa
14.  Perinatal transmission of hepatitis B virus infection and vaccination in China. 
Gut  1996;38(Suppl 2):S37-S38.
Hepatitis B remains one of the most important infectious diseases in China. In 1980, an overall hepatitis B virus (HBV) infection rate of 42.6% was reported and a hepatitis B surface antigen (HBsAg) carrier rate of 10.3%. HBsAg positivity among children under 1 year of age ranged from 5.1% in Beijing to 7% in Guangdong. A peak in carrier rate was observed in 7 to 14 year olds, reaching 24% in Guangdong. During the past decade, there has been no significant change in overall HBV carrier rates. However, in areas where hepatitis B vaccination for all neonates has been introduced, a decline in HBsAg positivity in lower age groups has been observed. Perinatal transmission is believed to account for 35-50% of carriers although horizontal transmission is also important, particularly within families. Infants born to HBeAg positive carrier mothers are at even greater risk of infection. HBV infection during childhood leads to an increased risk of serious longterm sequelae, including hepatocellular carcinoma (HCC). It is hoped that universal childhood immunisation will allow control of HBV infections in China within a few generations.
PMCID: PMC1398041  PMID: 8786051
15.  Cost-effectiveness of Augmenting Universal Hepatitis B Vaccination With Immunoglobin Treatment 
Pediatrics  2013;131(4):e1135-e1143.
To compare the cost-effectiveness of hepatitis B virus (HBV) control strategies combining universal vaccination with hepatitis B immunoglobulin (HBIG) treatment for neonates of carrier mothers.
Drawing on Taiwan's experience, we developed a decision-analytic model to estimate the clinical and economic outcomes for 4 strategies: (1) strategy V—universal vaccination; (2) strategy S—V plus screening for hepatitis B surface antigen (HBsAg) and HBIG treatment for HBsAg-positive mothers' neonates; (3) strategy E—V plus screening for hepatitis B e-antigen (HBeAg), HBIG for HBeAg-positive mothers' neonates; (4) strategy S&E—V plus screening for HBsAg then HBeAg, HBIG for all HBeAg-positive, and some HBeAg-negative/HBsAg-positive mothers' neonates.
Strategy S averted the most infections, followed by S&E, E, and V. In most cases, the more effective strategies were also more costly. The willingness-to-pay (WTP) above which strategy S was cost-effective rose as carrier rate declined and was <$4000 per infection averted for carrier rates >5%. The WTP below which strategy V was optimal also increased as carrier rate declined, from $1400 at 30% carrier rate to $3100 at 5% carrier rate. Strategies involving E were optimal for an intermediate range of WTP that narrowed as carrier rate declined.
HBIG treatment for neonates of HBsAg carrier mothers is likely to be a cost-effective addition to universal vaccination, particularly in settings with adequate health care infrastructure. Targeting HBIG to neonates of higher risk HBeAg-positive mothers may be preferred where WTP is moderate. However, in very resource-limited settings, universal vaccination alone is optimal.
PMCID: PMC4015450  PMID: 23530168
hepatitis B; carrier rate; vaccination; cost-effectiveness analysis; immunoglobulin
16.  Dynamic changes of HBV markers and HBV DNA load in infants born to HBsAg(+) mothers: can positivity of HBsAg or HBV DNA at birth be an indicator for HBV infection of infants? 
BMC Infectious Diseases  2013;13:524.
Neither HBV DNA nor HBsAg positivity at birth is an accurate marker for HBV infection of infants. No data is available for continuous changes of HBV markers in newborns to HBsAg(+) mothers. This prospective, multi-centers study aims at observing the dynamic changes of HBV markers and exploring an early diagnostic marker for mother-infant infection.
One hundred forty-eight HBsAg(+) mothers and their newborns were enrolled after mothers signed the informed consent forms. Those infants were received combination immunoprophylaxis (hepatitis B immunoglobulin [HBIG] and hepatitis B vaccine) at birth, and then followed up to 12 months. Venous blood of the infants (0, 1, 7, and 12 months of age) was collected to test for HBV DNA and HBV markers.
