CONGENITAL CYTOMEGALOVIRUS INFECTION

Alexander K.C. Leung, MBBS, FRCPC, FRCP(UK & Ire), FRCPCH,

Reginald S. Sauve, MD, FRCPC, and H. Dele Davies, MD, FRCPC
Alberta, Canada

Cytomegalovirus (CMV) is the most common congenital infection in humans. Congenital CMV
infection can follow either a primary or recurrent maternal infection, but the likelihood of fetal infection and the risk of associated damage is higher after a primary infection. Approximately 90% of
congenitally infected infants are asymptomatic at birth. Jaundice, petechiae, and
hepatosplenomegaly are the most frequently noted clinical triad in symptomatic infants. More frequent and more severe sequelae occur in symptomatic infants, notably psychomotor hearing loss
and retardation. Congenital CMV infection can be diagnosed by isolation of the virus from the urine
or saliva within the first three weeks of life. Rapid diagnosis can be accomplished by detection of
CMV DNA by DNA amplification or hybridization techniques. (J Natl MedAssoc. 2003;95:213-218.)

Key words: cytomegalovirus + primary

and recurrent infection * psychomotor
retardation * hearing loss
Cytomegalovirus (CMV) infection is the
most frequent congenital infection worldwide
and is diverse in its clinical manifestations.1 The
fetus can be infected by either a newly acquired
(primary) maternal infection or a recurrent
(reactivated) maternal infection.2 The likelihood
of fetal infection and the risk of associated damage and sequelae is higher after a primary infection.3 Although most congenitally infected
2003. From the Deparment of Pediatrics, the University of
Calgary and the Alberta Children's Hospital, Calgary, Alberta,
Canada. Address correspondence to: Dr. Alexander K.C. Leung,
#200, 233-16th Avenue NW, Calgary, Alberta T2M OH5, Canada;
telefax (403) 230-3322; e-mail [email protected]
213 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

infants are asymptomatic at birth, congenital

CMV infection is a leading cause of sensorineural hearing loss, mental retardation, and
neurologic deficits.4

DESCRIPTION OF THE VIRUS

CMV is the largest and most complex member of the Herpesviridae family of DNA viruses.5 The genome is composed of a linear doublestranded DNA, approximately 240 kilobases in
size (150x106 daltons), and is capable of isomerization.5,6 The genome has been completely
sequenced and shown to contain non-overlapping open-reading frames for more than 200
potentially immunologic proteins.1 The genome
is surrounded by an icosahedral capsid composed of 162 capsomeres.5 The capsid is surrounded by a poorly defined amorphous tegment
which is itself surrounded by lipid envelope, givVOL. 95, NO. 3, MARCH 2003

CONGENITAL CYTOMEGALOVIRUS INFECTION

ing the complete and mature viral particle a

diameter of about 200 n.5,7 The virus lacks the
enzyme thymidine kinase, which renders it
resistant to those antiviral agents that depend on
this enzyme for their action.
The virus is named for the intranuclear and
intracytoplasmic inclusions seen with symptomatic disease, cytomegalic inclusion disease.8
CMV is highly species specific, and humans are
the only known reservoir for disease among
humans.8

EPIDEMIOLOGY
Congenital CMV infection occurs in approximately 0.2%-2.5% of all live births; infection is
more prevalent in underdeveloped countries and
among lower socioeconomic groups in developed countries, where crowding is more common.4,5,7A9'10 Both primary and recurrent infections in the mother during pregnancy may result
in congenital CMV infection. On average, 1-4%
of susceptible women acquire primary CMV
infection during their pregnancy.1I0"
Approximately 10% of sero-positive pregnant
women have reactivation of CMV infection during their pregnancy. 10 The transmission rate after
primary infection is about 40%, whereas the
transmission rate after recurrent infection is
about 1-3%.12-14

PATHOGENESIS AND PATHOLOGY

Congenital CMV infection results from
transplacental transmission of the virus during
maternal viremia.15 Maternal viremia is more
likely to occur with primary than with recurrent
infection. After transplacental transmission, the
virus spreads through the fetus by a hematogenous route. Infection at an earlier gestational age
often correlates with a less favorable outcome. 13,14,16

Infants born to mothers with primary CMV

infection during pregnancy are more likely to
have symptoms at birth. The presence of maternal antibody to CMV before conception provides
substantial protection against intrauterine transJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

mission of the virus and severe fetal infections. 17

The protection, however, is incomplete, and congenital CMV infection may follow recurrent
maternal infection. 17,18 More recent studies suggest symptomatic congenital CMV infection
after a recurrent maternal infection occurs more
frequently than previously documented.17'19'20
Although CMV affects most cell types, it has
a special affinity for epithelial cells, ependymal
cells lining the ventricles, the organ of Corti, and
the neurons of the eighth cranial nerve.6 The
characteristic pathologic features include
cytomegaly, intranuclear inclusions ("owl's eye"
appearance), intracytoplasmic inclusions, and
multinucleated giant cells.

