Hepatitis C Mother-to-Child Transmission

Leidy Tovar Padua, MD,* Ravi Jhaveri, MD†

*Division of Pediatric Infectious Diseases, David Geffen University of California Los Angeles School of Medicine, Los Angeles, CA.
†
Division of Pediatric Infectious Diseases, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.

Educational Gaps
1. Clinicians should know the frequency of and risk factors for hepatitis C
virus vertical transmission.
2. Clinicians should understand the recommended follow-up testing for an
infant vertically exposed to hepatitis C virus and the postpartum advice
necessary for parents.

Abstract
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease in
adults and children, affecting more than 180 million individuals worldwide.
Vertical transmission is the primary route of HCV acquisition in children. Studies
have not found effective management strategies to reduce risk for transmission.
Pediatric HCV infection is different from adult infection in several aspects. This
review will provide a comprehensive understanding of the current knowledge of
HCV and its impact on pregnant women and infants and will offer specific
recommendations for diagnosis and management.

Objectives After completing this article, readers should be able to:

1. Describe the major routes of transmission for hepatitis C virus (HCV) and
identify groups at high risk for HCV acquisition.
2. Understand the frequency of vertical transmission of HCV and the
potential risk factors that may increase the rate of transmission and the
intrapartum measures that are necessary.
3. Understand the role for antibody and nucleic acid tests in the follow-up of
infants vertically exposed to HCV.
4. Distinguish the postpartum interventions that are required (vaccination)
and those that are not recommended (interruption of breastfeeding) for
AUTHOR DISCLOSURE Dr Tovar Padua has infants exposed to HCV.
disclosed no financial relationships relevant to
5. Recognize that with the new highly efficacious antivirals that were recently
this article. Dr Jhaveri has disclosed that he
receives research grant funding from Gilead approved for adults, treatment and intervention protocols for infants with
Sciences, MedImmune, Merck, and Alios. This vertical transmission of HCV may undergo major changes in the near future.
commentary does contain a discussion of an
unapproved/investigative use of a
commercial product/device.

Vol. 17 No. 9 SEPTEMBER 2016 e521

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 INTRODUCTION a microRNA to promote gene expression is in marked
contrast to conventional microRNA function in silencing
Hepatitis C virus (HCV) infection is a major global health
gene expression.
issue that affects patients across their lifespan. It is a leading
HCV has 6 major genotypes, which are associated with
cause of chronic liver disease in adults and children, affect-
important clinical phenotypes. (1) The most prevalent in the
ing more than 180 million individuals worldwide. In the
United States and Western Europe are genotypes 1a and 1b.
United States, about 3 million people are chronically
Genotypes 1a, 1b, and 4 are less susceptible to IFN-based
infected and nearly 50% are unaware of the infection.
therapies. Genotype 3 is associated with more frequent and
Mother-to-child transmission is the primary route of HCV
more severe steatosis.
acquisition in children. Prior studies have demonstrated that
The hepatocyte is the main target for HCV, but several
high HCV viral load and human immunodeficiency virus
other cell types appear to support lower levels of HCV
(HIV) coinfection are risk factors for perinatal HCV infec-
replication. In vivo studies have provided extensive evidence
tion; however, conflicting data exist on prolonged rupture of
of extrahepatic replication of HCV in B cells, T cells, mac-
membranes and other obstetric procedures. Breastfeeding
rophages, and monocytes. (2) Brain endothelial cell lines
is not contraindicated in hepatitis C infection. Studies have
also supported HCV entry and infection. (3) Cultured
not found effective management strategies to reduce risk for
human cytotrophoblasts were successfully infected with
transmission. Children with hepatitis C have a natural history
HCV, and microscopic characteristics were similar to the
that is quite different from that of adults.
HCV-infected human peripheral blood mononuclear cells.
The only licensed therapy available for chronic hepatitis
(4) Giugliano et al (5) demonstrated the expression of
C (CHC) in children is the combination of pegylated (PEG)-
multiple receptors required for entry and uptake of HCV in
interferon (IFN) and ribavirin, which is a regimen with a
human villous cytotrophoblast cells and syncytiotropho-
high rate of adverse effects and poor efficacy that is no
blasts. They also reproduced a number of placental anti-
longer used in adults. Recently approved therapies in adults
viral mechanisms against HCV such as type I and III IFN
that achieve almost universal virologic cure offer the prom-
responses from primary villous trophoblasts, increased ap-
ise of expanding the horizon for pregnant women and
optosis of trophoblast cells, and broad and robust produc-
infected children. This review will summarize the current
tion of antiviral cytokines and recruitment of natural killer
knowledge of HCV and its impact on pregnant women and
(NK) cells, which support the role of the placenta in local
infants and will offer specific recommendations for diag-
control of HCV infection.
nosis and management as well as a discussion of how the
treatment landscape could change with the use of new HCV
antivirals. PATHOGENESIS

