Congenital cytomegalovirus infection: Clinical

features and diagnosis

Author:
Gail J Demmler-Harrison, MD
Section Editors:
Morven S Edwards, MD
Leonard E Weisman, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2021. | This topic last updated: Apr 01, 2021.
●What's New
Newborn screening for congenital CMV infection (April 2021)
Universal screening for congenital cytomegalovirus (CMV) infection has been
proposed, but the optimal approach to screening remains uncertain. In a study
involving >12,000 newborns who were screened using polymerase chain reaction
(PCR) testing of dried blood spots (DBS), the sensitivity for detecting congenital
CMV infection ranged from 73 to 77 percent [1]. These estimates are considerably
higher than previous reports, likely reflecting improvements in the methodologies for
CMV PCR testing of newborn DBS. While these findings provide preliminary support
for incorporating congenital CMV screening into newborn screening programs,
additional data are needed before this can be implemented as a routine.
(See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section
on 'Universal newborn screening'.)
Read more

INTRODUCTION Congenital cytomegalovirus (CMV) infection is common

worldwide. It is the leading cause of nonhereditary sensorineural hearing loss

(SNHL) and can cause other long-term neurodevelopmental disabilities, including
cerebral palsy, intellectual disability, vision impairment, and seizures. At birth, most
infants with congenital CMV are asymptomatic, but approximately 10 percent have
symptoms.

The clinical features and diagnosis of congenital CMV infection will be reviewed
below. The management and outcome of congenital CMV infection, other TORCH
infections, CMV in pregnancy, and CMV infections in older infants and children are
discussed separately:

●(See "Congenital cytomegalovirus infection: Management and outcome".)

●(See "Overview of TORCH infections".)
●(See "Cytomegalovirus infection in pregnancy".)
●(See "Overview of cytomegalovirus infections in children".)
 TERMINOLOGY Infants with congenital CMV infection are classified

according to the presence or absence of apparent symptoms at the time of birth.

●The term "symptomatic" refers to infants with one or more symptoms at birth.
(See 'Symptomatic neonate' below.)
●We use the term "primary neurophenotype" to refer to patients with only
central nervous system manifestations. This is a newly described category of
symptomatic infants, and the use of this term in the published literature is
inconsistent. (See 'Primary neurophenotype' below and 'Neuroimaging' below.)
●The term "asymptomatic" refers to infants with no apparent symptoms at birth,
although some of these infants may develop hearing loss or subtle symptoms
later in life. (See 'Asymptomatic infection' below.)
●The term "asymptomatic with isolated hearing loss" refers to infants with
isolated hearing loss at birth but no other symptoms. In studies of congenital
CMV infection after the advent of universal newborn hearing screening,
categorization of these infants as "symptomatic" or "asymptomatic" is
inconsistent. Historically, they were often classified as "asymptomatic" because
the hearing loss may not have been detected at birth. However, with universal
newborn hearing screening, many such infants come to medical attention in the
newborn period. We consider these infants to represent a distinct category
because they are not truly asymptomatic, but their disease is generally milder
than that of symptomatic infants.

VIROLOGY CMV is a member of the herpesvirus family, along with

Epstein-Barr virus, herpes simplex viruses-1 and -2, varicella-zoster virus, and
human herpesviruses (HHV)-6, -7, and -8. These viruses share structural properties,
including a genome of double-stranded linear DNA, a virus capsid of icosahedral
symmetry, and a viral envelope [1].
Like other herpesviruses, CMV has the biologic properties of latency and
reactivation. With latent CMV infection, a low level of virus replication is detectable
and the viral genome may be present in the peripheral blood mononuclear cells and
bone marrow. Recurrent infections with CMV occur through reactivation of the host's
endogenous strain of CMV or reinfection with a new exogenous strain. CMV strains
may compartmentalize such that the strain in the urine, for example, may be different
from that in the blood, eye, or central nervous system [1].
CMV replicates slowly, often taking as long as 24 hours to produce progeny in
infected cells and several days to weeks to produce a visible cytopathic effect in
laboratory cell lines. Clinical samples with high titer of virus, such as urine or saliva
samples from congenitally infected newborns, have multiple foci of cytopathic effect
visible within a few days of incubation, whereas clinical samples with low titer of virus
may require one to three weeks of incubation to show classic focal cytopathic effect
(picture 1).
 EPIDEMIOLOGY Congenital CMV infection occurs worldwide, with a

prevalence of 0.6 percent in developed countries [2,3]. Approximately 40,000 infants

are born with congenital CMV infection annually in the United States [1].
The rate of congenital CMV infection, but not necessarily congenital CMV disease,
is proportional to the seroprevalence of CMV in women of childbearing years. In
areas of high CMV seroprevalence (80 to 100 percent), congenital CMV infection
rates range from 1 to 5 percent, whereas in areas of relatively low CMV
seroprevalence (40 to 70 percent), congenital CMV infection rates range from 0.4 to
2 percent [1,2,4-7].
Maternal CMV infection during pregnancy most often results from close contact with
young children, particularly children attending daycare centers [8,9]. The risk of
vertical transmission to the fetus is far higher with primary maternal infection than
with recurrent infection (32 versus 1.4 percent) [2]. Other factors that can influence
transmission of CMV infection during pregnancy include maternal age and parity
(increased risk in younger primigravid women) [2]. (See "Cytomegalovirus infection
in pregnancy", section on 'Maternal CMV infection'.)
Infants infected as a result of a primary maternal infection are more likely to have
symptoms at birth and suffer long-term sequelae than those infected as a result of
maternal recurrent CMV infection. The risk of hearing loss, however, appears to be
similar in both groups. [3,10,11].
Sequelae appear to be more severe when infection is acquired earlier in pregnancy,
particularly in the first trimester [12]. However, symptomatic congenital CMV
infection may result from maternal infection at any time during pregnancy.

