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To estimate the risk of mother-to-child transmission of hepatitis C virus (HCV) and identify
correlates of transmission, 245 perinatally exposed singleton children followed prospectively beyond
18 months of age were studied. Overall, 28 (11.4%) of the 245 children acquired HCV infection.
Transmission occurred in 3 of 80 children (3.7%) whose mothers had HCV infection alone and in
25 of 165 (15.1%; P .01) whose mothers had concurrent infection with human immunodeficiency
virus type 1 (HIV-1). The percentage of HIV-1-infected children was similar (22 of 165, 13.3%), but
each virus was transmitted independently; only six infants (3.6%) were coinfected with HCV and
HIV-1. The risk of HCV transmission was not associated with maternal HIV-1-related symptoms,
Mother-to-child transmission of hepatitis C virus (HCV) is birth weight, mode of delivery, and type of feeding were also
widely documented. However, in different investigations the investigated.
estimated risk of infection ranged from zero to 100% [1 15].
This variability derives from differences in methods used to
define the childs infection status, duration of follow-up, and Patients and Methods
size and features of the populations studied.
Transmission of HCV may occur in utero via the transplacen- Patients. A cohort of 245 children born to HCV-infected
tal route at any time during pregnancy, at the time of delivery, women were enrolled at 12 participating centers. In three cen-
and postnatally through breast-feeding. Several factors might ters all parturients were screened for HCV-seropositivity; in
favor or hamper infection of the offspring. Identification of the remaining centers, HCV testing was mostly performed only
these factors would allow the adoption of rational preventive for women who had a history of IVDU or were known to be
HIV-1-infected. Only singleton at-risk infants identified within
strategies and the offer of specific counseling, but little is
the first 2 weeks of life and followed up for at least 18 months
known about the timing and correlates of transmission. High
were included in this study.
levels of viremia [5 7], certain HCV genotypes [8], and mater-
Data collection. Specific information was collected by
nal coinfection with HIV-1 [1, 2, 4, 7, 9, 15] have been associ-
questionnaire on maternal risk factors for HCV infection
ated with increased HCV transmission rates, although the re-
(IVDU, transfusions, sexual contact with an infected partner,
sults are controversial [10 13]; breast milk does not seem to
other, unknown), mothers HIV-1 infection status at delivery
have a significant role [13 15].
(presence or absence of specific antibody), length of pregnancy
The aim of this study was to quantitate the risk of HCV
(weeks), mode of delivery (vaginal, elective/emergency cesar-
infection in children born to mothers with or without
ean), birth weight (grams), type of feeding (maternal, with
HIV-1 coinfection. The effects of other possible correlates
duration of breast-feeding, or formula only), and age at first
of transmission, such as maternal HIV-1 disease progression,
and last visit. The presence or absence of antibodies to HCV
history of intravenous drug use (IVDU), length of pregnancy,
and HIV-1 as well as of HCV RNA (with dates of the tests)
in the child was also reported.
Laboratory tests. Clinical examination and laboratory test-
ing were performed every 3 5 months over the first 18 months
Received 10 January 1997; revised 21 May 1997. of life; thereafter, only children with HCV and/or HIV-1 infec-
Grant support: Ministero della Sanita-I.S.S.-Rome (AIDS Projects) and
Ministero dellUniversitae della Ricerca Scientifica, Italy.
tion were regularly followed for a mean period of 28 months
* Other participants are listed at the end of the text. (range, 19 42 months), while most uninfected children were
Reprints or correspondence: Pier-Angelo Tovo, Department of Pediatrics, discharged or lost to follow-up. The mothers enrollment serum
Piazza Polonia 94, 10126 Turin, Italy.
samples and follow-up samples from their children were tested
Clinical Infectious Diseases 1997;25:11214
q 1997 by The University of Chicago. All rights reserved.
for HCV-seropositivity by a second-generation EIA and a re-
10584838/97/25050030$03.00 combinant immunoblotting assay (RIBA II or RIBA III). Anti-
bodies to HIV-1 were measured by ELISA and confirmed by differences in HCV transmission were observed between the
western blotting. centers.
The presence of HCV RNA was investigated by reverse Of 165 group B children, 22 (13.3%) acquired HIV-1, in-
transcriptase PCR, performed by single participating centers. cluding 6 (3.6%) coinfected with HCV.
Total RNA was extracted from serum samples of perinatally Table 1 shows the influence of other possible risk factors
exposed children; after a reverse transcription step, cDNA was on HCV transmission. The percentage of HCV-infected chil-
amplified with commercial primers of the 5* noncoding region dren was higher among those born by vaginal delivery than by
of the viral genome in a single PCR of 35 cycles. PCR product cesarean section, with differences at the limit of significance in
was separated by agarose gel electrophoresis and visualized by the cohort as a whole and in group B. No significant difference
ethidium bromide staining. emerged in comparison of elective and emergency cesarean
Childs HCV (and HIV-1) infection status. Children were deliveries (2 of 50 [4%] vs. 2 of 21 [9.5%], respectively). Mode
considered to be infected with HCV and/or HIV-1 when spe- of delivery was also associated with transmission of HIV-1,
cific antibodies persisted beyond 18 months of age. Children with 20 (16.8%) of 119 HIV-1-infected children delivered vagi-
with HCV RNA in at least two serum samples were also consid- nally and 2 of 46 (4.3%; P .05) by cesarean section.
ered infected. The presence of HIV-1-related symptoms in the mother was
Risk factors for transmission. To assess the impact of ma- not predictive of HCV infection (table 1). Likewise, the propor-
ternal HIV-1 coinfection on transmission of HCV to the off- tion of children who acquired HIV-1 was comparable between
Table 1. Influence of maternal and infant factors on transmission of hepatitis C virus (HCV).
