- The full version of this article is available in PDF
format.
- Latifa T. F. Yeung,1 Susan M. King,2 And Eve A. Roberts
1
- Hepatology Vol. 34, No. 2, August 2001
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- The rate of mother-to-infant HCV transmission is critical
to predicting the burden of HCV infection in future generations. Mother-to-infant
transmission of HCV may be intrauterine, intrapartum, or postnatal. The
factors that determine whether or not an infant actually becomes infected
need to be identified. If they can be manipulated, they represent areas
for intervention to minimize mother-to-infant transmission. This review
summarizes critically the current world-wide literature focusing on the
rate of mother-to-infant transmission of HCV. Improved polymerase chain
reaction (PCR) methods for detection of HCV RNA and larger studies will
further refine the estimate of the incidence of mother-to-infant hepa-titis
C.
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- An estimated 170 million people worldwide are chronically
infected with HCV. If 35% of these are women of child-bearing age, given
an annual fertility rate of 2%, then conservative estimates suggest that
10,000 to 60,000 newborn babies will be infected with HCV each year.
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- A review of published studies of mother-to-infant transmission
of HCV was performed from January 1990 to December 2000. Articles were
identified by computerized literature searches of MEDLINE and EMBASE, using
combinations of key and free text terms (hepatitis C, mother-to-infant
disease transmission, maternal-fetal exchange, placenta, mother-to-child,
mother-to-infant, infant, pregnant, pregnancy). Bibliographies from review
articles were manually cross-checked to identify additional references.
No language restrictions were applied.
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- For this review, mother-to-infant transmission of HCV
was defined as persistence of serum anti-HCV antibodies in the infant beyond
at least 12 months of age or detection of serum HCV RNA on at least 1 occasion.
Cord blood HCV RNA results were disregarded because of the possibility
of contamination with maternal blood. Only original articles with at least
10 cases of anti-HCVpositive mothers were included. Studies using first-generation
enzyme-linked immunosorbent assay (ELISA) or recombinant immunoblot assay
(RIBA) tech-niques without confirmatory PCR testing were excluded.
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- Spontaneous clearance of mother-to-infant HCV infection
(sometimes interpreted as transient viremia) was defined as seroreversion
of serum HCV RNA (detected on at least one occasion and then subsequently
found to be HCV-RNA nega-tive). This may be accompanied by elevated aminotransferases
(ALT) during HCV-RNA positivity and subsequent loss of serum antibody-HCV.
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- Seventy-seven studies were included, published between
1992 and 2000. The number of anti-HCVpositive mother-infant pairs ranged
from 10 to 1,338 per study. The articles in this review reported a total
of 363 cases of mother-to-infant transmission. The majority of studies
originated from Italy and Japan (Table 1). One Irish series focused on
women who had received HCV-contaminated anti-D immunoglobulin. Almost all
studies were prospective cohorts in design.
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- The quality of the studies was largely influenced by
the number of mother-infant pairs studied (sample size), the definition
of mother-to-infant transmission, the frequency and duration of infant
follow-up, and the method of virologic test-ing. All studies were of cohort
design (grade "C" evidence by Guyatt et al.16 guidelines).
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- Prevalence of Hepatitis C in Pregnant Women
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- The prevalence of antibody-HCVpositive women among all
pregnant women varied widely across these studies (0.6%-95.4%), reflecting
the heterogeneity of the populations studied. For example, the 3 studies
with highest prevalence (70.1%-95.4%) were limited to intravenous drug
users. Of anti-HCVpositive women, 26.8% to 94.4% tested positive for HCV
RNA. For inclusion into this review, mother-to-infant transmission of HCV
was defined as persistence of anti-HCV in the infant beyond at least 12
months of age or detection of serum HCV RNA on at least 1 occasion before
18 months of age. The majority of studies demanded at least one positive
HCV RNA result. Some studies required more rigorous definitions of mother-to-infant
transmission such as detection of antibody-HCV in the infant beyond 18
months of age, detection of HCV RNA after 6 months of age, detection of
HCV RNA on at least 2 occasions, elevated serum aminotransferases, or matching
genotype between mother and child.
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- Rate Of Mother-To-Infant Transmission
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- See Table 2below.