CLINICAL MANIFESTATIONS

In utero — The fetus may be silently infected or manifest CMV disease in utero. The
diagnosis and management of congenital infection often begins while the fetus is still
in utero. Findings on prenatal ultrasound that may suggest CMV disease in the fetus
include periventricular calcifications (image 1), ventriculomegaly (image 2),
migrational abnormalities of the brain (polymicrogyria, pachygyria, and
lissencephaly), microcephaly, hyperechogenic fetal bowel (image 3), fetal growth
restriction, ascites and/or pleural effusion (image 4A-B), and hepatosplenomegaly.
These and other findings are reviewed in a separate topic review.
(See "Cytomegalovirus infection in pregnancy", section on 'Ultrasound markers and
monitoring'.)
Symptomatic neonate — Approximately 10 percent of neonates with congenital
CMV infection have symptoms at birth. Clinical findings in the symptomatic neonate
can be similar to those in other congenital infections (table 1).
Clinical findings
Common findings — Clinical findings in the symptomatic neonate (picture 2) are
similar to those in other congenital infections [6,7,13-16]:
●Petechiae (50 to 75 percent)
 ●Jaundice at birth (40 to 70 percent)
●Hepatosplenomegaly (40 to 60 percent)
●Small size for gestational age (SGA; 40 to 50 percent)
●Microcephaly (35 to 50 percent)
●Sensorineural hearing loss (SNHL; present at birth in approximately 35
percent, delayed SNHL can also occur)
●Lethargy and/or hypotonia (approximately 30 percent)
●Poor suck (approximately 20 percent)
●Chorioretinitis (10 to 15 percent)
●Seizures (5 to 10 percent)
●Hemolytic anemia (5 to 10 percent)
●Pneumonia (5 to 10 percent)
SNHL is a common sequela of congenital CMV and is detected in one-third to one-
half of infants with symptomatic disease [1,3,15,17,18]. The hearing loss associated
with symptomatic congenital CMV may be detectable at birth, but, in 18 to 30 percent
of cases, it has delayed onset. In a systematic review, hearing loss was bilateral in
71 percent of children with symptomatic congenital CMV (compared with 43 percent
of children with asymptomatic congenital CMV) [3]. The hearing loss associated with
symptomatic congenital CMV is often progressive (18 to 63 percent of cases)
[14,15,17,19,20] and eventually becomes severe to profound in the affected ear(s)
of 78 percent of affected children [3].
Chorioretinitis is the most common ocular abnormality in symptomatic infants and
correlates with poor long-term neurodevelopmental outcome. Other findings on eye
examination may include retinal scars, optic atrophy, central vision loss, or
strabismus [21,22]. Cataracts and microphthalmos are not typical in infants with
congenital CMV and strongly suggest a disease other than CMV [23].

Ascites, myocarditis, cardiomyopathy, ventricular trabeculations, and enterocolitis

are less common findings in symptomatic neonates.