NOTE. Inconsistencies in total number of children for each variable are due to incomplete data.
* Children of HCV-positive, HIV-1-negative mothers.
Children of HCV-positive, HIV-1-positive mothers.
P .01.
P .06.
The presence of HCV RNA in some seroreverting children informed about the additional risk of transmitting HCV to their
is an intriguing phenomenon. As in other recent investigations offspring.
[5, 12, 13], we observed this phenomenon in few cases. PCR The greater HCV infectiousness of group B mothers may be
is a very sensitive technique to detect HCV RNA in serum accounted for by HIV-1-induced immunosuppression leading
samples from infected subjects, but the method has yet to be to impaired control of HCV, with consequent increased levels
standardized, and false-positive results cannot be ruled out. To of viremia. A direct correlation has been found between mater-
reduce this possibility, only children for whom results were nal viral load and HCV transmission [5 7], although other
positive in two separate determinations were considered to be investigators failed to find this association [13, 14].
HCV-infected. The higher the degree of immunosuppression, viral burden,
On the other hand, not all seroreverters were tested by PCR, and disease progression in the mother, the greater the risk of
and its sensitivity was not absolute in antibody-positive chil- vertical transmission of HIV-1 [17 22]. In the present analysis,
dren. In addition, results were not controlled in a central labora- HIV-1-related clinical manifestations were not predictive of
tory. With these limitations, the balance of evidence leads us HCV or HIV-1 transmission. This might be due to the relatively
to conclude that the proportion of seronegative HCV carriers small number of mother/child pairs studied.
among at-risk children is limited and thus should not bias the It is interesting that in women with HCV and HIV-1 coinfec-
results of this study. tion, the transmission of the two viruses was similar. However,
In areas where the HIV-1 epidemic has spread mostly be- each virus was acquired independently, attesting to the fact
cause of IVDU, many women are coinfected with HCV. In that distinct mechanisms regulate their passage to the offspring.
Italy, about three-quarters of HIV-1-positive women are also The fact that a substantial fraction of at-risk children escaping
HCV-positive [13, 15]. Whereas worldwide informational cam- infection with HIV-1 are infected with HCV must be taken
paigns have been instituted for the prevention of mother-to- into due account, particularly because perinatal HCV infection
child HIV-1 transmission, the risk connected with HCV has can give rise to an indolent chronic infection with no clear
not received adequate consideration. Our study points out that signs of hepatitis [23].
women faced with child-bearing decisions and pregnant Another common feature in transmission of HCV and
women, particularly those with at-risk behaviors (e.g., IVDU), HIV-1 was the lower percentage of infected children among
should be encouraged to undergo antenatal testing for both those delivered by cesarean section. Increasing evidence sup-
HIV-1 and HCV, and those with double infection should be ports the association between mode of delivery and perinatal
HIV-1 infection [21, 22, 24]. For HCV, the difference was just 4. Kuroki T, Nishiguchi S, Fukuda K, et al. Vertical transmission of hepatitis
C virus (HCV) detected by HCV-RNA analysis. Gut 1993; 34(suppl 2):
above the threshold of significance in the present study, while
S52 3.
a significant protective effect of cesarean section was observed 5. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus
by Paccagnini et al. [15]. from mothers to infants. N Engl J Med 1994; 330:744 50.
Abdominal surgical delivery can protect infants from infec- 6. Lin H-H, Kao J-H, Hsu H-Y, et al. Possible role of high-titer maternal
tion in several ways, as exposure to contaminated maternal viremia in perinatal transmission of hepatitis C virus. J Infect Dis 1994;
169:638 41.
blood during the passage through the birth canal is avoided as
7. Zanetti AR, Tanzi E, Paccagnini S, et al. Mother-to-infant transmission
well as additional risks linked to episiotomy and instrumental of hepatitis C virus. Lancet 1995; 345:289 91.
delivery. Further protection may be derived from the prevention 8. Zuccotti GV, Ribero ML, Giovannini M, et al. Effect of hepatitis C geno-
of maternal-fetal blood transfusions during labor. type on mother-to-infant transmission of virus. J Pediatr 1995; 127:
The preventive action of cesarean section suggests that a 278 80.
9. Giovannini M, Tagger A, Ribero ML, et al. Maternal-infant transmission
large proportion of infants are infected around the time of
of hepatitis C virus and HIV infections: a possible interaction [letter].
delivery. In fact, when tested for in the first days of life, HCV Lancet 1990; 335:1166.
RNA was undetectable in children who ultimately were shown 10. Cilla G, Perez-Trallero E, Iturriza H, Carcedo A, Echeverria J. Maternal-
to be infected in this and other investigations [5, 15, 23]. No infant transmission of hepatitis C virus infection [letter]. Pediatr Infect
difference in the HCV transmission rate was seen for children Dis J 1992; 11:417.
11. Perez Alvarez L, Gurbindo MD, Hernadez-Samplelayo T, et al. Mother-
delivered by elective vs. emergency cesarean section. This