HLA DR13 and HCV vertical infection

Risk factors affecting vertical hepatitis C virus (HCV) transmission are not completely known, if we exclude maternal HIV coinfection. We hypothesized that immunogenetic factors related to maternal or neonatal HLA profiles may affect HCV vertical transmission. HLA typing (microcytotoxicity assay on blood samples) was performed in 18 infants affected by vertically transmitted HCV infection and in 17 serum-reverted infants. (Serum-reversion is defined as antibody negative by 1 year of age and persistently HCV-RNA negative.) Moreover, HLA typing was performed in 20 mothers. Logistic regression analysis showed a significant negative association between children's HLA-DR13 antigens and risk of HCV vertical transmission (p < 0.01). This association persisted in a model including the maternal HIV status: HLA DR13 and maternal HIV coinfection showed a separate, opposite effect on vertical HCV infection (p < 0.01 and p < 0.001, respectively). The relative risk estimate for the ratio of not-infected to infected children in the presence of DR13 was 8.4 (95% confidence bounds, 1.1-60.8). Breast-feeding did not affect the risk of vertical HCV transmission. Maternal HLA profile did not relate to vertical infection. The present study reveals a significant association between HLA-DR13 and the likelihood of seroreversion in infants born to HCV-infected mothers. The findings of the present study could help in better understanding the pathogenesis of vertical HCV infection and in better identifying the cases at higher risk, which would be useful for the development of prevention strategies. It is possible that DR13 modulates the immune response to viruses, enhancing their clearance and, thus, in the case of HCV, exerting a protective role against the development of vertical infection.     

Follow-up of transmission of hepatitis C to babies of human immunodeficiency virus-negative women: the role of breast-feeding in transmission

BACKGROUND: The studies on hepatitis C virus (HCV) vertical transmission, the effect of potential risk factors and the role of breast-feeding have reported conflicting results. PATIENTS AND METHODS: Seventy-three infants of 63 anti-HCV-positive and anti-HIV-negative mothers were studied from 1993 to 1999 in the south of Spain. The mean period of follow-up in children was 29.2 +/- 19 months (range, 8 to 76 months); 6 (8%) children were lost to follow-up. Breast milk was studied for HCV-RNA in 68 samples of 35 mothers. RESULTS: Alanine aminotransferase was high in 19 (26%) and HCV-RNA was positive in 46 (63%) pregnant woman. Breast milk HCV-RNA was negative in nonviremic mothers and positive in 20% of the viremic mothers. The overall rate of vertical HCV transmission was 11.9% (n = 8) (95% confidence interval, 6 to 23%) if HCV-RNA was positive one or more times, but only 1.5% (n = 1) (95% confidence interval, 0.1 to 9%) if HCV-RNA was permanently positive. Seven HCV-infected children did not develop antibodies to HCV, and they had a spontaneous clearance of the virus. A 10-month-old baby was HCV-RNA-positive from birth to the end of the follow-up. The genotype in each of the infants was consistent with that of their mother. The rate of HCV transmission was higher for infants of mothers with higher HCV viremia (P < 0.01) and also for infants whose mothers were HCV-RNA-positive in breast milk (P < 0.05). There were no statistically significant differences between other risk factors. CONCLUSION: The presence of transitory viremia without seroconversion indicates that the vertical transmission of HCV is not important. This could be related to the viral charge and ingestion of milk of HCV-RNA-positive mothers. However, to advise avoidance of maternal breast feeding, it would be necessary to conduct larger studies.     

Vertical transmission of hepatitis C virus in a cohort of 2,447 HIV-seronegative pregnant women: a 24-month prospective study.