Endocrinopathies, such as Graves' disease and diabetes insipidus, and renal

disease, such as nephrotic syndrome, have been reported in newborns with
symptomatic congenital CMV, but it is unclear whether these conditions are caused
by CMV [24-26].
Life-threatening disease — Approximately 8 to 10 percent of newborns with
symptomatic congenital CMV infection have severe, life-threatening disease. Life-
threatening manifestations may include a sepsis-like illness, myocarditis, viral-
induced hemophagocytic lymphohistiocytosis, and/or other severe end-organ
involvement. Premature infants and infants with primary immune disorders of T cells
or natural killer cells are at greater risk for mortality from congenital CMV infection.
(See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical
manifestations' and "CD3/T cell receptor complex disorders causing
immunodeficiency" and "NK cell deficiency syndromes: Clinical manifestations and
diagnosis", section on 'Clinical features of NK disorders'.)
Many infants with fulminant disease at presentation die within days or weeks despite
antiviral treatment and neonatal intensive care supportive measures. Mortality
among such infants can be as high as 30 percent, whereas the overall mortality rate
among infants with congenital CMV infection is approximately 4 to 8 percent within
the first year of life [6,23,27].
Most infants die from viral-associated hemophagocytic syndrome or severe end-
organ disease of the liver, lungs, bone marrow, or central nervous system [6,7,28].
In survivors, jaundice and hepatosplenomegaly may subside, but neurologic
sequelae (eg, microcephaly, intellectual disability, cerebral palsy, and hearing
disorders) persist. (See "Congenital cytomegalovirus infection: Management and
outcome", section on 'Outcome'.)
Premature infants — Twenty-five to 35 percent of infants with symptomatic
congenital CMV are born at <37 weeks gestation [16,17]. Premature neonates <32
weeks gestation with symptomatic congenital CMV are more likely to have
pneumonitis, signs of viral sepsis, thrombocytopenia, and coinfections and less likely
to have microcephaly or intracranial calcifications than term neonates [1,7,13,29].
Laboratory findings — Typical laboratory abnormalities associated with
symptomatic congenital CMV include [1,6,7,14-17]:
●Elevated liver transaminases (50 to 83 percent)
●Thrombocytopenia (48 to 77 percent)
●Elevated direct and indirect serum bilirubin (36 to 69 percent)
Other less common findings include hemolytic anemia, neutropenia, lymphopenia,
lymphocytosis, thrombocytosis, or leukemoid reaction. In newborns who undergo
lumbar puncture, cerebrospinal fluid protein may be elevated (46 percent in one case
series) [16].
Neuroimaging — Imaging of the brain with ultrasonography, unenhanced
computed tomography (CT) (image 5A-B), or magnetic resonance imaging (MRI)
(image 6) demonstrates abnormalities in 70 percent of infants with symptomatic
congenital CMV infection [30-34]. Findings on neuroimaging include:
●Intracranial calcifications, usually periventricular (34 to 70 percent)
●Lenticulostriate vasculopathy (27 to 68 percent)
●White matter disease (22 to 57 percent)
●Ventriculomegaly (10 to 53 percent)
●Migrational abnormalities, including focal polymicrogyria, pachygyria, and
lissencephaly (10 to 38 percent)
●Periventricular leukomalacia and cystic abnormalities (11 percent)
Additional findings that have been reported include ventricular septations and
adhesions, cerebral atrophy, corpus callosum dysgenesis, and cerebellar hypoplasia
[30,33,34].
Abnormalities on cranial imaging, particularly microcephaly, intracranial
calcifications, and migrational abnormalities, correlate with poor long-term
neurodevelopmental outcome [30,31,35]. (See "Congenital cytomegalovirus
infection: Management and outcome", section on 'Outcome'.)
Primary neurophenotype — Some infants present with primarily neurologic
findings (what we refer to as the "primary neurophenotype"). These infants lack the
typical somatic manifestations, such as jaundice, petechiae, or
hepatosplenomegaly. They may appear completely healthy at birth or may have mild
microcephaly. They usually are not diagnosed with congenital CMV infection at birth
unless they are cared for at a center where all newborns are screened for CMV. As
they grow, they develop more significant microcephaly and neurologic
manifestations (eg, global developmental delay, abnormal tone, seizures). A
presentation similar to a genetic leukodystrophy has also been described [36]. If
neuroimaging is performed, it typically shows polymicrogyria or other cortical
dysplasia (see 'Neuroimaging' above). A high index of suspicion is necessary to
identify congenital CMV infection as the etiology.
Asymptomatic infection — Approximately 90 percent of newborns who are
congenitally infected with CMV are apparently asymptomatic at birth. Subtle
differences, such as lower birth weight and slightly earlier gestational age, have been
observed in newborns with asymptomatic congenital CMV infection [10].
Ten to 15 percent of apparently asymptomatic newborns experience SNHL
[3,11,37]. (See 'Isolated hearing loss' below.)
Ocular abnormalities, including retinal lesions and strabismus, occur in 1 to 2 percent
of infants with apparently asymptomatic congenital CMV but are rarely sight-
threatening [21,22,38].
Abnormal brain imaging findings of periventricular leukomalacia, ventriculomegaly,
and punctate calcifications have been observed in 5 to 20 percent of otherwise
asymptomatic congenitally infected newborns (image 7).
Isolated hearing loss — Approximately 10 to 15 percent of apparently
asymptomatic newborns with congenital CMV infection experience SNHL in infancy
and early childhood; by age 18 years, up to 25 percent experience SNHL
[3,11,18,37,39]. Some affected newborns have congenital hearing loss and may fail
newborn hearing screening in one or both ears. In a systematic review of 37
observational studies, children with asymptomatic congenital CMV infection were
less likely to have delayed-onset SNHL compared with symptomatic patients (9
versus 18 percent) and less frequently had bilateral severe to profound hearing loss
(43 versus 65 percent) [3]. The two groups had similar rates of progressive hearing
loss (approximately 20 percent) and fluctuating hearing loss (approximately 20 to 25
percent). In a study of 92 infants with asymptomatic congenital CMV infection, 20
children (22 percent) developed SNHL over a median follow-up of 17 years, including
nine with congenital/early-onset SNHL and 11 with delayed-onset (at a median age
of five years) [40]. Frequency-specific hearing thresholds were worse in ears with
congenital/early-onset compared with delayed-onset SNHL. The severity of SNHL
worsened over time in both groups. Approximately 2 percent of children with
otherwise asymptomatic congenital CMV infection eventually develop SNHL severe
enough to qualify for cochlear implantation [39]. With evolving considerations for
unilateral SNHL and unilateral early cochlear implantation procedures, this
percentage may be even higher. (See "Hearing loss in children: Treatment", section
on 'Cochlear implants'.)
Universal newborn hearing screening programs may identify some of these
otherwise asymptomatic infants. In a study of 572 newborns who failed newborn
hearing screening, 6 percent were found to have congenital CMV infection; 75
percent of infants with congenital CMV infection were identified solely on the basis
of the abnormal newborn hearing screen [41]. Studies in older infants and children
indicate that 10 to 20 percent of hearing-impaired children have hearing loss as a
result of congenital CMV [3]. (See 'Newborn screening for congenital
cytomegalovirus' below and "Screening the newborn for hearing loss".)
Late complications — Approximately 70 to 80 percent of infants who are
symptomatic at birth develop late complications that may include (see "Congenital
cytomegalovirus infection: Management and outcome", section on 'Outcome')
[1,23,42]:
●Hearing loss requiring hearing aids or cochlear implantation
●Vision impairment requiring glasses or corrective surgery
●Dental abnormalities
●Intellectual disability and delayed psychomotor development
●Behavioral problems such as inattention and hyperactivity
●Neuromuscular problems such as cerebral palsy and associated
neuromuscular scoliosis and/or hip dislocation and dysplasia
Hearing loss is by far the most common late sequela seen in asymptomatic
congenitally infected infants, occurring in up to 25 percent by age 18 years
[3,11,37,39,40]. As discussed above, hearing loss often progresses over time
[40,43] (see 'Isolated hearing loss' above). Thus, both ears should be closely
monitored for progression of known hearing loss or emergence of new hearing loss
in the normal hearing ear [43]. Vestibular and balance problems can also occur, with
or without associated SNHL [44].
Some studies have identified neurocognitive and language delays in children with
asymptomatic congenital CMV, but others found no lasting cognitive sequelae [45-
48]. If children with asymptomatic congenital CMV differ cognitively from children
without congenital CMV infection, the differences are likely to be subtle, involve one
area or domain of learning, or require in-depth testing to detect. Children born with
asymptomatic congenital CMV infection do not appear to have increased risk of
behavioral differences (eg, attention and hyperactivity disorders) as those born with
symptomatic infection do [49].
Lon-term outcomes and follow-up for children with congenital CMV infection are
discussed in greater detail separately. (See "Congenital cytomegalovirus infection:
Management and outcome", section on 'Outcome' and "Congenital cytomegalovirus
infection: Management and outcome", section on 'Long-term follow-up'.)