After HCV gains access to the bloodstream, the virus targets

VIROLOGY
HCV is a positive-sense, enveloped, single-stranded RNA
virus of the Flaviviridae family. Its genome is organized into
1 long open reading frame of approximately 9,500 nucleo-
tides. The structural proteins of HCV (core, E1, and E2) are
at the 59 end of the genome and the nonstructural proteins
(NS2, NS3, NS4A, NSB, and NS5B) toward the 39 end. HCV
has unique characteristics such as an internal ribosomal
entry site (IRES) for translation of the viral proteins, a
protein (E2) that responds to immune-mediated stress re-
sulting in hypermutation of the virus known as “quasi-
species,” a multifunctional protein (NS3) with helicase
and protease domains, and a cofactor (NS5B) for many viral
processes, including RNA replication and viral assembly.
(1) HCV relies on specific interaction with a liver-specific
microRNA (miR-122). The HCV RNA has 2 sites in its
genome that are complementary to miR-122. This use of
the liver. Although HCV primarily infects hepatocytes, it is
not considered to have a cytopathic effect. Viremia is usually
seen 7 to 8 weeks after infection but can vary from 2 to 26
weeks. Acute infection with HCV will induce a cellular and
humoral immune response. Hepatic injury and viral clear-
ance are associated with a robust cellular immune response
mediated by HCV-specific CD4 and CD8 T cells. Progres-
sion to CHC is associated with an exhausted T-cell response,
which is weak and ineffective against HCV. (1)
EPIDEMIOLOGY
CHC is a major global public health problem, accounting for
most cases of chronic liver disease in adults. In 2005, more
than 185 million people were infected with HCV globally,
approximately 3% of the world population, and most people
were unaware of their infection. (6) The prevalence of hep-
atitis C, as determined by anti-HCV antibodies, is highest in