Of the 148 infants enrolled in our study, 41 and 24 infants were detected as HBsAg(+) and HBV DNA(+) at birth, respectively. Nine were diagnosed with HBV infection after 7 mo follow-up. Dynamic observation of the HBV markers showed that HBV DNA and HBsAg decreased gradually and eventually sero-converted to negativity in the non-infected infants, whereas in the infected infants, HBV DNA and HBsAg were persistently positive, or higher at the end of follow-up. At 1 mo, the infants with anti-HBs(+), despite positivity for HBsAg or HBV DNA at birth, were resolved after 12 mo follow-up, whereas all the nine infants with anti-HBs(−) were diagnosed with HBV infection. Anti-HBs(−) at 1 mo showed a higher positive likelihood ratio for HBV mother-infant infection than HBV DNA and/or HBsAg at birth.
Negativity for anti-HBs at 1 mo can be considered as a sensitive and early diagnostic indictor for HBV infection in the infants with positive HBV DNA and HBsAg at birth, especially for those infants with low levels of HBV DNA load and HBsAg titer.
PMCID: PMC3829094  PMID: 24195671
17.  Hepatitis B in pregnancy 
Frontline Gastroenterology  2013;5(2):111-117.
Vertical transmission of the hepatitis B virus (HBV) is the commonest mode of infection and can be prevented with immunoprophylaxis of the infant and antiviral therapy in the mother. Our aim was to review a cohort of subjects with HBV in pregnancy to determine the prevalence of active disease or high HBV-DNA levels that required treatment to prevent transmission, and to review the management of mothers and infants.
A retrospective case-note review was conducted of all the HBV-infected pregnant women and their infants who attended the Newcastle obstetric services from 2007 to 2011.
There were 113 pregnancies in 81 women (median age 28 years; 15% hepatitis B e antigen (HBeAg) positive) during 2007–11. 71% of mothers were first diagnosed with HBV during pregnancy. The mothers were born in 28 different countries. 69% of mothers had an HBV-DNA level less than 2000 IU/mL and 13% had HBV-DNA levels greater than 1.0×107 IU/mL so would be eligible for antiviral therapy to prevent transmission to the infant. 9% had active eAg-positive HBV and 3% had active eAg-negative HBV requiring treatment. All infants born to HBeAg-positive mothers received hepatitis B immunoglobulin (HBIG) appropriately and 76% of infants received a full HBV vaccination course. One infant born to an HBeAg-negative mother was hepatitis B surface antigen positive 1 year post-delivery.
One in six women had active HBV requiring treatment or high HBV-DNA levels that would benefit from antiviral treatment to reduce the transmission risk. HBIG was administered appropriately but completion of the vaccination course was suboptimal.
PMCID: PMC3963528  PMID: 24683447
18.  Chronic HBV infection among pregnant women and their infants in Shenyang, China 
Virology Journal  2013;10:17.
The main transmission route of the hepatitis B virus (HBV) is mother to child transmission and contributes significantly to chronic HBV infection. Even though immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine is administrated to neonates whose mothers are hepatitis B surface antigen (HBsAg) positive, about 10% of the neonates suffer from HBV infection in their early life.
To survey chronic HBV infection among pregnant women and their infants and analyze the reason for immunoprophylaxis failure.
Serum HBsAg was tested in all pregnant women. HBVDNA and other serum HBV markers including hepatitis B e antigen (HBeAg), hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs) were tested among HBsAg positive pregnant women. All infants whose mothers were HBsAg positive were vaccinated with a standard immunoprophylaxis. Serum HBV markers and HBVDNA were tested among these infants at 7 months of age. HBV genotypes were analyzed among the infants and pregnant women who were HBVDNA positive.
The prevalence of HBsAg, anti-HBc and anti-HBs among 4,536 pregnant women was 5.49%, 29.65% and 58.55%, respectively. The prevalence of HBsAg, anti-HBc and anti-HBs among pregnant women older than 20 years of age was significantly different compared to pregnant women younger than 20 years of age (4.54, 5.69 and 0.61 times, prevalence older vs. younger, respectively. P<0.05, 0.01, 0.05, respectively). Among 249 HBsAg positive pregnant women, 167 (67.07%) were HBeAg positive, 204 (81.93%) were HBVDNA positive and only 37 (14.86%) had HBVDNA >107 IU/ml. Among the infants whose mothers were HBsAg positive, 214 (85.94%) infants were anti-HBs positive. There were 12 (4.82%) infants who were HBsAg and HBVDNA positive, and all 12 of these infants mothers were HBeAg positive and had HBVDNA >107 IU/ml. Genotypes B and C were present among 165 pregnant women and genotype C was present in 85 pregnant women. There were 12 infants who were HBsAg positive and had the same HBV genotypes as their mothers. There was a significant difference in genotypes between the pregnant women whose infants were infected with HBV compared to those without HBV infection (P < 0.05).