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- The reported rate of mother-to-infant HCV transmission
ranged from 0% to 35.3% among children born to anti-HCVpositive women.
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- The definition of mother-to-infant transmission differed
among studies. When all studies were grouped according to the rigorousness
of definition of mother-to-infant transmis-sion (defined as two or more
positive RNA, one or more positive RNA, or no positive RNA requirement),
the weighted rates of mother-to-infant transmission among anti-HCVpositive
women were 7.1% for studies requiring 2 or more positive RNA tests, 3.9%
for studies requiring 1 or more positive RNA tests, and 0.6% for those
with no requirement for a positive RNA test.
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- Human Immunodeficiency Virus Coinfection
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- The rate of mother-to-infant HCV transmission appears
increased among women coinfected with human immunodeficiency virus (HIV)
compared with women without HIV infection. Based on 8 studies that included
data in both HIV-positive and HIV-negative women, the crude rate of mother-to-infant
transmission was 22.1% and 4.3%, respectively. The weighted rate of mother-to-infant
transmission was 19.4% and 3.5%, respectively.
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- Intravenous Drug Use
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- Patients reporting intravenous drug use (IVDU) have a
high prevalence of chronic hepatitis C.29 Studies of mother-to-infant transmission
among intravenous drug users and nonusers suggest that IVDU correlates
with an increased risk of mother-to-infant HCV transmission. In 6 studies
that included data on women with IVDU and without IVDU, the crude rate
of mother-to-infant transmission among children born to anti-HCVpositive
women with IVDU was 10.8%. The weighted rate was 8.6%. The corresponding
crude and weighted mother-to-infant transmission rates for women who did
not report a history of IVDU was 4.2% and 3.4%, respectively.
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- Maternal Viral Titer
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- A correlation exists between higher maternal titers of
HCV RNA and the probability of mother-to-infant transmission. Although
mother-to-infant transmission occurred across a wide range of maternal
viral titers, in 9 studies statistically higher maternal viral titers corresponded
to a greater tendency for mother-to-infant transmission; in 9 studies there
was no difference. Most studies re-ported mother-to-infant transmission
at viral titers beyond the range of 10 5 to 10 6 copies/mL. In one study
higher levels of maternal serum HCV RNA also tended to correlate with higher
colostrum levels of HCV RNA.47 The timing at which serum was collected
for determination of maternal viral titer was reported with variable precision.
Although most studies described blood collection at or near delivery, others
ranged from the third trimester to after delivery. In 5 studies, including
several in which maternal titer of HCV RNA was reported as having no bearing
on rate of transmission, the timing of serum collection was unclear. (Commentary:
these conflicting results may highlight a flaw with this study).
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- Mode Of Delivery
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- The mode of delivery was evaluated as a risk factor for
mother-to-infant transmission in 11 studies. Between infants delivered
vaginally versus by Cesarean section, overall rates of mother-to-infant
transmission were similar. For vaginal delivery and Cesarean section respectively,
the weighted rate of mother-to-infant transmission was 4.3% and 3.0%, respectively.
Although Cesarean section was not further classified as elective or emergency,
one study suggested an increased likelihood of mother-to-infant transmission
with longer duration of membrane rupture. (Commentary: this also may highlight
a study flaw as a number of studies do suggest that C-section may reduce
transmission. These potential flaws also highlight the need to conduct
more & better research in HCV).
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- Breast Feeding
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- The role of breast feeding was evaluated as a risk factor
for mother-to-infant transmission of HCV in 10 studies. Only one of these
studies defined the extent (duration and exclusivity) of breast feeding.24
Overall rates of mother-to-infant transmission between breast-fed and nonbreast-fed
infants were similar. The weighted rate of mother-to-infant transmission
was 3.7% and 3.9% for breast-fed and non-breast-fed infants, respectively.
Although some investigators have detected HCV RNA in breast milk, no definite
case of mother-to-infant transmission of HCV via breast milk has been reported.
(Commentary: again, I feel this may highlight a flaw in this study. The
author says just above that only one study defined the extent of breastfeeding.
This is an important question to try to answer but without rigorous studies
I have to conclude at least for now that breast feeding does present a
potential risk for HCV transmission and pregnant women should be so advised.
Without realizing the limitations of these studies, individuals may underestimate
the risks of breast feeding and report that there is no risk).