BACKGROUND: Mother to infant transmission of hepatitis C virus (HCV) has been extensively studied in mothers with human immunodeficiency virus (HIV) infection, whereas fewer data are available on the vertical HCV transmission in HIV-negative women. METHODS: Between January 1995 and June 1997, 78 consecutive HCV-positive/HIV-negative women with their offspring entered this prospective study aimed to define the prevalence of and risk factors for HCV vertical transmission. Risk factors for HCV were carefully sought, and HCV viral load and genotype were determined in all positive mothers. The infants were tested for alanine aminotransferase (ALT) and HCV-RNA at birth and at 4, 8, 12, 18, and 24 months of age. RESULTS: Eight of 60 (13.3%) infants born to HCV-RNA positive mothers acquired HCV infection, but only 2 (3,3%) were still infected by the end of follow-up. Infants' genotypes matched that of the mothers. ALT levels were in the normal range in all study subjects throughout the follow-up. High maternal viral load (P < 0.05), possession of HCV risk factors (P < 0.004), and history of blood transfusion (P < 0.05) were associated with increased risk of HCV vertical transmission. CONCLUSIONS: This long-term prospective study shows that, although vertical transmission from HIV-negative mothers occurs in 13% of cases, there is a high rate of spontaneous viral clearance (75%). High maternal viral load and mothers belonging to HCV risk categories were the only variables predictive of the vertical transmission.     

感染丙型肝炎病毒的孕妇及其新生儿随访观察

目的了解丙型肝炎病毒(HCV)母婴垂直传播情况及HCV感染后对新生儿体格发育的影响。方法用ELISA法对1023名孕妇静脉血做抗HCV检测,阳性者对其新生儿脐带血做抗HCV检测。阳性者(包括产妇及其新生儿)进一步做HCVRNA检测;对抗HCV阳性新生儿做10～12个月随访,观察HCV感染指标及新生儿喂养、患病、生长发育情况。结果产妇HCV感染率为2.74％(28/1023);抗HCV阳性产妇中HCVRNA检出率为75％(21/28);抗HCV阳性产妇的新生儿脐血中抗HCV检出率为46.43％(13/28),其中检出HCVRNA阳性5例。对抗HCV阳性新生儿1年随访,抗HCV阴转率为69.23％(9/13),实验组新生儿母乳喂养率57％明显低于对照组85％,实验组儿童人均患病1.25次,而对照组儿童为0.5次,有非常显著性差异,身长、体重指标明显落后于对照组。结论母婴间存在着HCV的垂直传播;HCVRNA的存在不但增加了母婴垂直传播的比率,而且延缓了抗HCV的阴转;HCV的感染非常明显地影响了新生儿的体格发育。     

High rate of maternal-infant transmission of hepatitis G virus in HIV-1 and hepatitis C virus-infected women

The prevalence of hepatitis G virus (HGV) infection was investigated in 56 mothers with both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection. Thirty-three (58.8%) women had markers of HGV infection, including 7/15 (46.6%) with no history of parenteral exposure to blood. Sixteen (48%) had HGV RNA in serum by a polymerase chain reaction assay, and 17 (52%) had antibody to E2 viral protein. No woman was positive for both markers. Of 20 infants born to the 16 mothers with HGV viremia, 9 (45%, 95% CI 34-56%) acquired the infection. No infected child seroconverted to HGV during the first year of life. At the latest visit (mean: 37.1 mo, range: 9-89 mo) 7 children were still seronegative HGV RNA carriers, 1 was both RNA- and antibody-negative, while 1 RNA-negative child had developed the E2 antibody. Of the 20 HGV-exposed infants, 2 contracted HCV and 1 HIV-1 (all 3 with HGV coinfection). No abnormalities in clinical findings and ALT levels were observed throughout the follow-up period in the six children with HGV infection alone. Our findings show that HGV infection is widespread among HIV-1- and HCV-infected women. Maternal-infant transmission of HGV is common and occurs independently from that of HIV-1 and HCV in women with triple infection. Most perinatally HGV-infected children develop persistent infection with no clinical or biological signs of liver damage, at least in the first years of life.     

Breastfeeding and hepatitis C virus (HCV): the need for a careful appraisal]

We review the available data on the possible role of breast-feeding in hepatitis C virus (HCV) transmission to infants of HCV-RNA-positive mothers. Current knowledge about HCV excretion through breast milk, HCV infection of breast-fed infants by mothers contaminated after delivery, and vertical transmission risk to infants breast-fed by chronic HCV viremic mothers are presented. Vertical transmission risk by breast-feeding HCV-RNA-positive mothers is unclear: no study has been performed with the aim and the required methodology to evaluate HCV transmission risk related to breast-feeding duration. Recommendations to HCV-RNA-positive mothers who wish to breast-feed their infant are discussed in light of present knowledge about HCV secretion in breast milk, mother-to-infant HCV transmission, and historical records on vertical transmission of other viruses to infants breast-fed by their viremic mothers.     