There was a significant decline in HBsAg prevalence among pregnant women and their infants in Shenyang. Genotype C might be a risk factor for mother to child transmission of HBV.
PMCID: PMC3568011  PMID: 23294983
HBV; Infection; Pregnancy; Mother to child transmission
19.  A nested case-control study of maternal-neonatal transmission of hepatitis B virus in a Chinese population 
AIM: To examine the determinants of maternal-neonatal transmission of hepatitis B virus (HBV).
METHODS: A nested case-control study was conducted in Changsha, Hunan, People’s Republic of China from January 1, 2005 to September 31, 2006. To avoid potential maternal blood contamination, we collected vein blood of newborns immediately after birth and before initial hepatitis B vaccination to determine the HBV infection status of the newborn. For each HBsAg-positive infant, one HBsAg-negative infant born to an HBsAg-positive mother was matched by hospital at birth (same), gender (same), and date of birth (within 1 mo). A face-to-face interview was conducted to collect clinical and epidemiological data. Conditional logistic regression analysis was used to estimate the independent effects of various determinants on maternal-neonatal transmission of HBV.
RESULTS: A total of 141 HBsAg-positive infants and 141 individually matched HBsAg-negative infants were included in the final analysis. Maternal first-degree family history of HBV infection, intrahepatic cholestasis, and premature rupture of membranes were risk factors for perinatal transmission of HBV, whereas systematic treatment and HBV immunoglobulin injections for mothers with HBV infection were protective factors for maternal-neonatal transmission of HBV, after adjustment for potential confounding factors.
CONCLUSION: For HBsAg-positive mothers, systematic treatment, HBV immunoglobulin administration, and controlling intrahepatic cholestasis and pregnancy complications may reduce the incidence of perinatal transmission of HBV.
PMCID: PMC3180022  PMID: 21987612
HBsAg-positive; Hepatitis B virus; Perinatal transmission: Nested case-control study
20.  Importance of perinatal versus horizontal transmission of hepatitis B virus infection in China. 
Gut  1996;38(Suppl 2):S39-S42.
China has one of the highest rates of hepatitis B virus (HBV) endemicity in the world. In a survey of five provinces, the overall HBV infection rate in the general population was found to be 42.6%, with 10.3% testing positive for hepatitis B surface antigen (HBsAg). Higher rates were found in rural than in urban areas. The prevalence of HBsAg among children under 1 year of age is quite low but increases rapidly thereafter, reaching a peak among 5 to 9 year olds. The pattern of age distribution suggests that horizontal transmission is an important route of HBV infection during early childhood, and the proportion of chronic HBsAg carriage attributable to perinatal transmission has been estimated at only 13-20%. Contact with infected family members probably accounts for much of the horizontal transmission in children. In a nationwide survey, 27.2% of families were found to have one or more HBsAg positive members and a strong tendency for family clustering has been identified. The strategy for prevention of HBV infection includes vaccination of all newborns, whether their mothers are HBsAg positive or negative, together with vaccination of high risk populations, and improved control measures in clinics and blood transfusion centres.
PMCID: PMC1398042  PMID: 8786052
21.  Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B carriers. 
