Increased Risk of Mother-to-Infant Transmission of Hepatitis C Virus by
Intrapartum Infantile Exposure to Maternal Blood
In developed countries, the majority of new hepatitis C virus (HCV) infections are acquired through injection drug use (IDU). Although vertical transmission of HCV from mother to child during delivery is a rare route of infection, with reported average transmission rates of 5%-10%, it is the predominant mode of infection among children.
Until now, only a few risk factors influencing vertical HCV transmission during the perinatal period have been identified (i.e., human immunodeficiency virus [HIV] type 1 coinfection and the presence of HCV RNA in maternal blood). However, it is still controversial whether high maternal virus load also poses a higher risk for transmission. Furthermore, the timing of perinatal transmission is uncertain, and understanding of the obstetrical factors that influence vertical transmission of HCV is still limited. Although several studies did not find an increased risk of
transmission during vaginal delivery, a recent investigation of a large cohort found evidence that elective cesarean delivery results in a reduction in mother-to-child transmission rates. Because the factors influencing transmission are still unclear, screening of pregnant women for HCV infection is currently not recommended, and
preventive measures during delivery are not available. This uncertainty about risk factors that influence vertical transmission of HCV stands in contrast to mother-to-infant transmission of HIV-1, where risk factors for transmission have been clearly identified (i.e., plasma HIV-1 RNA level and vaginal delivery). As a consequence, medical interventions that significantly reduced vertical transmission rates of HIV-1, including antiviral drugs and elective cesarean section, have been introduced.
The aim of the present study was to identify preventable risk factors associated with HCV transmission and to provide a basis for the prevention of HCV infection in newborns. For this purpose, we retrospectively evaluated virological and clinical parameters (e.g., mode and course of delivery) within a large, well-defined cohort of
HCV-infected pregnant women. Although vaginal delivery itself was not a risk factor for transmission in the present study, we found that perinatal infantile hypoxia and vaginal or perineal laceration that occurred during vaginal delivery significantly increased the risk for HCV transmission.
The Journal of Infectious Diseases 2003;187:345-351
Virological and clinical data from 73 hepatitis C virus (HCV)infected
pregnant women who gave birth to 75 children were merged retrospectively,
by logistic regression analysis, to investigate risk factors for vertical
transmission of HCV. Eighty-two percent of the HCV-infected mothers were
HCV-RNApositive during pregnancy, and 10% were coinfected with human
immunodeficiency virus (HIV). Nine children were HCV infected, 1 was HIV
infected, but none was HIV-HCV coinfected. Among vaginal deliveries, the
mean HCV load of mothers who transmitted HCV to their infants was higher
than that of those who did not (8.1 x 10 5th vs. 1.4 x 10 4th copies/mL; P = .056).
A reduction in umbilical cordblood pH (relative risk, 3.9; P = .04) or the
occurrence of perineal or vaginal laceration (relative risk, 6.4; P = .028)
during vaginal delivery significantly increased the risk of vertical HCV
transmission. In conclusion, high maternal viremia, infantile hypoxia, and
intrapartum exposure to virus-contaminated maternal blood increased the risk
of HCV transmission during vaginal deliveries. Consequently, cesarean
section may reduce the risk of vertical HCV transmission in selected cases. (editorial note from Jules Levin: study results appear to be mixed on the benefit of caesarian section in reducing vertical HCV transmission).
For the evaluation of possible risk factors for the vertical transmission of HCV, 73 pregnant, HCV-infected women were identified between 1994 and 1999. Serum samples of 71 women (97%) were tested by RT-PCR; 58 women (82%) were HCV RNA positive. Four mothers had been HCV RNA positive before pregnancy but were negative during pregnancy. For 11 mothers, HCV infection was confirmed by the identification of HCV-specific antibodies by use of an immunoblot.
The 73 women gave birth to 75 children, including 2 sets of twins; 9 of the children were HCV infected. Seven (10%) mothers were HIV-HCVcoinfected, 59 (81%) were HIV seronegative, and, for 7 (10%), HIV status could not be determined. For 6 of the 7 HIV-HCVcoinfected mothers, HCV- and HIV-PCRs were done, and both HCV RNA
and HIV DNA were detected. Of the 7 mothers with HIV coinfection, 1 transmitted HCV to her offspring and 1 transmitted HIV, but none transmitted both viruses to her child. One of these 7 children (the HIV-infected one) was delivered vaginally, 5 (including the HCV-infected child) were delivered by elective cesarean section, and the mode of
delivery was unknown for 1 child.