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Central and East Asia and in the North Africa/Middle East
regions. (6) The global prevalence of CHC among pregnant
women, detected with anti-HCV antibody and HCV RNA
polymerase chain reaction (PCR), is approximately 0.75%
(0.49%–1.7%) but varies by population and geographic
location. Studies suggest hepatitis C affects 0.6% to 2.4%
of all pregnancies in the United States, but these rates are
likely underestimated due to selective screening for HCV
among high-risk patients. (6)(7)
In the United States, approximately 3.5 million people are
chronically infected and nearly 50% have no knowledge of
their HCV status. Reported cases of acute hepatitis C (AHC)
increased from 1,778 in 2012 to 2,138 in 2013. However, the
Centers for Disease Control and Prevention estimated that
29,718 AHC cases occurred in 2013, with increased infec-
tion rates among young adults. (8) Nearly 85% of infected
individuals were white, with an even gender distribution.
Surveillance data reported an alarming increase (364%) in
cases of acute HCV infection among the central Appalachian
population from 2006 to 2012, related to opioid dependence
and intravenous drug use. (9)
Data from the National Health and Nutrition Examina-
tion Survey (NHANES) III for 1999 through 2002 indicate
HCV seropositive rates of 0.2% to 0.4% in the pediatric
population of the United States. CHC affects approximately
25,000 to 50,000 children, with approximately 750 infants
infected via vertical transmission each year. (10) Prevalence
rates in developing countries range from 1.8% to 5%. (11)(12)
Children perinatally infected with HCV clear the infection
in 20% to 45% of cases. Liver disease from CHC usually
progresses slowly during childhood, thus serious compli-
cations of chronic liver disease are not common. However,
young adults infected with HCV during childhood have
suboptimal outcomes after liver transplantation. (13) The
estimated direct medical costs related to HCV in childhood
over the next decade include 26 million US dollars (USD)
for screening, 117 to 206 million USD for monitoring, and
56 to 104 million USD for treatment costs. (10)
TRANSMISSION
HCV is primarily transmitted through exposure to blood
and blood-containing solutions, tissue, and equipment. Be-
fore the institution of rigorous screening of all donated
blood and blood products in the early 1990s, nearly all
recipients of blood products became chronically infected
with hepatitis C. Currently, persons who inject drugs ac-
count for at least 60% of acute HCV infections in the
United States (8) and worldwide (14); thus, the use of in-
jected drugs is considered a major risk factor for infection.
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Sexual transmission also occurs but at a negligible rate
except among HIV-infected individuals and men who have
sex with men. (15) Tattooing and piercing are currently not
considered high-risk exposures. (16) Shared use of razors
and toothbrushes of HCV-infected persons should be
avoided given the risk of microscopic blood exposure and
thus risk of infection. The 2015 recommendations for
testing, managing, and treating HCV from the American
Association for the Study of Liver Diseases (AASLD), Infec-
tious Diseases Society of America (IDSA), and International
Antiviral Society (IAS), as well as the 2014 guidelines for the
screening, care, and treatment of persons with HCV infec-
tion from the World Health Organization (WHO) are sum-
marized in the Table.
TABLE. Summary of Recommendations for
Hepatitis C Screening
1. Persons born between 1945 and 1965.
2. Persons who have history of injection-drug use and intranasal illicit
drug use.
3. Long-term hemodialysis.
4. Getting a tattoo in an unregulated setting.
5. Healthcare, emergency medical, and public safety workers after
needle sticks, sharps, or mucosal exposures to HCV-infected blood.
6. Children born to HCV-infected women.
7. Prior recipients of transfusions (blood products before 1992 and
clotting factor concentrates before 1987) or organ transplants.
8. Individuals who are part of a population with high HCV
seroprevalence.
9. Persons who were ever incarcerated.
10. HIV infection.
11. People with sexual partners who are HCV-infected, particularly
MSM population.
12. Unexplained chronic liver disease and chronic hepatitis,
including elevated alanine aminotransferase levels.
13. Solid organ donors (deceased and living).
14. Children with chronically elevated transaminases.
15. Children from a region with high prevalence of HCV infection.
Adapted from AASLD/IDSA/IAS HCV Guidance: Recommendations for
Testing, Managing, and Treating Hepatitis C 2015 and World Health
Organization. Guidelines for the screening, care and treatment of persons
with hepatitis C infection. (14) AASLD¼American Association for the Study
of Liver Diseases, IDSA¼Infectious Diseases Society of America,
IAS¼International Antiviral Society, HCV¼hepatitis C virus, HIV¼human
immunodeficiency virus, MSM¼men who have sex with men,
WHO¼World Health Organization.
Vol. 17 No. 9 SEPTEMBER 2016 e523
 NATURAL HISTORY
Individuals infected with HCV are asymptomatic in most
cases. Diagnosis of HCV infection is usually an incidental
finding; only a few patients will display clinical evidence
of acute hepatitis. (1) Liver disease secondary to HCV
infection is classified as AHC and CHC. Acute HCV
infection is usually defined as detectable HCV RNA in
a blood specimen in the setting of a negative antibody
against HCV. AHC is usually clinically asymptomatic. In-
fants with detectable HCV RNA in blood within the first