DIAGNOSTIC APPROACH A high index of suspicion is important for

timely diagnosis. The manifestations of congenital CMV infection are variable and
nonspecific, and infants may present with most, some, or just one clinical sign or
symptom.
Clinical suspicion — Congenital CMV should be suspected in the following clinical
scenarios [50]:
●Newborns with signs and symptoms consistent with congenital CMV
disease – Findings that may warrant testing for CMV, especially if not explained
by other causes, include microcephaly, small size for gestational age (SGA),
thrombocytopenia, hepatosplenomegaly, and jaundice or direct
hyperbilirubinemia at birth. Jaundice that fits other patterns does not necessarily
warrant testing for CMV (eg, ABO incompatibility). (See 'Symptomatic
neonate' above and "Unconjugated hyperbilirubinemia in the newborn:
 Pathogenesis and etiology", section on 'Causes of significant unconjugated
neonatal hyperbilirubinemia'.)
The yield of CMV testing is greatest when there are multiple suggestive clinical
findings. The diagnostic yield of CMV testing in the setting of an isolated finding
(eg, SGA) is relatively low [50-53]. The author of this topic review still favors
testing for CMV in the setting of isolated SGA; however, other experts do not
recommend CMV testing in this setting.
●Newborns with abnormal neuroimaging consistent with CMV, if the
findings are not explained by other causes. Suggestive neuroimaging findings
include periventricular calcifications, lenticulostriate vasculopathy, white matter
disease, ventriculomegaly, migrational abnormalities (eg, polymicrogyria), or
periventricular leukomalacia. (See 'Neuroimaging' above.)
●Newborns who have documented sensorineural hearing loss (SNHL),
whether or not they have other symptoms of congenital CMV [50].
For infants who fail the newborn hearing screen but have not yet had a formal
audiologic evaluation, the decision of whether or not to test for CMV is
controversial and practice varies. In our practice, newborns who fail the initial
hearing screen in one or both ears have a repeat screen performed before
discharge from the nursery. If the newborn fails the repeat screen, he or she is
referred for audiologic assessment and tested for congenital CMV before
discharge or at least within the first three weeks of life. Other centers do not
routinely screen for CMV in this setting. This issue is discussed in greater detail
separately. (See "Screening the newborn for hearing loss", section on
'Screening for cytomegalovirus'.)
●Newborns born to mothers with known or suspected CMV infection
during pregnancy, including mothers with:
•Maternal seroconversion during pregnancy
•Presumptive maternal primary CMV infection with positive CMV
immunoglobulin G (IgG) and CMV immunoglobulin M (IgM) antibody
•Mononucleosis-like illness during pregnancy
•Abnormal fetal imaging suggestive of in utero CMV infection (see 'In
utero' above)
●Immune-compromised newborns, particularly infants with an abnormal T cell
receptor excision circles (TRECs) result on newborn screening, which is
indicative of severe combined immunodeficiency disorder (SCID), because
congenital CMV infection can have devastating consequences in these severely
immune-compromised hosts. (See "Newborn screening for primary
immunodeficiencies" and "Severe combined immunodeficiency (SCID): An
overview".)
Approach to testing — Laboratory diagnosis of congenital CMV infection is
accomplished by isolation or molecular detection of CMV from urine or saliva
samples collected within the first three weeks of life.
We prefer urine samples over saliva samples for CMV testing. Although saliva is
easier to collect, false-negatives and false-positives are more common with saliva
samples compared with urine [54]. False-negatives may occur at a higher rate
because saliva samples are more susceptible to sampling errors (ie, inadequate
amount). False-positives may occur rarely in infants with CMV-infected mothers due
to contamination of the saliva sample with retained breast milk in the mouth of the
newborn [55]. When this occurs, the quantitative CMV DNA level is usually lower
than in neonates with true infection.
Viral culture, modified culture (also called rapid culture or shell vial assay), and
polymerase chain reaction (PCR) are the preferred diagnostic tests for newborns
with suspected congenital CMV infection (table 2). PCR is more sensitive compared
with rapid culture and may be more accurate, especially if the sample must be
transported to a reference lab over a long distance. In addition, PCR provides
quantitative results [56]. Most newborns with congenital CMV have high levels of
CMV DNA in their urine and saliva. If a low level is detected on CMV PCR, the results
should be confirmed by culture or repeat PCR testing.
The choice of test may depend upon availability at different laboratories. Testing
blood samples for CMV is not recommended as a first-line test because not all
infected infants are viremic. However, detection of CMV by PCR in blood or plasma
samples can be diagnostic. Serologic testing for CMV IgM antibody
is not recommended for neonates and young infants, because CMV IgG antibody in
the blood at this age reflects maternal IgG level and is not diagnostic of a congenital
CMV infection.
Prenatal — Diagnosis of in utero CMV infection can be made by viral culture or CMV
DNA detection in amniotic fluid or also by CMV IgM antibody measurement in fetal
blood of the symptomatic fetus. (See "Cytomegalovirus infection in pregnancy",
section on 'Prenatal (fetal) diagnosis'.)