Detectable HCV viremia in the mother was a prerequisite for transmission, since only children from mothers with detectable viral RNA became HCV infected. The mothers of infected children had a higher mean HCV load than did mothers of uninfected children (7.3 x 10 5th vs. 2.5 x 10 4th copies/mL), and this difference in HCV load was even more pronounced among mothers who underwent vaginal delivery (8.1 x 10 5th vs. 1.4 x 10 4th copies/mL). However, no statistically significant association could be found between maternal HCV RNA level and the risk of mother-to-infant transmission of HCV, although a trend toward a higher risk of transmission with increasing levels of maternal viremia was noted.
In mothers with HIV-HCV coinfection, no increased risk for mother-to-infant transmission of HCV was observed in the present study, although the number investigated was small. In the 7 HIV-HCVcoinfected mothers for whom a
quantitative HCV-PCR result was available, the mean HCV load was not significantly higher than that in mothers without HIV-HCV coinfection (1.7 x 10 5th vs. 3.2 x 10 4th HCV RNA copies/mL; n = 53; P = .113, Mann-Whitney U test).
In the present study, vaginal delivery itself did not increase the risk for transmission, compared with cesarean section. However, children who were delivered vaginally and whose mothers sustained a perineal or vaginal laceration had a 6-fold higher risk of becoming HCV-infected than did vaginally-delivered children whose mothers had no
laceration (table 1). In contrast, no significantly increased risk was observed when an episiotomy was performed. The transmission rate of HCV did not differ between emergency and elective cesarean sections, although the number observed was small.
In addition, every reduction in umbilical cordblood pH by 0.1 increased the risk of mother-to-infant transmission of HCV by 4-fold (assuming a pH standard value of 7.27). An APGAR score of 9/10 at 1 and 5 min was noted for all these HCV-infected newborns.
Interactive effects of the risk factors investigated were subsequently evaluated by a multivariate analysis. Results of this analysis were similar to those obtained by univariate logistic regression, except for perineal or vaginal laceration
(RR, 2.99; 95% confidence interval, 0.3227.70) and umbilical cordblood pH (RR, 5.0; 95% confidence interval, 1.0623.80).
To evaluate the course of the HCV infection in infected children and the clearance of maternal HCV antibodies in uninfected children, the 75 children were monitored for as long as possible. All 9 HCV-infected infants were singleton births and were surveyed for a minimum follow-up period of 11 weeks (median, 54 weeks; interquartile range, 2289 weeks). The earliest time that 1 newborn was tested and HCV RNA could be detected was at the age of 9 days. Two other children were HCV RNA positive already at the age of 15 and 22 days, respectively. Eight of the 9 HCV-infected children had consistently positive RT-PCR results in the samples collected after the age of 1 month (in 2 children, HCV RNA could be still detected at the age of 5 years). One
infected child with detectable HCV RNA became HCV RNA negative at the age of 15 months and remained negative thereafter.
All 66 HCV-uninfected children were at least 5 weeks old when last tested for HCV viremia by PCR (median age, 28 weeks; interquartile range, 1035 weeks). Altogether, 114 samples were collected from these HCV-uninfected children and tested for HCV-specific antibodies by ELISA. When ELISA results were analyzed in relation to the age of the children, a 50% probability of an HCV antibodynegative result was attained at the age of 9.6 months.
Vertical transmission from infected mothers has become the most important mode of HCV infection among children. Although numerous studies have addressed this issue, the mechanisms of vertical HCV transmission, including the timing of infection, remain largely unknown.
It is generally agreed that the risk of vertical HCV infection in mothers without detectable HCV viremia is exceedingly low. We also found HCV viremia to be a prerequisite for transmission, because none of the HCV RNAnegative mothers transmitted the virus to her child.
However, there is no general consensus that the risk of transmission is higher in mothers with high HCV load than in mothers with low HCV load. In the present study, the mean maternal HCV load was higher in mothers whose children were HCV infected than in those whose children were not infected, but high viremia was not a statistically significant risk factor for transmission. However, when we included the mode of delivery into our analysis, it became apparent that, in the case of a vaginal delivery, this difference in mean virus load was even more pronounced. In addition, except for 1 HIV-HCVcoinfected woman, none of the 23 mothers who had a cesarean section transmitted HCV to her offspring.