6 months after birth are considered infected. Perinatal
transient viremia may occur during the first days after
birth and must be distinguished from neonatal HCV
infection. (17) Individuals with evidence of liver injury
and detectable HCV RNA in blood for at least 6 months
have CHC.
DIAGNOSIS
AHC infection is not usually diagnosed, given the lack of
symptoms. In most individuals, HCV remains undiagnosed
until the development of CHC. Diagnosis of hepatitis C
infection requires laboratory testing (serologic and molec-
ular testing). Anti-HCV enzyme-linked immunosorbent
assays are used for screening of high-risk patients. Anti-
body-based assays cannot distinguish whether a patient has
active HCV infection because anti-HCV immune globulin
(Ig) G may be detectable after resolution of viremia. Anti-
HCV IgM antibody responses are unreliably identified in
both acute and chronic phases, therefore IgM is not used as
a diagnostic marker of acute HCV infection. Detection of
HCV RNA remains the gold standard for diagnosing active
hepatitis C infections. Real-time PCR-based assay offers
the advantages of both reliability for the presence of viral
RNA and a broad dynamic range for quantitation down to 25
IU/mL. Determination of HCV genotype is useful in ad-
dressing therapy.
TREATMENT
The goal of HCV treatment is persistent eradication of viral
RNA 24 weeks after discontinuation of IFN-based therapies
and 12 weeks after discontinuation of direct-acting antivirals
(DAAs), also known as sustained virologic response. Treat-
ment of HCV infection reduces the burden of virus in the
liver by either completely eradicating HCV from the system
or reducing it to such low levels that the immune system is
able to control the virus to be undetectable in the blood-
stream. Strategies for preventing HCV vertical transmission
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are not yet available. Treatment of HCV-infected women of
childbearing age could reduce the risk of perinatal trans-
mission. Ribavirin (Food and Drug Administration [FDA]
pregnancy category X) is contraindicated during preg-
nancy for its significant teratogenic effects. Female pa-
tients and female partners of male patients using a ribavirin-
containing regimen should avoid pregnancy for at least
6 months after discontinuation of therapy. Birth defects
associated with the use of ribavirin during pregnancy
include torticollis, polydactyly, hypospadias, neonatal
tooth, glucose-6-phosphate dehydrogenase deficiency,
ventricular septal defect and cyst of fourth ventricle of the
brain. (18)
The only FDA-approved therapy available for CHC in
children ages 3 years and older is a combination of PEG-IFN
and ribavirin. This regimen is given to children with geno-
types 1 and 4 for 48 weeks. Children infected with HCV
genotypes 2 and 3 may require only 24 weeks of therapy,
similar to adults, but data to recommend this approach are
insufficient. Detailed guidance from the AASLD, IDSA, and
IAS-USA regarding testing, managing, and treating hep-
atitis C can be accessed at http://www.hcvguidelines.org.
FUTURE OPTIONS
DAAs have transformed the treatment of CHC. These
agents target nonspecific proteins of the virus and suc-
cessfully interrupt the HCV life cycle. They are classified
into 4 main groups: NS3/4A protease inhibitors (telaprevir,
boceprevir, simeprevir, etc); NS5B nucleos(t)ide polymerase
inhibitors such as sofosbuvir; NS5B non-nucleotide poly-
merase inhibitors such as dasabuvir; and NS5A inhibitors
(dacalastasvir, ledipasvir, and ombitasvir). DAAs are all oral,
IFN-free regimens that may achieve sustained virologic
response rates of 85% to 100% in adult patients with all
HCV genotypes. (19) Single-drug DAA regimen was asso-
ciated with the development of resistance, which was over-
come with combination therapy. Sofosbuvir and ledipasvir
are both category B drugs in pregnancy. Simeprevir is a
category C drug because of the significant adverse events
seen in animal studies (reduced fetal weights, increased
fetal skeletal variations, in utero fetal losses, and early
maternal deaths at high drug exposures). (20) Further
research is required to evaluate sofosbuvir and ledipasvir in
limiting neonatal transmission and maternal HCV treat-
ment in pregnancy or postpartum. DAA trials have unveiled
a significant response in patients and the possible eradication
of HCV in the near future. As of May 2016, 2 pediatric studies
using DAAs are currently underway (NCT#02486406;
NCT#02249182).
ISSUES SPECIFIC TO PREGNANT WOMEN AND INFANTS
HCV and Pregnancy
MATERNAL-FETAL TOLERANCE. A successful pregnancy repre-
sents a challenge for the maternal immune system. The
fetus is a semiallogeneic graft that shares both maternal and
paternal antigens and grows within the maternal uterus.
The maternal immune system is responsible for tolerating
the fetus and protecting both the mother and fetus from
external intruders. Several mechanisms develop during preg-
nancy to avoid deleterious effects (rejection) on the fetus,
including: (a) trophoblast cells express nonclassic major
histocompatibility complex molecules that avoid fetal cell
cytolysis by NK cells; (b) inhibition of T-cell proliferation
as a result of tryptophan catabolism by indoleamine 2,3-
dioxygenase (IDO) enzyme; (c) expression of Fas ligand by
the fetal trophoblast that may cause apoptosis of activated
maternal T cells; and (d) inhibition of complement activa-
tion by decay-accelerating factor (CD55) and membrane co-
factor protein (CD46). (21) More studies are needed to fully
understand the immune process behind the pregnancy.