OBJECTIVE: To measure the risk of perinatal transmission of HBV in chronic carriers who undergo amniocentesis. METHODS: This was a prospective, longitudinal study from 1990 to 1995 of women who were HBV carriers and underwent amniocentesis. The infants of these women were followed from birth to one year of age. Maternal data examined included HBV antigen and antibody status, liver function tests (LFTs) and the amniocentesis report. RESULTS: Twenty-eight women were identified. Two of 28 neonates were stillborn unrelated to hepatitis. Five infants were lost to follow-up leaving 21 mother-child pairs to evaluate. All 21 women were chronic HBV carriers at the time of amniocentesis for delivery. No mother had abnormal LFTs, and only one of 21 women was positive for hepatitis B e antigen (HBeAg). Thirteen amniocenteses were for advanced maternal age, and four were for abnormal maternal serum alphafetoprotein (MSAFP) screening. None of the amniocenteses were recorded as bloody, and the placenta was anterior in 6 of 21 procedures. None of the 21 infants (95% CI: 0-16.8%) were positive for HbsAg during the first month of life or at 12 months of age. All infants received HBV vaccine and HBIG immunoprophylaxis. CONCLUSION: The risk of transmission of HBV to the fetus after amniocentesis in women who are HBV carriers is low. Immunoprophylaxis in these infants was successful.
PMCID: PMC1784765  PMID: 10598917
22.  Evaluation of the Impact of Hepatitis B Vaccination in Adults in Jiangsu Province, China 
PLoS ONE  2014;9(6):e101501.
Hepatitis B immunization programs for newborns, children, and adolescents in China have shown remarkable results. To establish whether there would be any benefit in extending the program to cover older individuals, we examined both the epidemiology of hepatitis B virus (HBV) infection and the coverage of hepatitis B vaccinations among adults born before routine vaccinations were implemented. We then evaluated the impact of hepatitis B vaccination in adults aged 20–59 years. A large-scale cross-sectional epidemiological survey of HBV infection was performed in the province of Jiangsu, south-east China, between September 2009 and March 2010. A total of 86,732 adults aged 20–59 years were included, of which 8,615 (9.9%, 95% CI = 9.7–10.1%) were HBsAg sero-positive. Self-reported vaccination status suggested that the coverage was approximately 23.7% (95% CI = 23.4–24.0%). It was shown that higher HBV vaccination coverage was associated with a lower rate of HBsAg seropositivity among adults. There was a negative correlation between hepatitis B vaccination coverage and HBsAg prevalence (correlation coefficient = −0.805, p = 0.016), which might demonstrate the combined effects of vaccination and pre-vaccination HBsAg screening. In the unvaccinated group, the HBsAg-positive rate had an obvious upward trend with age growing among 20–39 year-olds (Trend χ2 = 22.605, P<0.001), while the vaccinated group showed no such trend (Trend χ2 = 3.462, P = 0.063). Overall, hepatitis B vaccination in adults might reduce the rate of HBsAg positivity. Therefore, routine immunization of adults aged 20–39 years should be seriously considered.
PMCID: PMC4076282  PMID: 24979048
23.  Hepatitis B (prevention) 
Clinical Evidence  2009;2009:0916.
Nearly a third of the world’s population has been infected by hepatitis B at some point, and at least 350 million people have become chronic carriers. Progressive liver damage occurs in up to 25% of carriers. In areas of high endemicity, transmission occurs largely in childhood; from an infected mother to her baby, or between members of a household.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of vaccination against hepatitis B infection in countries with high endemicity? What are the effects of vaccination against hepatitis B infection in countries with low endemicity? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: selective vaccination of high-risk individuals; selective vaccination of people with chronic liver disease not caused by hepatitis B; universal vaccination of adolescents; and universal vaccination of infants.
Key Points
Nearly a third of the world's population has been infected by hepatitis B at some point, and at least 350 million people have become chronic carriers. Progressive liver damage occurs in up to 25% of carriers. In areas of high endemicity, transmission occurs largely in childhood, from an infected mother to her baby, or between members of a household.In areas of low endemicity, transmission usually occurs as a result of sexual activity, intravenous drug use, or occupational exposure.The risk of developing hepatitis B depends largely on the vaccination policy of the country of residence, and routine vaccination of all infants is recommended by the WHO.
Selective vaccination of infants with recombinant or plasma-derived vaccines in countries with high endemicity of hepatitis B reduces occurrence and chronic carrier state. Combining vaccine with hepatitis B immunoglobulin is more effective than vaccine alone.
Universal vaccination of infants with recombinant or plasma-derived vaccines, in countries with high endemicity of hepatitis B, reduces the risk of acute hepatitis, chronic carrier state, and complications of chronic infection, and may be more effective than selective vaccination of high-risk individuals. Vaccination of children born to hepatitis B surface antigen (HBsAg)-positive mothers prevents development of a chronic carrier state compared with placebo.