Birth to three weeks — The diagnosis of congenital CMV infection can be
established within the first three weeks of life by detection of CMV in the urine or
saliva (table 2). Testing should be carried out as soon as the diagnosis is suspected
so that evaluations for end-organ disease can be performed and, if indicated,
antiviral therapy can be started promptly. (See "Congenital cytomegalovirus
infection: Management and outcome", section on 'Antiviral treatment'.)
Three weeks to one year — After three weeks, the detection of CMV in urine or
saliva may indicate either congenital or postnatal CMV infection. Postnatal CMV
infection usually is clinically benign or self-limited. (See "Overview of
cytomegalovirus infections in children", section on 'Early postnatal infection'.)
Congenital CMV infection may be retrospectively diagnosed on the basis of PCR
analysis of dried blood samples (Guthrie cards) obtained for newborn screening [57-
61]. Detection of CMV DNA in the newborn dried blood spot sample indicates that
CMV viremia was present and confirms congenital CMV infection.
In the United States, with written parental permission, newborn dried blood spot
cards may be retrieved from state newborn screening laboratories and tested for
CMV DNA by selected research or public health laboratories experienced in this
specialized testing. Positive CMV PCR on a dried blood spot confirms the diagnosis
of congenital CMV infection. However, a negative result does not exclude CMV
infection; false-negative results may occur, particularly in newborns with few or mild
symptoms. (See "Newborn screening".)

If testing of the dried blood sample is negative or cannot be performed, alternative

methods of testing in this setting include:
 ●Testing the urine or saliva for CMV (via viral culture, shell vial assay, or PCR)
●Measurement of CMV IgG antibody in the blood

Detection of CMV (by any of these methods) in a symptomatic infant at age three
weeks to one year suggests, but does not confirm, congenital CMV infection
because of the possibility of postnatal infection.

Older than one year — Establishing a diagnosis of congenital CMV infection

beyond the first year of life is generally not feasible. Retrospective diagnosis of
congenital CMV via PCR analysis of dried blood spots as described above may be
possible in some regions; however, this is not possible in the United States because
most state health laboratories that perform newborn screening discard the dried
blood spot samples after one year. In addition, many young children, particularly
those attending daycare, become infected with CMV during the first few years of life.
Hence, detection of CMV in the urine or saliva or CMV antibodies in the blood of a
child older than one year is far more likely to represent postnatal infection than
congenital infection. However, a negative CMV IgG antibody and a negative CMV
culture of urine or saliva provides evidence against a congenital CMV infection.
A small number of studies have reported late diagnosis of congenital CMV infection
using PCR methods on preserved umbilical cords [62-64]. However, this method is
not recommended, because it has not been adequately studied and the reliability of
results of umbilical cord testing is unclear. In addition, contamination of the sample
with maternal blood or other sources may cause false-positive results.
Interpretation/diagnosis — The presence or absence of congenital CMV infection
can be determined based on the timing and results of diagnostic tests, as follows:
●Virologically proven congenital CMV infection can be diagnosed on the
basis of any of the following:
•Detection of CMV via viral culture in urine or saliva samples obtained within
the first three weeks of life
•Detection of CMV via shell vial assay in urine or saliva samples obtained
within the first three weeks of life, with a positive confirmatory test (either
viral culture or PCR)
•Detection of CMV via PCR in urine, saliva, or blood samples obtained
within the first three weeks of life, confirmed on repeat testing
•Detection of CMV via PCR in the newborn screening dried blood spot
●Possible congenital CMV infection – It may not be possible to confirm the
diagnosis of congenital CMV infection if testing is performed after the first three
weeks of life (because of the possibility of postnatal acquisition). Newborn dried
blood spot testing can be helpful if available, but negative results do not exclude
congenital CMV infection. A diagnosis of "possible" congenital CMV infection
may be made if all of the following criteria are met:
•One or more signs or symptoms of congenital CMV
•Other conditions that cause these abnormalities have been excluded
(see 'Differential diagnosis' below)
•CMV is detected in urine or saliva samples (via viral culture, shell vial
assay, or PCR) or CMV IgG antibody is detected in the blood after the first
three weeks of life, up to one year of age
 ●Not infected – Infants in whom CMV is not detected in urine or saliva (via viral
culture, shell vial assay, or PCR) during the newborn period do not have
congenital CMV. Because of the high specificity of these tests (table 2), a
negative result excludes the diagnosis of congenital CMV infection. In our
practice, we usually perform at least two tests (urine or saliva or both) to exclude
the diagnosis with confidence. Congenital CMV infection can also be excluded
beyond the newborn period if CMV IgG antibody testing is negative (provided
the infant has a normal immune system), indicating that CMV infection never
occurred in the child.