Moreover, a shift from T-helper type 1 cell-mediated immu-
nity to T-helper type 2 that occurs as pregnancy prog-
resses may affect successful immunity against intracellular
pathogens.
NATURAL HISTORY DURING PREGNANCY. Most women with CHC
have uneventful pregnancies. Some of them may experience
an improvement in serum aspartate aminotransferase and
alanine aminotransferase levels along with fluctuation of
their HCV viral load; such changes may occur due to
suppression of cellular immunity by the maternofetal tol-
erance mechanisms. Interestingly, some studies have re-
ported an intense decrease in viremia within the first 3
months after delivery (22) and others have described reso-
lution of chronic infection during the postpartum period.
(23) These women have broader HCV-specific T-cell IFN-
g–producing responses, which might be responsible for a
robust cellular-mediated immune response. (24) The post-
partum period could potentially be a strategic time for HCV
treatment.
In a large population study from Washington State,
maternal HCV infection was associated with cholestasis
of pregnancy, gestational diabetes, and preterm birth. In-
creased risk for gestational diabetes was seen only when
combined with excessive gestational weight gain. (25)(26)
Infants born to HCV-infected women were more likely to be
of low birthweight, small for gestational age, and require
neonatal intensive care and assisted ventilation. (26) History
of maternal drug use was strongly associated with poor
neonatal outcomes. (27)
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VERTICAL TRANSMISSION. Mother-to-infant transmission has
become the primary route of HCV infection in children.
Intrauterine and intrapartum transmission have been doc-
umented in several studies. (28)(29)(30) Le Campion et al
(31) described several potential mechanisms for transplacen-
tal HCV transmission such as viral transcytosis, maternal
mononuclear cell trafficking, receptor-mediated entry into
and possibly infection of trophoblasts, and direct or indirect
injury of the placental barrier. Although HCV virions may
reach the placenta and have contact with the fetus, HCV
vertical transmission rates remain low, suggesting that the
placenta has a key role in controlling HCV infection.
Rates of HCV vertical transmission vary between studies.
Large prospective analyses estimate a rate between 7% and
15%. Ceci et al (32) found an HCV vertical transmission rate
of 13% in a prospective cohort of 2,447 mother-child pairs.
The European Paediatric HCV Network (EPHN) data sug-
gest a transmission rate of 6.2%. (33) An Italian study of
1,372 mother-child pairs estimated a rate of 7.1%. (34) A
recent study performed in Egypt, where the overall HCV
seroprevalence is almost 15 times higher than in the United
States, found an estimated HCV vertical transmission rate
of 14.3%. (35) The unique feature of HCV vertical trans-
mission is that not every transmission event results in
chronic infection. (32)(36)
Several studies demonstrated a positive correlation be-
tween HCV viral load and risk of perinatal transmission.
(17)(30)(37) Mothers with high HCV RNA are more likely
to transmit the virus than mothers with low or no viremia.
However, perinatal infection from mothers with an initial
negative or very low HCV RNA has been reported, likely
secondary to intermittent viremia. (33)(35)(36)
In studies performed before effective antiretroviral ther-
apy became available, maternal HIV-coinfection increased
the risk of HCV transmission to the infant 3- to 5-fold.
(38)(39) In a more contemporary study, Checa and colleagues
(40) found that no HCV-HIV coinfected women transmitted
HCV to their infants while they were receiving highly active
antiretroviral therapy, and their mean HCV viral load was
similar to that in HCV monoinfected mothers. Therefore,
good control of HIV in this subpopulation of pregnant
women could be a protective factor against HCV vertical
transmission.
Rupture of membranes for 6 or more hours and fetal
monitoring (scalp electrodes and intrauterine pressure ca-
theter) were associated with increased risk of HCV trans-
mission. (17)(33)(41) However, these findings were not
duplicated in another study. (42) The method of delivery
does not appear to have an impact on HCV vertical trans-
mission, (35) and cesarean delivery does not reduce risk of
Vol. 17 No. 9 SEPTEMBER 2016 e525
 transmission. (33)(34)(42) Current evidence does not sup-
port the use of cesarean delivery to prevent vertical trans-
mission of HCV, unless indicated for other reasons.
Differences in HCV genotype has not been linked with
varied rates of vertical transmission. (37)(43) Female in-
fants have a higher likelihood of acquiring HCV from their
mothers than male infants. (33)
Breastfeeding
HCV RNA has been detected in human milk and colostrum
at levels 100 to 1,000 times lower than in plasma. These low
virus levels are not associated with infection. (44)(45) Most
studies have not demonstrated increased transmission risk
with breastfeeding. (33)(41)(42)(46) An in vitro study sug-
gested that natural lipases within human breast milk damage
the lipid envelope of HCV and other viruses as a mechanism
to protect young infants from infection. (47) The American
Academy of Pediatrics (AAP) and The American Congress of
Obstetricians and Gynecologists do not contraindicate breast-
feeding in HCV-infected mothers. However, breastfeeding
should be avoided in the presence of mastitis, nipple bleed-
ing, or a postpartum flare of hepatitis with jaundice in the
mother.
Follow-up of Infants with Vertical Transmission of HCV