CLINICAL MANIFESTATIONS
About 90% of congenitally infected infants are
asymptomatic at birth.2'5 Jaundice (62%), petechiae (58%), and hepatosplenomegaly (50%) are the
most frequently noted classical triad (Figure 1).10
Other clinical manifestations include oligohydramnios, polyhydramnios, prematurity, intrauterine growth retardation, nonimmune hydrops, fetal
ascites, hypotonia, poor feeding, lethargy, thermal
instability, cerebral ventriculomegaly, microcephaly, intracranial calcifications usually
periventricular in distribution, "blueberry muffin"
spots, and chorioretinitis.5'10'21-23 Sensorineural
hearing loss develops in 30% of symptomatic
infants at birth.2 Infants with symptomatic CMV
infection may be at increased risk for congenital
malformations such as inguinal hernia in males,
high-arched palate, defective enamelization of the
deciduous teeth, hydrocephalus, clasp thumb
deformity, and clubfoot.24 Some affected infants
may develop hepatitis, pneumonia, osteitis, and
intracranial hemorrhage.25

LABORATORY DIAGNOSIS
Congenital CMV infection can be diagnosed by
isolation of the virus from the urine or saliva within the first three weeks of life. '14 This can be
accomplished by traditional virus culture methods
which may take one to two weeks to obtain a result
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CONGENITAL CYTOMEGALOVIRUS INFECTION

or rapid culture methods ("shell vial assay")

using centrifugation to enhance infectivity and
monoclonal antibody to detect early antigens in
infected tissue culture cells which may yield
results in 24 hours.4'20'26 Rapid diagnosis of
CMV can also be accomplished by detection of
CMV DNA by DNA amplification techniques
via the polymerase chain reaction (PCR) or DNA
hybridization techniques.26'27 Culture, however,
maintains a slight advantage over PCR in terms
of specificity.28
The presence of CMV-specific IgM in cord
blood or in the infant's blood within the first
three weeks of life suggests the diagnosis of congenital CMV infection.10'14 However, CMVspecific IgM can only be detected in about 70%
of congenitally infected newborn infants.10'14
On the other hand, a negative CMV-specific IgG
titer in cord blood excludes the diagnosis of congenital CMV infection whereas its presence may

merely imply passive transfer from the mother or

may indicate a congenital infection. 10
Prenatal detection of fetal infection can be
established by isolation of the virus from the
amniotic fluid obtained by amniocentesis.26 A
negative culture does not exclude fetal infection
especially if the amniocentesis is carried out too
early with respect to the maternal infection.7'28
Diagnosis of a primary maternal CMV infection
can be established by the demonstration of an
IgG seroconversion during pregnancy, especially
if accomplished by the detection of CMV-specific IgM antibodies in the maternal blood.5'29 Fetal
abnormalities detected by prenatal ultrasonography generally indicate more severe fetal disease.
In symptomatic infants, anemia, thrombocytopenia, hyperbilirubinemia, atypical lymphocytosis, elevated serum transaminases, and elevated cerebrospinal fluid protein may be found.
Skull radiographs, CT scan, and MRI may

7f. ...r.,...X... _~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

,&.

...''

_..:.

Figure 1. A newborn infant with symptomatic congenital CMV infection presenting with petechiae,

jaundice, and hepatosplenomegaly.

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CONGENITAL CYTOMEGALOVIRUS INFECTION

demonstrate periventicular calcifications and

venticulomegaly. Radiographs of the long bones
many show longitudinal radiolucent streaks
("celery stalk" appearance).