When does mother to child transmission of hepatitis C virus occur?

OBJECTIVE: To investigate when hepatitis C virus (HCV) infection from mother to child occurs, and evaluate possible associated factors. DESIGN: Prospective cohort study. PATIENTS: Fifty four HCV infected children tested within three days of birth and their mothers. MAIN OUTCOME MEASURES: HCV RNA polymerase chain reaction (PCR) results. RESULTS: Seventeen of the children (31%, 95% confidence interval 19% to 46%) were positive in the first 3 days of life and could be assumed to have acquired infection in utero. Testing PCR positive was not associated with sex (53% v 49% boys; p=0.77) or mode of delivery (29% elective caesarean section in both groups; p=0.98). Children with evidence of intrauterine infection were significantly more likely to be of lower birth weight and infected with genotype 1 (58% v 12%, p=0.01). Although a higher proportion of infants born to HCV/HIV co-infected women were PCR positive in the first 3 days of life, this difference did not reach statistical significance; excluding infants born to co-infected women did not affect the results. Thirty seven of the children (68%) were negative in the first 3 days of life, 27 of whom were positive when tested again at 3 months, and nine were first PCR positive after 3 months (one child had no further tests). CONCLUSIONS: These results suggest that at least one third and up to a half of infected children acquired infection in utero. Although postpartum transmission cannot be excluded, these data suggest that it is rare. The role of HCV genotypes in the timing and mechanism of infection should be explored further.     

HIV-I infection in perinatally exposed siblings and twins. The Italian Register for HIV Infection in Children.

In a multicentre study on perinatal HIV-I infection including 1493 children born from 1471 pregnancies to 1415 infected mothers, 22 twin pairs and 56 sibships (115 children) were recorded. The frequency of twin pregnancies was 1.5 (22/1471) and 3.9% (56/1415) seropositive women had more than one at risk pregnancy. In 18 twin pairs with a known infection status nine of the 36 children (25%) were infected. Discordance in infection status was present in only one (5.5%) dizygous pair. A high relative risk of infection (23.1) in a twin was observed when the other was infected. Infection was unrelated to gestational age, mode of delivery, or birth weight. Infection status was defined in 41 sibships (84 children including one first born twin pair and one third born child). When the first born was infected, 11/26 (42.3%) second born children were also infected, whereas this happened in only 2/16 (12.5%) second or third born children when the first born was uninfected. Two out of nine first born (22.2%) and 5/21 (23.8%) second born children prospectively followed up from birth acquired the infection. Results of this study demonstrate that neither twin nor second pregnancies are at increased risk of mother to child HIV-I transmission. Overall data suggest that non-casual factors in mother and/or child influence perinatal infection.     

Impaired neutralizing activity by transplacental measles antibodies in infants born to HIV‐1‐infected mothers

Aim: Growing numbers of newborns are saved from HIV infection through increased access to mother‐to‐child transmission prevention programmes. The maternally derived humoral immunity of these children might be impaired, both in terms of quantity and in terms of quality, with consequences for the timing of immunization against measles. Methods: A cell‐ELISA technique compared the neutralizing activity on Edmonston strain measles virus of sera from 1‐ to 4‐month‐old infants. Ten serum specimens came from noninfected infants of HIV‐infected mothers and another 10 from infants of healthy mothers. The sera were matched for the level of conventional ELISA measles antibodies. Results: Reflecting infection of the Vero cells by non‐neutralized virus, optical density values were significantly higher for the sera from the children of the HIV‐infected mothers than for those of the noninfected mothers (p < 0.001). Conclusion: Maternally derived protection against measles may be impaired by the mother’s HIV infection, relating to the quality rather than to the quantity of transplacental antibodies. Selective, early immunization with live attenuated measles vaccine should be evaluated in noninfected children of HIV‐1‐infected mothers.     