Infants with vertical transmission of HCV may develop only
episodic viremia, acute infection that resolves, or sustained
viremia, which evolves into chronic infection. Children
who have perinatally acquired hepatitis C are almost always
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asymptomatic. However, some infants may develop signif-
icant elevation of liver enzymes along with high levels of
viremia within the first year after birth. Interestingly, in up
to 50% of these infants, the infection will resolve sponta-
neously. (36)(40)(48) Older children have a lower rate of
spontaneous viral clearance—only 6% to 12% of cases. (49)
According to the EPHN, there are 3 categories for children
with vertical transmission of HCV infection (48):
1. Acute resolving infection: Children with apparent viral
clearance (about 20%)
2. Chronic asymptomatic infection: Children with inter-
mittent viremia, usually normal transaminase levels, and
rarely, hepatomegaly (50%)
3. Chronic active infection: Persistent viremia with frequent
abnormal transaminases and hepatomegaly in some cases
(about 30%)
CHC in children is a slow progressive disease. Liver his-
topathology usually shows minimal fibrosis, and rarely, cir-
rhosis after 15 to 20 years of infection. However, significant
liver disease can occur and fibrosis scores have a tendency
to be significantly higher in adolescents and young adults.
(50) Long-term complications of CHC can present in child-
hood but are infrequent. The risk of cirrhosis in childhood
is approximately 1% to 2%, and teenagers with HCV-
induced hepatocellular carcinoma have been reported. (50)
Diagnosis of HCV-exposed infants is more complex
because maternal IgG antibodies passively cross the pla-
centa and may persist for up to 18 months. The AAP rec-
ommends “The duration of presence of passive maternal
Figure. Suggested algorithm for evaluation
of the infant vertically exposed to hepatitis C
virus (HCV). IgG¼immunoglobulin G,
LTF¼liver function tests.
antibody in infants can be as long as 18 months. Therefore,
testing for anti-HCV should not be performed until after 18
months of age. If earlier diagnosis is desired, a nucleic acid
amplification testing (NAAT) to detect HCV RNA may be
performed at or after the infant’s first well-child visit at 1 to 2
months of age.” Testing is not recommended during the
first year after birth because treatment is only available for
children of age 3 years and older.
Children born to HCV-positive mothers are considered
infected if they have detectable HCV RNA for more than 6
months and/or they have persistence of anti-HCV anti-
bodies after 18 months of age. A positive HCV RNA indi-
cates infection but still leaves open the possibility that the
infection may spontaneously resolve over the next 1 to 2
years after birth. A suggested alternative would be to test
using HCV RNA PCR within the first few months after
birth, and then repeat the test several months later. If results
of both tests are negative, infection is unlikely. Any other
scenario requires further evaluation and possible consulta-
tion with an HCV-experienced specialist. Immunizations are
highly encouraged in HCV-exposed and -infected infants,
especially vaccines against hepatitis A and B. Coinfection
with other hepatitis viruses can lead to significant morbidity
and mortality. A suggested algorithm for the evaluation of
an HCV-exposed infant is outlined in the Figure.
Looking into the Crystal Ball
Diagnosis of HCV in pregnant women can be made during
prenatal care through HCV serology. However, prenatal
screening is only recommended based on maternal risk
factors. Universal hepatitis C screening during pregnancy
could identify mothers and infants at risk who may not be
recognized otherwise. Some studies support antenatal uni-
versal HCV screening as a cost-effective tool for early id-
entification and treatment. (51)(52) DAAs offer very high
(>95%) sustained response rates with fewer apparent se-
vere adverse effects compared with PEG-IFN and ribavirin.
Studies have repeatedly demonstrated that pregnant women
who are negative for HCV RNA do not transmit the virus to
their infants. Therefore, it appears logical that with the
availability of highly efficacious, safe antivirals, at some
point they could be used to treat pregnant women and
ultimately prevent vertical transmission.
In conclusion, although vertical transmission rates of
HCV are variable and spontaneous clearance rates are sub-
stantial, there is still a subpopulation of HCV-infected in-
fants who will develop CHC. Few risk factors have been
associated with vertical transmission of HCV, and no inter-
ventions are available to prevent such transmission. Data
are needed for a validated diagnostic algorithm to accurately
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confirm or exclude infection in HCV-exposed infants. Pre-
ventive measures and therapeutic options for HCV vertical
transmission may not be not far away.
American Board of Pediatrics
Neonatal–Perinatal Content
Specifications
• Know the rationale, methods, and interpretation of results of
screening for maternal infections such as rubella, CMV, viral
hepatitis, HIV, and syphilis.
• Know the epidemiology, prevention, and pathogenesis of
perinatal infections with hepatitis A, hepatitis B, and hepatitis C.
• Know the clinical manifestations, diagnostic features,
management, and complications of perinatal infections with
hepatitis A, hepatitis B, and hepatitis C.
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 NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.
aappublications.org/content/journal-cme.

