Maternal transmission is the main mode of contamination for HCV-infected children and the underlying mechanism remains unresolved [1–4]. Transmission has been suggested to occur during delivery or intrapartum, but no study has found its exact determination [5,6]. Risk factors for mother-to-child transmission (MTC) of HCV have been shown to include the presence of HCV RNA in maternal blood and HIV co-infection [1,7,8–12]. Gibb et al. suggested a protective effect of elective caesarean section (CS) compared to vaginal delivery or emergency caesarean  while others have not shown any effect of mode of delivery . The aim of our study was to identify risk factors for MTC transmission among a prospective cohort of HCV-infected pregnant women, focusing on maternal virological characteristics and circumstances of delivery.
Patients and methods
At their first prenatal visit at one of six maternity hospitals in southern France, between October 1998 and September 2002, pregnant women were tested for HCV antibodies (ELISA version 3; Ortho Clinical Diagnostics, Issy les Moulineaux, France), regardless of former HCV test results. Inclusion required a positive ELISA test and patients' written informed consent. Foreseeable impossibility of a minimum 6 months' follow-up of the child, and nondisclosure of maternal identity were non-inclusion criteria. Women whose children received a blood transfusion were also excluded. Upon inclusion, a questionnaire administered by the obstetrician investigated sociodemographic data, past medical and obstetrical history, and biological and virological parameters. These included serum HCV RNA detection by Polymerase Chain Reaction (PCR) (AMPLICOR HCV test v2; Roche Molecular Systems, Basel, Switzerland) and genotyping by direct sequencing of the 5′NC region. At delivery, circumstances of delivery were recorded, as well as maternal levels of HCV RNA [MONITOR v2.0 (Roche Molecular Systems) with a 600 IU/mL detection limit], alanine amino-transferase (ALT) as times the upper limit of normal and for HCV/HIV-co-infected women, HIV viral load and CD4 T-cell count.
Paediatric tests were performed at birth and at 3, 6 and 12 months of age (M3, M6 and M12, respectively). Children detected at M3 with circulating HCV RNA coinciding with the maternal genotype, and therefore considered to be HCV-infected, were followed for a further 12 months, at M18 and M24. Tests included HCV-serology, HCV RNA, HCV-genotype and ALT determination as well as HIV RNA for children born from HIV/HCV-co-infected mothers.
HCV-MTC transmission rate was calculated with its 95% confidence interval. Univariate analysis was conducted using chi-squared and Fisher's exact test, and the non-parametric Mann–Whitney test (median and 25th and 75th quartile). Odds ratios and their 95% confidence intervals (Miettinen's method) were determined for each factor. A logistic regression model was used to estimate adjusted odds ratios (SPSS software; SPSS Inc., Chicago, Illinois, USA). A P-value < 0.05 was considered statistically significant.
Among the 347 women with a positive HCV ELISA test, 32 refused to participate. No significant difference was observed concerning age of pregnancy, proportion of HCV/HIV-co-infection, HBs antigen carriers and presumed mode of contamination between participating and non-participating women.
Among participating women (N = 315), 15 dropped out (miscarriage, unexpected departure). The 300 remaining mothers delivered 311 infants (six mothers had twins and five mothers had two successive pregnancies). Of 311 children within the study, 97 (31%) were lost to follow-up before the M3 visit. The proportion of HCV/HIV-co-infected mothers was lower in the lost to follow-up group of children (11 versus 27%; P = 0.003). Finally, the analysis concerned 214 mother-and-child pairs.
Polymerase chain reaction results were available for 198 (94%) mothers. Circulating HCV RNA was detected in 137 (69%), genotypes 1 and 3 accounting for 81%. Fifty-five women (26%) were HCV/HIV-co-infected and 57 (27%) carried HBs antigen. The most frequently suspected HCV mode of contamination was intra-venous drug use. Median age at delivery was 34 years [interquartile range (IQR), 30–37] and median duration of pregnancy was 39 weeks (IQR, 38–40). Child-feeding was documented for 176 children and three were breast-fed.