POST-DIAGNOSIS EVALUATION Infants with virologically confirmed

congenital CMV infection should be evaluated for evidence of organ involvement.

Comprehensive evaluation should be performed even in infants who appear
asymptomatic to detect subtle or subclinical subtle findings. The evaluation includes:
●Thorough physical, neurologic, and neurodevelopmental examination,
including measurements of weight, length, and head circumference (to detect
microcephaly).
●Laboratory testing, including:
•Complete blood count with differential and platelet count
•Liver function tests
•Kidney function tests
•Coagulation studies in selected cases with liver disease or viral sepsis
●Hearing evaluation by auditory brainstem response.
●Ophthalmology evaluation.
●Neuroimaging – Ultrasonography should be performed in all infected infants.
Ultrasonography is better able to detect lenticulostriate vasculopathy than
advanced imaging and will detect most major, obvious abnormalities. Infants
with abnormal ultrasonography, abnormal neurologic examination (eg, focal
abnormalities, globally increased or decreased tone, abnormal reflexes),
seizures, or abnormal head circumference should undergo additional advanced
neuroimaging with computed tomography (CT) and/or magnetic resonance
imaging (MRI) of the brain. CT is quickly performed and is useful in detecting
ventriculomegaly or calcifications but entails radiation exposure, whereas MRI
requires a longer procedure time, often requires sedation, but does not entail
initial radiation exposure and is more sensitive in detecting vasculitis,
polymicrogyria, white matter abnormalities, and other neuronal migrational
abnormalities. (See "Approach to neuroimaging in children".)
Cranial imaging with ultrasound, CT, or MRI helps to assess the degree of
central nervous system involvement. Ultrasound is the preferred initial study for
most infants, but MRI should be obtained if there are abnormal neurologic
examination findings (eg, microcephaly, focal deficits, seizures or other
abnormal movements, delayed milestones, increased or decreased tone), if
there is evidence of clinically significant CMV disease, or if the ultrasound is
abnormal. The choice between MRI versus CT should be individualized based
on the relative advantages and disadvantages. The advantage of MRI is that it
is far more sensitive than CT for identifying structural abnormalities, though it is
less sensitive for identifying calcification. Newer MRI imaging techniques, such
as susceptibility-weighted imaging, may visualize calcium better and can be
performed in infants and newborns.
The main disadvantage of MRI is that some infants may require
sedation/anesthesia and it is a longer procedure. In some institutions, a
"neonatal MRI protocol" may be available, where the infant is swaddled and the
MRI is performed under natural sleep. The main disadvantage of CT is that it
exposes the infant to ionizing radiation; however, because it is quick and
generally does not require sedation, it is sometimes the preferred choice for
imaging unstable infants. If the infant also has documented significant
sensorineural hearing loss (SNHL), coordination with the otolaryngologist may
be important because imaging of the temporal bones and the internal auditory
canals also may be needed, especially if a cochlear implant procedure is under
consideration, and can be performed at the same time as brain imaging.
●We suggest measuring CMV DNAemia by quantitative polymerase chain
reaction (PCR) of whole blood or plasma for any infant receiving antiviral
therapy. (See "Congenital cytomegalovirus infection: Management and
outcome", section on 'Whom to treat'.)