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- Genotype
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- Viral genotype was reported infrequently in 32 studies.
In most cases, only the genotypes of vertically infected babies were noted.
No conclusion could be drawn as to the effect of genotype on rate of mother-to-infant
transmission.
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- Outcome Of Infants
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- Inconsistent follow-up among studies resulted in only
sporadic description of clinical outcome for infected infants. No symptoms
of liver disease were reported in the majority of case series; this may
be an underestimate because many stud-ies focused on the rate of transmission
rather than the long-term outcome. However, in one Egyptian study of 20
HCV-RNA positive infants, 4 died of severe liver disease by 6 months of
age. The remaining 16 infants were chronically sick with liver disease.
Only 9 of these 16 infants later became asymptomatic despite remaining
chronically infected. It is uncertain why these Egyptian infants were much
sicker than other affected infants of HCV-infected women. Among studies
describing mother-to-infant transmission rates, liver histology was described
in only 17 infants. The reported age at time of liver biopsy ranged from
9 months to 5.5 years. The majority of liver biopsies revealed changes
consistent with chronic hepatitis. Fibrosis on liver biopsy was described
in 3 cases. One infant was successfully treated with interferon alfa.25
Three of the 17 infants died ;1 of these was coinfected with HIV 27 whereas
another received 6 months of parenteral nutrition.
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- Spontaneous loss of serum HCV RNA, interpreted as either
clearance of mother-to-infant HCV infection or transient viremia, was suggested
in 59 cases. In these infants, serum HCV RNA was detected on at least one
occasion and then the infant was subsequently found to be HCV-RNA negative.
Many of these infants subsequently cleared serum anti-HCV. Six of these
infants had elevated aminotransferases during the period of serum HCV-RNA
positivity.
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- Passive transfer of maternal antibody accounted for a
majority of infants born to women with hepatitis C. The gradual loss of
serum anti-HCV in infants occurred by 18 months of age in the vast majority
of cases, and many lost anti-HCV earlier, by 12 months of age. Of the 45
studies that described time to clearance of anti-HCV, there were only 3
outlying cases described, in whom clearance of anti-HCV occurred between
20 and 24 months of age.
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- Discussion
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- Several factors have been proposed as determinants in
mother-to-infant HCV transmission, including maternal coinfection with
HIV, IVDU, maternal viral titer, mode of delivery, breast feeding, and
viral characteristics (e.g., genotype). In this summary, women coinfected
with HIV or those who re-port a history of IVDU tended to have a higher
rate of mother-to- infant transmission compared with those without such
co-factors. By contrast, mode of delivery and prevalence of breast feeding
did not significantly influence rates of mother-to-in-fant transmission.
Suggested viral factors such as genotype and viral titer were not consistently
measured across studies; their roles as significant risk factors in mother-to-infant
transmission remain to be conclusively shown.
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- Furthermore, the suspected risk factors for mother-to-infant
transmission deserve clarification. Some patients may not report a history
of IVDU. Alternatively, some physicians may not probe carefully enough
for a history of IVDU. Rather than mode of delivery, the extent of maternal-fetal
blood exchange at time of delivery may be the major determinant of transmission
as suggested by the duration of membrane rupture. Similarly, the definition
of breast feeding remains ambiguous: a spectrum exists between being exclusively
and never fed breast milk. Although maternal viral titer may serve as a
useful risk factor, the timing of measurement for each woman relative to
delivery should be specified. For maternal viral titer to become adopted
as a prognostic factor in mother-to-infant HCV transmission, its timing
will require standardization.
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- Thus far, the outcome of most infants with chronic hepatitis
C acquired through mother-to-infant transmission appears mild. Most such
children were asymptomatic. However, in the few infants who underwent liver
biopsy, most had evidence of chronic hepatitis. The progression of liver
disease for these children remains to be assessed. Fibrosis has been documented,
even in asymptomatic infants.
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- www.natap.org
- http://www.natap.org/2001/sep/mother_to_infant091401.htm
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- Patricia A. Doyle, PhD
- Please visit my "Emerging Diseases" message
board at: http://www.clickitnews.com/ubbthreads/postlist.php?Cat=&Board=emergingdiseases
- Zhan le Devlesa tai sastimasa
- Go with God and in Good Health
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