DIFFERENTIAL DIAGNOSIS
Congenital CMV infection should be distinguished from other congenital infections such as
toxoplasmosis, rubella, herpes simplex, and
syphilis. Such distinction can be done both clinically and serologically. Toxoplasmosis is more
likely to be associated with chorioretinitis,
microphthalmia, hydrocephalus, and scattered
cerebral calcifications. Petechial and purpuric
eruptions, which are common in symptomatic
congenital CMV infections, are rare in congenital toxoplasmosis; the latter often presents with a
maculopapular rash. The presence of congenital
heart disease and cataracts points to congenital
rubella infection. Vesicular skin lesions or scarring present at birth suggest congenital herpes
simplex infection. Rhinitis and radiological evidence of osteochondritis and epiphysitis favor
the diagnosis of congenital syphilis. Other differential diagnoses include bacterial sepsis, erythroblastosis fetalis, and metabolic disorders
such as galactosemia and tyrosinemia.

PROGNOSIS
Infants with symptomatic congenital CMV
infection have a mortality rate of 10-15%o.4
Approximately 50-90% of symptomatic survivors have long-term sequelae such as sensorineural hearing loss, mental retardation,
developmental delay, cerebral palsy, epilepsy,
ocular abnormality, and microcephaly.4,9"10,30
The former occurs in up to 50% of affected
infants.4 The worst prognosis occurs in infants
born to mothers with primary CMV infection
during pregnancy, infants with CMV-specific
IgM in the cord blood, and infants symptomatic
at birth, particularly those with microcephaly,
intracranial calcifications, chorioretinitis, or
raised cerebrospinal fluid protein.5'15'31 Some of
the late complications such as hearing loss and
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

central nervous system damage presumably

result from ongoing viral replication.28
Approximately 7-15% of asymptomatic
infants have sensorineural hearing loss.4,30
Whether these infants are at increased risk of
mental retardation is controversial.32'33
Hanshaw et al compared 44 children with
asymptomatic congenital CMV infection with
both matched and random controls and found
school failure and deafness to be associated with
asymptomatic congenital CMV infection.32 On
the other hand, Kashden et al. compared 204
children who had asymptomatic congenital
CMV infection with 177 uninfected siblings and
found that there was no statistically significant
difference between the two groups on intellectual measure.33

MANAGEMENT
Ganciclovir, a synthetic acyclic nucleotide
analog of guanine, is phosphorylated to a
triphosphate within the cell and acts as an
inhibitor of viral DNA synthesis. Preliminary
data have shown ganciclovir effective in the
treatment of symptomatic congenital CMV
infection.34 A phase II study with ganciclovir
showed hearing improvement or stabilization in
five of 30 infants with symptomatic congenital
CMV infection at six months or later.34 During
the treatment period, quantitative excretion of
CMV in the urine decreased. However, after cessation of therapy, viruria returned to near pre
treatment levels. A phase III randomized trial
suggests that ganciclovir may benefit infants
with severe congenital CMV infection.4 Central
nervous system damage that has already
occurred will not be reversed, but ongoing viral
replication causing postnatal damage is controlled campared to untreated CMV-infected
controls. The value of ganciclovir for the prevention or treatment of hearing loss in asymptomatic children has not been determined. Side
effects of ganciclovir include bone narrow suppression and potential gonadal toxicity.1
Presently there is insufficient data to justify the
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CONGENITAL CYTOMEGALOVIRUS INFECTION

routine use of ganciclovir in the treatment of

congenital CMV infection.35
Children with congenital CMV infection are
at risk for hearing loss, mental retardation, psychomotor delay, cerebral palsy, and impaired
vision. This is especially so for the hearing loss,
for as many as 80% of cases are of late-onset or
progressive.6 As such, children with congenital
CMV infection should have long-term audiologic, neurodevelopmental, and ophthalmic followup for early identification of these problems.

PREVENTION
Women of childbearing age should practice
meticulous personal hygiene, such as avoidance of
contact with urine or saliva of others and proper
hand-washing after such contact. Nurses who
practice good handwashing do not have increased
rates of CMV acquistition, but daycare workers
often do, suggesting that barrier precautions are
effective in interrupting transmission. Several candidate vaccines are under development. These vaccines are urgently needed and ultimately may be
an important preventive measure.36

ACKNOWLEDGMENT
The authors are grateful to Miss Enrica Ng
for her expert secretarial assistance and Mr.
Sulakhan Chopra of the University of Calgary
Medical Library for help in the preparation of
the manivqcrint-

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