DIFFERENTIAL DIAGNOSIS

●Other congenital and neonatal infections – The classic findings of

symptomatic congenital CMV infection include petechiae, jaundice,
hepatosplenomegaly, small size for gestational age (SGA), and microcephaly.
These nonspecific findings may also occur in:
•Other TORCH infections (including Zika virus infection) (see "Overview of
TORCH infections" and "Congenital Zika virus infection: Clinical features,
evaluation, and management of the neonate")
•Other less common pathogens such as lymphocytic choriomeningitis virus
(see "Viral meningitis: Epidemiology, pathogenesis, and etiology in
children", section on 'Lymphocytic choriomeningitis virus')
•Neonatal sepsis (see "Clinical features, evaluation, and diagnosis of
sepsis in term and late preterm infants")
Although other congenital infections may have characteristic clinical findings
(table 1), appropriate virologic and microbiologic studies generally are
necessary to make a specific diagnosis. (See "Overview of TORCH infections",
section on 'Initial evaluation' and "Clinical features, evaluation, and diagnosis of
sepsis in term and late preterm infants", section on 'Evaluation and initial
management'.)
●Abnormal neurologic findings – A variety of genetic and metabolic
disorders, as well as in utero exposure to drugs and toxins (eg, alcohol,
cocaine, isotretinoin), may mimic the neurologic findings of congenital CMV
infection. The presence and pattern of calcifications on computed tomography
(CT) imaging of the brain can be helpful in distinguishing between CMV infection
and other causes of neurologic disease. Intracranial calcifications, particularly
in periventricular distribution, are a common finding in CMV-infected neonates.
Additional testing such as chromosomal analysis, metabolic studies, and drug
screening may be used to exclude other causes of neurologic disease in
newborns, including [1]:
•Tuberous sclerosis complex (see "Tuberous sclerosis complex: Genetics,
clinical features, and diagnosis")
•Sturge-Weber syndrome (see "Sturge-Weber syndrome")
•Aicardi syndrome
•Galactosemia (see "Galactosemia: Clinical features and diagnosis")
•Urea cycle deficiencies (see "Urea cycle disorders: Clinical features and
diagnosis")
•Organic acidemias (see "Organic acidemias: An overview and specific
defects")
•Lysosomal storage disorders (see "Inborn errors of metabolism:
Classification", section on 'Lysosomal storage disorders')
•Peroxisomal disorders (eg, Zellweger syndrome, infantile Refsum disease,
adrenoleukodystrophy) (see "Peroxisomal disorders" and "X-linked
adrenoleukodystrophy and adrenomyeloneuropathy")
•Other inherited leukodystrophies (see "Metachromatic
leukodystrophy" and "Alexander disease")
•In utero exposure to drugs and toxins (eg, alcohol, cocaine, isotretinoin)
(see "Fetal alcohol spectrum disorder: Clinical features and
diagnosis" and "Infants of mothers with substance use disorder", section on
'Cocaine')
●Hepatitis and hyperbilirubinemia – The differential diagnosis for the hepatic
findings associated with congenital CMV infection includes:
•Other causes of viral hepatitis (hepatitis A, hepatitis B, hepatitis C, Epstein-
Barr virus, herpes simplex virus, enterovirus, adenovirus) (see "Hepatitis
viruses and the newborn: Clinical manifestations and treatment")
•Ischemic injury
•Thrombosis
•Hemolytic disease (see "Unconjugated hyperbilirubinemia in the newborn:
Pathogenesis and etiology", section on 'Causes of significant unconjugated
neonatal hyperbilirubinemia')
•Biliary atresia (if conjugated hyperbilirubinemia is present and persistent)
(see "Biliary atresia")
•Metabolic and genetic disorders that involve the liver (see "Inborn errors
of metabolism: Identifying the specific disorder", section on
'Hepatosplenomegaly')
The clinical course and appropriate virologic tests distinguish CMV from these
other causes. Infants with congenital CMV and persistent liver dysfunction or
persistent conjugated hyperbilirubinemia should be evaluated for biliary atresia
or alpha-1 antitrypsin deficiency since CMV may coexist with other disorders of
liver function, presenting a diagnostic challenge. (See "Unconjugated
hyperbilirubinemia in the newborn: Pathogenesis and
 etiology" and "Unconjugated hyperbilirubinemia in term and late preterm
infants: Screening".)

NEWBORN SCREENING FOR CONGENITAL

CYTOMEGALOVIRUS Newborns are not routinely screened for CMV.

