Mother-to-infant transmission of hepatitis C virus

Mei-Hwei Chang, MD

Clin Invest Med 1996; 19 (5): 368-72

[résumé]

From the Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.

Reprint requests to: Dr. Mei-Hwei Chang, Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; fax: 886 2 393-8871.

Contents

Abstract

Mother-to-infant (vertical) transmission of hepatitis C virus (HCV) has been documented, but vertical transmission of HCV is less efficient (affecting 0% to 15% [mean 4.7%] of the infants of mothers with HCV infection) than that of hepatitis B virus. This lower rate of vertical transmission is likely due to the lower viral level of HCV in the sera of most mothers with an infection. Infants of mothers with an HCV and HIV coinfection or with a high HCV RNA titre (greater than 1 million copies per millilitre) are at a high risk of HCV infection (with a mean 39% of infants of mothers with HCV and HIV coinfection having an HCV infection). In most infants (81%) with an HCV infection studied longitudinally, the infection is persistent, and the alanine aminotransferase levels are transiently or persistently abnormal; however, normal liver function is also observed in some patients. There is currently no effective way to prevent vertical transmission of HCV. Further investigation aimed at better understanding the natural history of perinatal HCV infection and the indications for antiviral therapy is needed.

Résumé

La transmission mère-enfant (verticale) du virus de l'hépatite C (HCV) a bien été démontrée. Par contre, en comparaison avec le virus de l'hépatite B, la transmission verticale de l'HCV est moins efficiente, puisqu'elle n'affecte que de 0 % à 15 % (moyenne 4.7 %) des enfants en bas âge des mères infectées au HCV. Ce taux plus faible de transmission verticale est vraisemblablement dû au niveau plus faible de HCV dans le sérum de la plupart des mères infectées. Les enfants en bas âge de mères avec co-infection par le HCV et le VIH ou avec un titre élevé d'ARN de l'HCV (plus d'un million de copies par millilitre) sont à risque élevé d'infection par le HCV puisqu'une moyenne de 39 % des enfants développent une infection à HCV en présence de co-infection maternelle par l'HCV et le VIH. L'étude longitudinale d'enfants avec infection au HCV démontre que la plupart d'entre eux (81 %) ont une infection persistante, avec un niveau anormal d'alanine amino-transférase de façon transitoire ou prolongée. Par contre, une fonction hépatique normale est présente chez certains sujets. Il n'existe aucun moyen connu de prévenir la transmission verticale de l'HCV. Il est nécessaire de procéder à des recherches additionnelles afin de mieux comprendre l'histoire naturelle de l'infection périnatale au HCV et de définir les indications de traitement anti-viral.

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Introduction

Hepatitis C virus (HCV) is a hepatotropic, single-stranded RNA virus of about 9.4 Kb. It is the main etiologic agent of parenterally transmitted non-A, non-B hepatitis.[1,2] Blood transfusion, injection of infected blood products (such as those administered to patients with hemophilia) and injections administered with contaminated syringes (by intravenous-drug addicts, for example) are important routes of HCV transmission. However, a large proportion of patients (about 40% to 50%) infected by HCV have no known history of parenteral exposure. Other routes of transmission of HCV, such as mother-to-infant (vertical)[3] and sexual transmission[4,5] have been extensively investigated.

In hepatitis B virus (HBV), perinatal transmission from infected mothers to their infants is an important route of transmission.6,7 About 40% of the infants of mothers who are carriers of hepatitis B surface antigen (HBsAg) have positive test results for HBsAg within the first 6 months of life.

My colleagues and I have investigated the role of vertical transmission of HCV. The seroprevalence rate of antibody to HCV (anti-HCV) is about 0.8% to 1.5% in the adult population in most parts of the world.[8,9] In children, the seroprevalence rate is much lower (0% to 0.1%) than that in adults in most areas.[10,11] It is more difficult to conduct studies of vertical transmission of HCV than of HBV because of the relatively lower seroprevalence rate and the lower serum viral titre of HCV than of HBV in pregnant women in hyperendemic areas.[12]

It has been proven that HCV infection can be transmitted vertically. In infants of mothers who are HCV RNA seropositive and HIV seronegative, studies have reported rates of transmission from 0% to 15%, with a mean rate of 4.7% (Table 1).[13­19] Vertical transmission occurs in 0% to 12% (mean 3.6%) of infants of mothers in whom anti-HCV was detected by second-generation enzyme-linked immunosorbant assay (ELISA) or recombinant immunoblotting assay (RIBA) (Table 2).[17,19­21] The rate of vertical transmission of HCV is higher (5% to 36%, with a mean of 16%) if the mother is both anti-HCV and anti-HIV seropositive (Table 3),[19,20­24] and it is even higher (39%) if the mother has positive test results for serum HCV RNA and anti-HIV. The variation in the rate of vertical transmission in the reported data depends on the level of maternal serum HCV RNA, the mothers' HIV status, the population studied (mothers who are anti-HCV seropositive only or both anti-HCV and HCV RNA seropositive) and the study method.