Prospective study of mother-to-infant transmission of hepatitis C virus

BACKGROUND: Mother-to-infant transmission of hepatitis C virus (HCV) could become the main route of HCV infection in the future because there are no methods available to prevent vertical infection. The aim of this study was to determine the incidence of mother-to-infant transmission in infants born to mothers who tested positive for anti-HCV antibodies and to elucidate associated risk factors for transmission. METHODS: Screening was conducted for 16,800 pregnant women with an anti-HCV antibodies test, and 154 mothers were positive. From the positive group 141 mothers were enrolled in the study and their 147 infants were followed from birth for serum alanine aminotransferase activity, anti-HCV antibodies and HCV RNA. HIV infection was tested in 73 of 141 mothers, all of whom were negative. RESULTS: Thirty-three infants were dropped from the study because they were followed for <6 months or were not tested adequately. Of the 114 infants finally evaluated 9 (7.8%) had detectable HCV RNA. The transmission rate was not influenced by the mode of delivery [vaginal delivery, 8 of 90 vs. cesarean section, 1 of 24 (P = 0.396)] or by the type of feeding [9 of 98 for breast-fed infants vs. 0 of 16 for formula-fed infants (P = 0.243)]. All infected infants were born to mothers who had HCV viremia at the delivery (P = 0.040) and to those with a high viral load (P = 0.019). CONCLUSIONS: Our prospective study showed that the transmission rate of mother-to-infant HCV infection was 7.8% in anti-HCV antibody-positive mothers. Risk was related to the presence of maternal HCV viremia at delivery and a high viral load in the mothers.     

Growth in the first 5 years of life is unaffected in children with perinatally-acquired hepatitis C infection

OBJECTIVES: To identify the effect of vertical hepatitis C virus (HCV) infection or exposure on growth in childhood. STUDY DESIGN: Children (n=1203) born to HCV-infected mothers were followed up from birth prospectively in centers of the European Paediatric Hepatitis C virus Network. Z-scores compared height- and weight-for-age in HCV-infected and -uninfected children, adjusting for other factors using linear regression. We also quantified the effect of maternal chronic infection with HCV on childhood growth. RESULTS: There was no significant effect of vertical HCV infection on growth (height P=.223, weight P=.095) nor a significant effect of maternal chronic infection with HCV (height P=.733, weight P=.274). Prematurity and maternal injecting drug use were associated with a significant reduction in height (P < .001) and weight (P < .001) in all HCV-exposed children. CONCLUSIONS: This population of HCV exposed infants has higher rates of maternal injecting drug use and prematurity than standard populations and so there are implications for growth of these children, but this is not a direct result of HCV infection or exposure to chronic maternal HCV infection.     

Mother-to-infant transmission of hepatitis C virus: A prospective study

To investigate the risk of mother-to-infant transmission of hepatitis C virus (HCV) and the natural course of HCV-infected infants, we prospectively studied 31 offspring of pregnant women who were anti-HCV positive and anti-HIV negative. Sera were serially tested for anti-HCV by the second-generation ELISA-test (ELISA-2) and for HCV-RNA by the polymerase chain reaction procedure. The mean period of follow up was 19 months (range 6–41 months). The presence of HCV-RNA in the mothers was associated with a high titre of anti-HCV by ELISA-2 or a positivity of the second generation recombinant immunoblot assay. At birth, 26 babies were positive for anti-HCV. Passively transferred maternal antibodies became undetectable within 2–15 months. HCV-RNA was detected in only 3 infants (9.7%) within 1–4 weeks after birth and persisted there-after. The genotype of HCV-RNA in each of the infants was consistent with that of their mother. These 3 showed chronic transaminase elevation during the follow up that started at 1–2 months of age, although they revealed no clinical symptoms. Re-elevation of anti-HCV titre was observed in the HCV-infected infants within 10 months of age, suggesting an endogenous production of anti-HCV. The mean titre of HCV-RNA in three mothers of infected infants was higher than that in the mothers of uninfected infants (10^5.3±0.3 vs 10^4.4±0.2/ml).Conclusion Our findings indicate that HCV was most likely to have been transmitted from mothers to infants at the time of delivery and that it was capable of evoking the chronic carrier state.     