Twelve children had circulating HCV RNA at M3: among them, six were born of HCV/HIV-co-infected mothers and six of mothers infected with HCV alone. No MTC occurred among the 61 HCV RNA-negative women. The different MTC transmission rates appear in Table 1. Among 137 HCV RNA-positive mothers, 93 (68%) were HIV-negative (MTC transmission rate, 6.5%; 95% CI, 1.2–11.5) and 44 (32%) were HIV-positive (MTC transmission rate, 13.6%; 95% CI, 3.4–23.5). No child became infected with HIV. Upon univariate analysis, mothers of infected children were more likely to have significantly higher ALT levels (1.12 versus 0.74; P = 0.01) at delivery.
Among 55 HCV/HIV-co-infected mothers, 16 (29%) had been treated with HAART for HIV-MTC transmission prophylaxis and one of these had an HCV-infected child. No difference was observed between HCV viral load in HAART-treated mothers (median = 5.89; IQR, 4.79–6.38) and non-HAART-treated mothers (median = 5.82; IQR, 5.54–6.10). Among all of them, neither HIV viral load nor CD4 T-cell count was associated with HCV MTC transmission.
HCV/HIV co-infection was associated with a higher risk of HCV MTC transmission when HCV RNA levels were below 6.0 log-IU/ml (P = 0.01), but not for mothers with HCV RNA levels of at least 6.0 log-IU/ml (Table 2). In a logistic regression model, the interaction term between HCV RNA levels and HIV status remained significant, showing that among women with low HCV viral load, HIV infection is a significant risk factor for HCV MTC transmission.
All HCV-infected children were born at full term. In comparison with non-infected children, significantly increased ALT median values were observed at M3, M6, and M12 (P = 0.001). For three of the 12 infected children, HCV RNA levels fell below the detection limit and ALT levels returned to normal between M12 and M18. None of the six children whose mothers underwent amniocentesis was contaminated.
Delivery was vaginal in 134 cases, and in 80 cases by CS and, among the latter, 64% concerned HCV/HIV-co-infected mothers (P > 0.001). There was no significant difference in HCV-MTC transmission rate between the two modes of delivery (Table 1). No child was contaminated after emergency CS. All CS were conducted prior to spontaneous membrane rupture for all contaminated children. Furthermore, for all modes of delivery, HCV MTC transmission rates were comparable regardless of timing of membrane rupture. These results are not explained by different HCV RNA levels between mothers who delivered after spontaneous membrane rupture and women who delivered before (5.29 versus 5.59 log-IU/ml, respectively, P = 0.12) nor by circumstances of CS (5.57 log-IU/mL for emergency CS 5.59 log-IU/ml for elective CS; P = 0.6).
Adjusting on mode of delivery (elective CS versus vaginal delivery or emergency CS) did not result in a larger proportion of contaminated children among HCV/HIV-co-infected women.
Our study, conducted in an area with a high prevalence of HCV and HIV infection, shows an overall HCV MTC transmission rate of 5.6% and confirms the role of HCV RNA levels as the main risk factor for transmission. Moreover, our study highlights the lack of a protective effect of elective caesarean delivery to prevent HCV MTC transmission.
MTC rates of transmission are similar to previous reports and no MTC transmission was observed in women with undetectable HCV RNA [6,7,9,11,14–19]. In our study, we observed three cases of spontaneous resolution of HCV RNA after M12. This phenomenon has already been described [16,20], but to our knowledge no explanation has been put forward. Therefore, follow-up of RNA-positive children should be continued up to the age of 24 months, regardless of maternal HIV status, as suggested by Mast et al. and as recommended in recently published guidelines [16,21,22].
Risk of transmission appeared significantly higher in women with HCV RNA > 6.0 log-copies/ml. HCV/HIV co-infection has been shown to increase HCV RNA levels, therefore increasing the risk of MTC transmission . Recently, the European Paediatric Hepatitis C virus Network has suggested, however, that HAART, by reducing HIV-RNA levels, also reduces the risk of HCV vertical transmission . We did not observe a decreased risk of transmission among HAART-treated mothers but this may be due to the small number of women concerned .