Universal vaccination of infants or adolescents in low-endemic areas may reduce the risk of infection, or of developing a chronic carrier state, but we don't know how different vaccination strategies compare, as no studies have been done.
Selective vaccination of high-risk individuals in countries with low hepatitis B endemicity may prevent acute infection and development of a chronic carrier state. Uptake of vaccination may be low, even in high-risk groups.
Vaccination is associated generally with mild adverse effects, although more serious autoimmune adverse effects can occur rarely.
We don't know whether selective vaccination of people with known chronic liver disease not caused by hepatitis B reduces subsequent infection rates, as few studies have been done.
The evidence reported here is the best available evidence for this type of intervention, and further research is unlikely to change the conclusions reached.
PMCID: PMC2907831  PMID: 21726479
24.  Evidence of protection against clinical and chronic hepatitis B infection 20 years after infant vaccination in a high endemicity region 
Journal of Viral Hepatitis  2011;18(5):369-375.
Vaccination against hepatitis B virus (HBV) immediately after birth prevents neonatal infection by vertical transmission from HBV carrier mothers. There is an ongoing debate whether infant vaccination is sufficient to protect against infection when exposed to HBV later in life. We studied 222 Thai infants born to HBsAg −/+ and HBeAg −/+ mothers who were vaccinated with recombinant hepatitis B vaccine at 0-1-2-12 months of age. A subset of 100 subjects received a booster dose at age 5 years. Blood samples collected yearly for 20 years were examined for anti-HBs antibodies and serological markers of hepatitis B infection (anti-HBc, HBsAg, and in selected cases HBeAg, anti-HBe, HBV DNA). During the 20-year follow-up, no subject acquired new chronic HBV infection or clinical hepatitis B disease. During the first decade, possible subclinical breakthrough HBV infection (anti-HBc seroconversion) was only observed in subjects born to HBsAg +/HBeAg + mothers (6/49 [12.2%]). During the second decade, breakthrough HBV infections were detected in all groups (18/140 [12.8%]). Increases in anti-HBs concentrations that were unrelated to additional HBV vaccination or infection were detected in approximately 10% of subjects in each decade. Primary infant vaccination with a recombinant hepatitis B vaccine confers long-term protection against clinical disease and new chronic hepatitis B infection despite confirmed hepatitis B exposure. ( NCT00240500 and NCT00456625)
PMCID: PMC3110864  PMID: 20384962
efficacy; hepatitis B; vaccine
25.  Immunological mechanisms of hepatitis B virus persistence in newborns 
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about a half million people die every year. India represents the second largest pool of chronic HBV infection worldwide with an estimated 40 million infected people. The prevalence of chronic HBV infection in pregnant women is shown to be 0.82 per cent with the risk of mother-to-child vertical transmission. Hepatitis B e antigen (HBeAg) positivity indicates replicative form of HBV which may play a role in immunotolerance in utero by crossing the placenta. In case of HBeAg positivity and high viral load of mother, HBV immunoglobulin is preferably given along with HBV vaccination. Antiviral therapy is recommended for use in the third trimester of pregnancy to reduce the perinatal transmission of HBV, however, use of antiviral therapy should be individualized during pregnancy. Chronic HBV infection in neonates is linked with strong presence of Tregs (T regulatory cells) and defective CD8 T cells pool to produce interferon (IFN)-γ. T cell receptor (TCRζ) chain defects were also associated with decreased CD8 T cell dysfunction. Decreased TCRζ expression could be due to persistent intrauterine exposure of the viral antigens early in embryonic development leading to immune tolerance to HBV antigens in the newborns positive for hepatitis B surface antigen (HBsAg+ve). Therefore, due to HBV infection, T cell tolerance to HBV-antigen may probably leave the newborn as a chronic carrier. However, HBV vaccination may have benefits in restoring acquired immunity and better production of HBV specific antibodies.
PMCID: PMC3928700  PMID: 24434322
Chronic infection; HbeAg; HbsAg; hepatitis B virus (HBV); perinatal; pregnancy

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