However, given the substantial public health impact of congenital CMV, most CMV
experts support targeted and/or universal newborn screening for congenital CMV
infection. The goals of newborn screening include early identification of infected
infants with subtle symptoms who may benefit from antiviral therapy, and
identification of asymptomatic infants who are at risk for delayed hearing loss and
warrant more frequent audiologic evaluation [65-68]. (See "Congenital
cytomegalovirus infection: Management and outcome", section on 'Antiviral
treatment' and "Congenital cytomegalovirus infection: Management and outcome",
section on 'Long-term follow-up'.)
Targeted newborn screening — Targeted newborn screening involves testing for
CMV in all newborns who fail their newborn hearing screen in either one or both
ears. Many hospitals have adopted targeted CMV screening programs that aim to
identify infected infants in the newborn period, so that appropriate evaluations for
end-organ involvement can be performed and antiviral treatment, if indicated, may
be provided. As discussed above, our practice is to screen for CMV in newborns
who fail both the initial and repeat follow-up hearing screen in one or both ears
(see 'Clinical suspicion' above). In such neonates, we perform testing for congenital
CMV before discharge or at least within the first three weeks of life. However, other
centers do not routinely screen for CMV in this setting.
Targeted screening for CMV in the setting of a failed newborn hearing screen is
discussed in greater detail separately. (See "Screening the newborn for hearing
loss", section on 'Screening for cytomegalovirus'.)
Universal newborn screening — Universal newborn screening for congenital CMV
has been proposed by many CMV experts, audiologists, otolaryngologists, and
public health officials [67,69,70]. The main goal of this approach is to identify
asymptomatic infected infants in order to provide careful monitoring for delayed-
onset hearing loss. As discussed above, asymptomatic newborns with congenital
CMV infection have a risk of delayed-onset hearing loss that is not detected by
newborn hearing screen protocols (see 'Isolated hearing loss' above). If delayed-
onset hearing loss is identified, educational accommodations, speech/language
therapies, and other appropriate interventions can be initiated at an early stage in
order to optimize the child's language development and learning. (See "Hearing loss
in children: Treatment".)
Antiviral treatment is generally not recommended for infected infants who pass the
newborn hearing screen and are otherwise asymptomatic, although an ongoing
prospective study is evaluating whether antiviral therapy reduces the risk of late-
onset hearing loss in asymptomatic infected newborns [71] (see "Congenital
cytomegalovirus infection: Management and outcome", section on 'Whom to treat').
A National Institutes of Health-sponsored multicenter clinical trial evaluating the
potential benefit of treatment of asymptomatically infected newborns to reduce the
risk of later-onset hearing loss is now being conducted. However, another potential
benefit of universal newborn screening for CMV is that it may eliminate the diagnostic
odyssey experienced by many newborns with atypical signs and symptoms of
congenital CMV or those with failed newborn hearing screens.
Universal newborn screening appears to be cost effective [72,73]. However, the
most reliable and cost-effective method for universal newborn screening for
congenital CMV is not established. It may involve detection of CMV in saliva or urine
collected at birth and tested by central laboratory high-throughput technology or by
simple point-of-care detection methods that are under development; or testing of
dried blood spots (DBS) collected for routine newborn screening panels [61,69,74].
Improvements in PCR testing methodologies has led to improved sensitivity of DBS
testing [61]. In a report from two centers in Europe, performing testing on pooled
saliva samples reduced the cost of screening [75]. (See "Newborn screening".)

In the absence of universal screening, the diagnosis of congenital CMV is often

delayed because many infected newborns do not exhibit classic signs and
symptoms. Among newborns who fail newborn hearing screening, testing for CMV
often is not performed until completion of confirmatory auditory testing and
evaluation by otolaryngology specialists, which often is around two to three months
of age.

SUMMARY AND RECOMMENDATIONS

●Congenital cytomegalovirus (CMV) infection affects approximately 30,000 to

40,000 infants annually in the United States and is associated with long-term
neurodevelopmental disabilities, including sensorineural hearing loss (SNHL),
cerebral palsy, intellectual disability, vision impairment, and seizures. It is the
leading cause of nonhereditary SNHL. (See 'Introduction' above.)
●Most infants with congenital CMV infection are asymptomatic, but
approximately 10 percent of infected neonates have symptoms at birth. Clinical
findings are nonspecific and include petechiae, jaundice, hepatosplenomegaly,
small size for gestational age (SGA), and microcephaly. (See 'Symptomatic
neonate' above.)
●Common laboratory findings in the symptomatic neonate include
thrombocytopenia, elevated transaminases, and elevated direct and indirect
serum bilirubin. Imaging of the brain often shows periventricular intracranial
calcifications, migrational abnormalities, or other abnormalities (image 5A-
B and image 6). (See 'Laboratory findings' above and 'Neuroimaging' above.)
●SNHL is the most common sequela of congenital CMV infection, occurring in
33 to 50 percent of symptomatic infants and approximately 25 percent of
asymptomatic infants. The newborn hearing screen is a valuable tool for
detecting otherwise asymptomatic infants with CMV infection. (See 'Clinical
 findings' above and 'Isolated hearing loss' above and "Screening the newborn
for hearing loss".)
●Congenital CMV infection should be suspected in infants with (see 'Clinical
suspicion' above):
•One or more of the typical signs of symptomatic disease (eg,
microcephaly, SGA, thrombocytopenia, petechiae or purpura,
hepatosplenomegaly, or jaundice at birth)
•Abnormal neuroimaging with otherwise unexplained periventricular
calcifications, lenticulostriate vasculopathy, white matter disease,
ventriculomegaly, migrational abnormalities (eg, polymicrogyria), or
periventricular leukomalacia
•Documented SNHL in one or both ears
•Mother who had known or suspected maternal CMV infection during
pregnancy or abnormal fetal imaging suggestive of in utero CMV infection
●Laboratory diagnosis of congenital CMV infection is accomplished by isolation
or molecular detection of CMV from urine or saliva samples collected within the
first three weeks of life (table 2). Both viral culture and polymerase chain
reaction (PCR) tests have high sensitivity and specificity for detection of CMV
in infected neonates. Serology should not be used for the routine diagnosis of
congenital CMV infection. (See 'Diagnostic approach' above.)
●The differential diagnosis of congenital CMV infection includes other congenital
infections, neonatal sepsis, genetic and metabolic disorders, and in utero
exposure to drugs and toxins. Appropriate virologic and microbiologic studies,
chromosomal analysis, metabolic studies, drug screening, and presence and
pattern of calcifications on computed tomography (CT) imaging of the brain will
aid in differentiating among these possibilities. (See 'Differential
diagnosis' above.)
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