Active surveillance of hepatitis C infection in the UK and Ireland.

AIM: To investigate the prevalence, distribution, and clinical details of paediatric hepatitis C virus (HCV) infection in the UK and Ireland. METHODS: Active monthly surveillance questionnaire study coordinated through the British Paediatric Surveillance Unit, to all consultant paediatricians in 1997 and 1998. RESULTS: A total of 182 HCV infected children were reported from 54 centres and by paediatricians from eight different specialties. In 40 children HCV was acquired through mother to child transmission (MTC children); 142 were infected by contaminated blood products (n = 134), organ transplantation (n = 2), needles (n = 4), or unknown risk factor (n = 2). Intravenous drug use was the risk factor for 35 mothers of MTC children. Twelve children were coinfected with HIV and four with HBV. Recent serum aspartate aminotransferase or alanine aminotransferase values were at least twofold greater than the upper limit of normal in 24 of 152 children; this occurred in five of 11 HIV coinfected children. Liver histology, available in 53 children, showed normal (7%), mild (74%), moderate (17%), or severe (2%) hepatitis. Twenty eight children had received therapy with interferon alfa. CONCLUSION: Most current paediatric HCV infection in UK and Ireland has been acquired from contaminated blood products, and most children are asymptomatic. There is a need for multicentre trials to inform clinical practice and development of good practice guidelines in this area. Long term follow up of this cohort of HCV infected children is planned to help determine the natural history over the long term of HCV acquired during infancy and childhood.     

Timing and interpretation of tests for diagnosing perinatally acquired hepatitis C virus infection

The diagnosis of hepatitis C virus (HCV) infection in children born to HCV-infected women is based on serologic assays and HCV RNA measurement by PCR. Interpretation of the results of these tests is hampered by uncertainty about the age distribution of loss of maternal antibody and the sensitivity and specificity of PCR at different ages. On the basis of findings from a recent vertical transmission study, we estimated the posttest probability of a child's being infected or uninfected under several test result scenarios. These estimates may assist clinicians in assessing the likelihood of infection in an individual child and in using the currently available assays cost effectively.     

Clinical implications of mother-to-child transmission of HCV

Testing for vertical transmission of hepatitis C virus (HCV) infection in infants and children will enable early identification of the majority of uninfected HCV-exposed infants and children, and will provide significant emotional relief for the parents.

Conclusion: The small percentage of infected children should be offered enrolment in well-designed clinical trials of optimal medical management for prevention of the predicted long-term outcomes of chronic HCV infection: chronic hepatitis, cirrhosis and hepatocellular carcinoma.     

Excluding hepatitis C virus (HCV) infection by serology in young infants of HCV-infected mothers

Aim: To identify the age at which HCV infection can be accurately excluded by serology in young children born to HCV-infected mothers and to determine an appropriate schedule of antibody testing, most informative to clinical practice. Methods: Children born to HCV-infected mothers were followed in centres of the European Paediatric HCV Network. Turnbull survival analysis techniques were used to estimate the age at which HCV-uninfected children will lose maternally acquired HCV antibodies. Factors associated with age at antibody loss were assessed in logistic regression. Results: In 1104 children followed from birth and later confirmed to be HCV uninfected, an estimated 57% will have lost passively acquired HCV antibodies before 6 mo of age and an estimated 95% by 12 mo. Maternal HCV viraemia antenatally was associated with later, and maternal HIV-HCV co-infection with earlier loss of antibody. Actual antibody testing of uninfected children at 12 mo identified 82% of those tested to be anti-HCV negative.

Conclusions: Serological confirmation of HCV uninfection remains necessary given the uncertainty in the specificity of virological tests. These results suggest that, in most children, HCV infection can be ruled out with serological testing at an earlier age than previously thought, and that nearly all children born to HCV-infected mothers will have lost passively acquired maternal antibodies by 1 y of age. Antibody loss was significantly later among children born to HCV viraemic mothers. The earlier loss of HCV antibodies in children born to HIV co-infected mothers may be due to HIV treatment.     