The role of HCV/HIV co-infection in MTC transmission appeared to depend on HCV RNA levels. For values of at least 6 log-IU/ml, the risk of transmission was independent of maternal HIV status, whereas for lower levels, the probability of HCV transmission was higher among HCV/HIV-co-infected women. This suggests that other mechanisms could be involved to explain HCV MTC transmission. Mast et al. recently reported that in HCV/HIV-co-infected women, transmission occurred with lower mean HCV viraemia than in non HCV/HIV-co-infected women although the difference was not statistically significant .
Contrary to the European Paediatric hepatitis C virus Network study, we found no difference in HCV transmission rate between genders .
No decreased risk of vertical transmission was observed when delivery was performed by elective CS, as opposed to results reported by Gibb et al. . Their study concerned a larger population but the proportion of deliveries by CS was 19%, and 36% of those were elective. In our cohort 37% of women were delivered by CS among which 56% were elective. A recent communication related a similar HCV MTC transmission rate among HCV/HIV-co-infected women (11.3 versus 10.9%) and it was concluded that elective CS might reduce the risk of vertical HCV transmission . The prolonged period of observation (1987 to 2004) may, however, influence these findings, owing to changes in obstetrical attitudes following the availability of HAART. An increased risk of HCV MTC transmission has been noted in case of prolonged vaginal delivery or with episiotomy or lacerations , reinforcing the notion that vaginal delivery is associated with higher rates of MTC in these particular situations.
Our analysis concerned not only the type of delivery (vaginal or CS) but also the delay since membrane rupture and we did not observe an increased rate of HCV transmission among children delivered vaginally or those born by CS following membrane rupture. In contradiction with two studies conducted among viraemic women infected with HCV alone, the delay between membrane rupture and delivery did not appear as a risk factor for HCV transmission . In a report by Spencer et al. excluding elective CS, median duration of membrane rupture was 18 h in case of transmission versus 5.5 h when no transmission occurred, whereas in our study these values were 4 and 3 h, respectively. Average delay between membrane rupture and delivery was 3 h for both contaminated and non-contaminated children.
The number of women who underwent amniocentesis, as well as women who chose to breast-feed, was too low to draw any conclusions about their possible roles in vertical HCV transmission. Low rate of breastfeeding resulted from established recommendations for HIV/HCV-co-infected mothers and locally provided advice to HCV RNA-positive mothers, the remaining mothers being offered the choice.
In conclusion, high levels HCV RNA constitute a major risk factor for HCV MTC transmission. In mothers with low HCV RNA levels, the risk of transmission is increased when HCV/HIV co-infection is present. Caesarean section before membrane rupture does not appear to protect against MTC transmission of HCV.
This work was supported by a grant from Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) and Fondation de France.
We would like to thank the mothers who participated in this study. We are indebted to Dr Catherine Laffont, Dr Brigitte Dunais and Professor P Dellamonica for their assistance in this project.
Members of the ALHICE (Alpes-Maritimes, Languedoc, Haute Garonne Infection C chez l'Enfant) group include:
General Hospital Antibes: T. Duforestel, G. Flamand, S. Magnaldo, M. Moreigne, F. Raynaud.
General Hospital Cannes: L. Badetti, B. Bébin, H. Boimond, F. Carmagnole, F. Sebag.
General Hospital Grasse: P. Azuar, F. Court, H. Martin, C. Ménéguz-Bleuse, C. Tomassi, C. Sassi.
University Hospital Montpellier: P. Benos, P. Boulot, C. Chanal, J. Ducos, S. Fournier-Favre, N. Guigue, E. Mazurier, J.CH. Picaud, D. Rieu, A. Saillard.
University Hospital Nice: A. Bongain, P. Boutté, C. Checchi, P. Dellamonica, L. Ejnès, A. Fafin, E. Galiba, J.Y. Gillet, V. Gilly, H. Haas, C. Laffont, S. Malerba, E. Mariné Barjoan, A. Markarian, F. Monpoux, C. Pradier, I. Ricard, C. Trastour, A. Tran, V. Triolo.
University Hospital Toulouse: M Antras, A. Berrébi, J. Izopet, J. Tricoire.
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