1. A woman presents to the clinic for a routine prenatal visit at 24 weeks and notes that she NOTE: Learners can take
has found out that her partner has been diagnosed with hepatitis C virus (HCV) infection. NeoReviews quizzes and
Which of the following statements concerning HCV is correct? claim credit online only
A. Hepatitis C is a transient infection that has no long-term implications for patients, at: http://Neoreviews.org.
but may cause microcephaly if transmitted during pregnancy.
B. Breastfeeding will be contraindicated for this mother for the first 6 months after To successfully complete
delivery if she tests positive for HCV. 2016 NeoReviews articles
C. The use of acyclovir in the last trimester has been highly effective in reducing for AMA PRA Category 1
perinatal transmission of HCV. CreditTM, learners must
D. Mother-to-child transmission is the primary route of HCV acquisition in children. demonstrate a minimum
E. It is unlikely that the mother has HCV infection, because she would have expe- performance level of 60%
rienced an acute illness and displayed symptoms such as jaundice. or higher on this
2. A woman is known to have chronic hepatitis C and presents to the clinic with pregnancy at assessment, which
16 weeks’ gestation. Which of the following statements about treatment options for HCV is measures achievement of
correct? the educational purpose
A. Ribavirin is the primary method of treatment of HCV in pregnant women. and/or objectives of this
B. The goal of HCV treatment is persistent eradication of viral RNA at 24 weeks after activity. If you score less
discontinuation of interferon-based therapies, and 12 weeks after discontinuation than 60% on the
of direct-acting antivirals. assessment, you will be
C. Strategies to prevent HCV vertical transmission outlined by the American Academy given additional
of Pediatrics include use of both direct-acting antivirals and interferon-based opportunities to answer
therapies. questions until an overall
D. Children infected with HCV cannot receive treatment until they are 12 years old. 60% or greater score is
E. Direct-acting antivirals can only be given intravenously. achieved.
3. A mother with chronic hepatitis C infection is admitted to the labor and delivery unit and is
in active labor. Which of the following statements regarding vertical transmission of HCV is This journal-based CME
correct? activity is available
A. The likelihood of HCV vertical transmission varies between 50% and 70% de- through Dec. 31, 2018,
pending on the population studied. however, credit will be
B. Rupture of membranes for more than 6 hours is a high risk factor for transmission, recorded in the year in
with cesarean delivery recommended to prevent prolonged rupture. which the learner
C. Coinfection with human immunodeficiency virus (HIV) leads to almost 100% completes the quiz.
transmission of HCV infection, regardless of HIV status of the infant.
D. There is a positive correlation between HCV viral load and risk of perinatal
transmission, with mothers having higher HCV RNA more likely to transmit the virus
than mothers with low or no viremia.
E. Male infants are more likely than female infants to acquire HCV infection from their
mothers.
4. A female infant is born to a mother who has tested positive for HCV. Which of the following
statements is correct about infants who are infected with HIV via vertical transmission?
A. Children who have perinatally acquired hepatitis C are almost always
asymptomatic.
B. Of those infants with elevated liver enzymes during the first year, 95% will go on to
have lifelong chronic hepatitis.
C. Approximately 90% of children with vertically transmitted HCV infection will have
acute resolving infection with apparent viral clearance.
D. A small subset (10%) of infants are labeled as having chronic asymptomatic
infection and have intermittent elevation of transaminase levels and hepatomegaly.