Vertical transmission of HCV in Taiwan

We screened 2220 pregnant women for HCV. Twenty-five women had a positive result for anti-HCV by second-generation ELISA, and 20 had a positive result for HCV RNA by reverse-transcription nested polymerase chain reaction. During follow-up, among the 20 HCV-RNA-seropositive mothers, 3 had infants who were seropositive for HCV RNA and anti-HCV. Two of the infants had a persistent and one had a transient HCV infection.[25] The one with a transient infection had detectable serum levels of HCV RNA on at least two occasions during long-term follow-up but then lost serum HCV RNA and anti-HCV after 10 months of age.[26] All three infants had negative results of an immunoblotting test for anti-HCV IgM, although they had been infected very recently.

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Risk factors for vertical transmission of HCV

High serum HCV titre in the mother

A high maternal serum HCV RNA titre is an important risk factor for vertical transmission of HCV. Among the infants of 14 mothers studied by Ohto and associates,[17] 50% of those whose mothers had an HCV titre of more than 1 million copies per millilitre were also infected. A study conducted by our group also demonstrated that HCV was never transmitted to infants of mothers whose HCV RNA titre was less than 1 million copies per millilitre.[26]

HIV and HCV coinfection in the mother

Coinfection with HIV and HCV can increase the risk of vertical transmission of HCV. Infants born to mothers who are seropositive for both anti-HIV and anti-HCV are at higher risk[19,20,22,24] of HCV infection than infants born to mothers who are anti-HCV seropositive but HIV seronegative. Infants with AIDS have a much higher prevalence of HCV infection than those without an HIV infection.

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Breast-feeding plays minimal role in HCV transmission

Our group has investigated the role of breast milk in HCV transmission in a study involving 15 mothers with an HCV infection.[27] The supernatant and precipitate of colostrum samples from these mothers were studied. The titre of anti-HCV (1 to 20 times dilution) in colostrum tested by second-generation ELISA was much lower than that in maternal serum (80 to 40 000 times dilution). HCV RNA was detected in colostrum, but the virus titres (125 to 12 500 copies per millilitre in the samples from six mothers in which levels were detectable) were also much lower than those in maternal serum (10 000 to 250 million copies per millilitre). Eleven of the 15 infants were breast-fed, but none of them had an HCV infection. We therefore suggest that breast-feeding need not be discouraged in mothers with an HCV infection. Perinatal transmission of HCV, like that of HBV, is more efficient than transmission through breast-feeding.

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Mode of delivery and HCV transmission

The rate of HCV infection in infants delivered vaginally was reported to be higher than that of infants delivered by cesarean section (32% v. 6%, p < 0.05).[24]

Clinical course of HCV infection in infants

In some infants HCV declines and finally disappears, but in most there is a persistent infection. Most infants with an infection have no symptoms. Their liver function is usually normal during early infancy. However, transient or persistent elevation of alanine aminotransferase levels during infancy and afterwards is common, occurring in about 80% of the reported cases (Table 4)[15,17,18,20,24,28]. Further observation is required before a conclusion concerning long-term outcome can be arrived at. Histologic studies of livers in affected infants are limited. Chronic persistent hepatitis or minimal histologic changes are the main findings.[24,30]

Selective vertical transmission of HCV variants

Weiner and associates[29] cloned and sequenced the hypervariable domain of the putative envelope glycoprotein E2 region of the HCV genome from three infants, including a set of twins. All three infants were HCV RNA seropositive within 48 hours of birth. The maternal HCV sequences showed quasispecies distributions. The HCV sequences in the three infants were one or two single dominant variants, similar or closely related to the variants found in their mothers, but not to those found in unrelated people in the population. These data show conclusively that HCV is vertically transmitted and also that a subset of viral variants may be selectively transmitted from mother to infant.

Our recent study supports the findings of Weiner and associates. We further demonstrate that the annual nucleotide-sequence substitution rate of the HCV hypervariable region is much slower in infected infants than in their mothers.

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Intergenerational mother-to-child transmission of HCV

Mother-to-child transmission of HCV through two generations has been demonstrated by comparative nucleotide-sequence analysis.[28] In the case studied, a female infant born to a mother with an HCV infection had self-limited hepatitis C. Her grandmother and uncle also had an HCV infection. The nucleotide sequence of the HCV complementary DNA fragment from the infant was identical to that from her mother and much closer to those from her grandmother and the uncle than to those from other unrelated patients with HCV or carriers in the same population. The HCV infection spanning three generations and including the infant, her mother, her uncle and her grandmother demonstrates that HCV may be transmitted effectively from generation to generation, most likely vertically.

Conclusions

Vertical transmission of HCV occurs, but its efficiency is low, most likely as a result of the low level of HCV RNA in the serum of most mothers with HCV infection. Infants of mothers with HCV and HIV coinfection or with a high HCV RNA titre (higher than 1 million copies per millilitre) are at a high risk of acquiring HCV infection. Most infants with HCV infection studied longitudinally have a persistent infection with transiently or persistently abnormal levels of alanine aminotransferase, although some infants have normal liver function. Histologic information about the livers of these children is inadequate. There is currently no effective way to prevent vertical transmission of HCV. Further investigation is needed to better understand the natural history of perinatal HCV infection and the indications for antiviral therapy. Continued research on and development of an HCV vaccine is mandatory.

Acknowledgements

The publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. The author would like to thank the Canadian Liver Foundation for its sponsorship of the invited speakers' program.

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