Previous reports found strong evidence that mother-to-child transmission rates and substantial intrapartum transmission of HCV may possibly be reduced by elective cesarean delivery. However, some studies were criticized for testing only a minority of women for HCV RNA and for not addressing possible mechanisms involved in the reduction of vertical transmission of HCV by elective cesarean section. We not only tested 97% of the mothers for HCV RNA but also identified factors that may increase the risk of HCV transmission in vaginal deliveries.
We observed a significantly increased risk of HCV infection in children with a low umbilical cordblood pH, which is indicative of infantile hypoxia. Whether this intrapartum hypoxia may have led to aspiration of HCV-contaminated maternal fluids or to other hypoxia-related mechanisms of virus transmission can only be speculated.
Moreover, a significantly increased risk of mother-to-infant transmission of HCV was observed in the case of leakage of maternal blood into the birth canal by tears of the cervix or vagina. In contrast, when an episiotomy, which also is associated with maternal bleeding, was performed, it did not increase the risk for vertical transmission of HCV. This apparent contradiction may suggest a more extensive, and possibly longer, exposure of children to virus-contaminated maternal fluids during vaginal deliveries that involve vaginal or perineal lacerations than during those that involve an episiotomy. Although it may be theorized that passage through the birth canal may be prolonged in mothers with relatively large children or that, in women with vaginal or cervical tears, the canal first had to be dilated by the child before passing through it, which allowed for more extensive exposure to virus-contaminated maternal blood, these details will have to be elucidated in prospective clinical trials. Still, since an episiotomy is, in general, performed at the end of labor, intrapartum exposure to maternal blood is very likely shorter in this incidence than in the case of vaginal or perineal lacerations.
Evidence for the significance of labor-associated factors for the transmission of blood-borne pathogens was already found in investigations of vertical HIV transmission in twin births. First-born twins were more likely to be infected with HIV-1 than their second-born siblings, especially when the former was of greater birth weight. It was suggested in these studies that the first-born twin would have dilated and, to some extent, mechanically cleansed the birth canal, thereby reducing the duration of exposure of the second twin and, consequently, the risk of transmission.
Nevertheless, these observations on the transmission of HCV or HIV represent only indirect evidence for an increased risk in vaginal deliveries with prolonged passage through the birth canal. Data on the exact time required for passage of the birth canal, however, are not routinely recorded during delivery and will have to be collected in future prospective clinical trials.
Results of studies on HIV infection as a risk factor for vertical HCV transmission also have been ambiguous. Nevertheless, HIV-HCV coinfection reportedly accelerates HCV disease progression by increasing HCV load, and a higher HCV load in HCV-HIVcoinfected patients may be explained by the observed inverse relation between baseline CD4+ cell count and HCV load. In addition, the risk for transmission is exceedingly low in women who are HIV-HCV coinfected but who have little or no detectable HCV RNA. Consequently, we propose that the more important predictive factor for HCV transmission is very likely HCV load, and not HIV coinfection. In the present study, which included only a small number of HIV-HCV coinfected mothers, no increased risk for vertical HCV transmission was observed in mothers with HIV coinfection. This finding may be explained by the fact that HCV load in our group of HIV-HCVcoinfected mothers did not significantly differ from that in HIV-uninfected mothers.
Reported average mother-to-infant transmission rates of HCV are 5%10%; we observed a somewhat higher transmission rate of 12%. However, because of the retrospective design of the present study and the fact that HCV infection status could not be assessed for all children, a selection bias cannot be excluded for this parameter. In addition, our laboratory is the major reference laboratory for the geographic region covered by this study; therefore, preselection of patients possibly occurred.
In conclusion, vaginal delivery itself does not appear to be a significant risk factor for mother-to-infant transmission of HCV, but the risk of transmission increased with increasing maternal HCV load and with the occurrence of infantile hypoxia or vaginal or perineal lacerations during vaginal delivery. Although it would be premature to recommend routine cesarean section for HCV-infected women, elective cesarean section may reduce the risk of vertical transmission of HCV among mothers with high HCV viremia, those who are at risk for birth injuries during vaginal delivery, or those whose children are at risk for intrapartum hypoxia.