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 E. Chronic active infection refers to infants who will go on to have fulminant liver
failure and require a transplant before 3 years of age.
5. The mother of the infant who has been exposed asks about testing and management
during the first year. Which of the following statements regarding diagnosis and follow-up
of this infant is correct?
A. A positive HCV RNA before age 6 months indicates that this patient will have
lifelong HCV infection.
B. Maternal anti-HCV IgG antibodies do not cross the placental barrier.
C. Immunizations are highly encouraged in HCV-exposed and infected infants,
particularly vaccines against hepatitis A and hepatitis B.
D. The optimal time to perform the HCV RNA test is within the first week after delivery.
E. Testing for anti-HCV antibodies can be a helpful adjunct test in the first year when
the diagnosis is unclear by HCV RNA.

Parent Resources from the AAP at HealthyChildren.org

Hepatitis C Mother to Child Transmission
• https://www.healthychildren.org/English/health-issues/conditions/abdominal/Pages/Hepatitis-C.aspx
• Spanish: https://www.healthychildren.org/spanish/health-issues/conditions/abdominal/paginas/hepatitis-c.aspx

Vol. 17 No. 9 SEPTEMBER 2016 e531

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 Hepatitis C Mother-to-Child Transmission
Leidy Tovar Padua and Ravi Jhaveri
NeoReviews 2016;17;e521
DOI: 10.1542/neo.17-9-e521

Updated Information & including high resolution figures, can be found at:
Services http://neoreviews.aappublications.org/content/17/9/e521
References This article cites 48 articles, 13 of which you can access for free at:
http://neoreviews.aappublications.org/content/17/9/e521#BIBL
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 Hepatitis C Mother-to-Child Transmission
Leidy Tovar Padua and Ravi Jhaveri
NeoReviews 2016;17;e521
DOI: 10.1542/neo.17-9-e521

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/17/9/e521

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