An update on HIV in children

HIV transmission in childhood occurs almost exclusively from the HIV-infected mother to her child via placenta in utero, during labour and delivery or through the gastrointestinal tract by ingested breast milk. Treatment of infected women achieving an undetectable viral load and postnatal antiretroviral prophylaxis as well as avoidance of breastfeeding reduces risk of vertical transmission to less than 1%. Screening all children of HIV-infected mothers born in settings without measures to prevent vertical transmission for HIV infection is essential as they may have grown up reaching adolescence without any symptoms. Treatment with three antiretroviral drugs of all HIV-infected infants and if CD4 count less than 1000 in 1–3 year olds, CD4 count less than 500 in 3–5 year olds and if CD4 count less than 350 in above 5 year olds is important to reduce morbidity and mortality. Use of a ritonavir-boosted protease inhibitor containing regime in HIV-infected children with anticipated problems with compliance may reduce development of resistance of HIV to antiretroviral drugs.     

Perinatal group B streptococcal infection in midgestation

In a series of 32 fetuses and neonates studied at autopsy at Women and Infants Hospital, group B streptococcus (GBS) was isolated from the right atrial blood or from the lung. Eleven or 34% (5 stillborn fetuses and 6 liveborn infants) were delivered in midgestation, between 18 and 28 weeks, and all weighed less than 1000 g. Maternal clinical features in GBS infection during midgestation included vaginal hemorrhage in 4 and premature rupture of membranes in 8. The high rate of fetal death associated with this infection in midgestation (45%) bears emphasizing. Reproductive loss among mothers with previous pregnancies seems to be a risk factor for subsequent perinatal loss due to GBS. Of 17 pregnancies among these 11 mothers, only 3 resulted in living children. Colonized mothers with GBS are usually treated late in the third trimester, if at all. This study indicates that attention must be directed to midgestation, at least among the high-risk group.     

Perinatal Group B Streptococcal Infection in Midgestation

In a series of 32 fetuses and neonates studied at autopsy at Women and Infants Hospital, group B streptococcus (GBS) was isolated from the right atrial blood or from the lung. Eleven or 34% (5 stillborn fetuses and 6 liveborn infants) were delivered in midgestation, between 18 and 28 weeks, and all weighed less than 1000 g. Maternal clinical features in GBS infection during midgestation included vaginal hemorrhage in 4 and premature rupture of membranes in 8. The high rate of fetal death associated with this infection in midgestation (45%) bears emphasizing. Reproductive loss among mothers with previous pregnancies seems to be a risk factor for subsequent perinatal loss due to GBS Of 17 pregnancies among these 11 mothers, only 3 resulted in living children. Colonized mothers with GBS are usually treated late in the third trimester, if at all. This study indicates that attention must be directed to midgestation, at least among the high-risk group.     

Mother-to-child transmission of human immunodeficiency virus type 1: risk of infection and correlates of transmission.

One thousand eight hundred eighty-seven children born to human immunodeficiency virus type 1 (HIV-1) seropositive mothers, including 1045 infants prospectively followed up from birth, were studied. Intravenous drug use was the most frequent maternal risk factor, although the percentage of women infected by sexual contact increased from 5.8% in 1985 to 28.5% in 1990. Of the 551 first children followed up from birth and older than 15 months of age, 101 (18.3%) acquired infection and seroconverted to HIV-1. Another 31 (5.6%) asymptomatic seronegative children showed the presence of viral markers, for an apparent mother-to-offspring transmission rate of 23.9%. Overlapping results were seen in 22 second-born children followed up from birth. Of 59 sibships with definite infection status, when the first child was infected, 14 (40%) of 35 second children were infected, whereas when the first child was not infected, only 2 of 24 (8.3%) second children were infected. Discordance in HIV-1 transmission was found in 1 of 18 pairs of twins. Univariate and multivariate analyses of possible risk factors for HIV-1 transmission performed on the entire population of children and in the cohort of those followed up from birth were basically in agreement in indicating that the development of symptoms in the mother before delivery and breast-feeding (indeed adopted in only 22 infants in whom HIV-1 infection was identified at birth) were significantly and independently associated with a higher transmission rate. In addition, girls were more frequently infected than boys.(ABSTRACT TRUNCATED AT 250 WORDS)