Paediatrics & Child Health, 2017, 72–74

doi: 10.1093/pch/pxx002
Commentary
Advance Access publication 4 April 2017

Commentary

Diagnosis and management of infants with congenital

cytomegalovirus infection
Soren Gantt MD PhD MPH FRCPC1, Ari Bitnun MD MSc FRCPC2, Christian Renaud MD MSc
FRCPC3, Fatima Kakkar MD MPH FRCPC3, Wendy Vaudry MDCM FRCPC4
1
University of British Columbia and BC Children’s Hospital, Vancouver, British Columbia; 2University of Toronto
and Sick Kids Hospital, Toronto, Ontario; 3Université de Montréal and Hôpital Ste. Justine, Montreal, Quebec;
4
University of Alberta and Stollery Children’s Hospital, Edmonton, Alberta
Correspondence: Soren Gantt, BC Children’s Hospital, 950 W. 28th Avenue, Vancouver, British Columbia V5Z 4H4. Telephone
604-875-2151, fax 604-875-2226, e-mail sgantt@bcchr.ca

Abstract
Congenital cytomegalovirus infection (cCMV) is the most common congenital infection, occurring in approximately 0.5% of
live births. Most infected newborns are asymptomatic, but up to 20% develop sensorineural hearing loss or other permanent
neurologic sequelae. The presentation of newborns with symptomatic cCMV is highly variable, and the infection is usually
not diagnosed in the absence of a screening program. Newborn cCMV screening programs are estimated to be beneficial
and cost-effective, and are increasingly being implemented. Diagnosis requires direct detection of virus in a sample obtained
before 3 weeks of life, and is best performed by polymerase chain reaction (PCR) of saliva or urine, either of which is more
sensitive than dried blood spot. Antiviral treatment of selected newborns with cCMV-related disease appears to improve
hearing and neurocognitive outcomes. All infected infants should be evaluated promptly to determine appropriate therapy,
and receive close audiologic and developmental follow-up.

Keywords:  Congenital cytomegalovirus infection; Diagnosis; Treatment; Childhood hearing loss; Newborn screening.

Cytomegalovirus (CMV) is the most common congenital infection and the
most common cause of acquired hearing loss in childhood. There have been
a number of advancements in the testing and treatment of congenital (c)CMV
infection in recent years, which are outlined here along with guidance on the
current best practices regarding management of infants with cCMV.
Epidemiology and burden of disease
CMV is a herpesvirus that infects approximately half of adults in North
America. Infection is life-long, and is transmitted through contact with saliva,
urine, breast milk, genital fluids or blood. In otherwise healthy people, CMV
infection is typically asymptomatic or causes a non-specific, usually mild,
febrile illness. However, when CMV is acquired congenitally, morbidity is com-
mon. cCMV occurs in roughly 1 per 150 live births, and is a major cause of sen-
sorineural hearing loss (SNHL) and other neurologic deficits among children
worldwide (1). It is estimated that 10–25% of all SNHL in children is due to
cCMV. Although the risk of cCMV is approximately 30–40% among infants
whose mothers acquire CMV during pregnancy, most infants with cCMV are
born to women with evidence of pre-existing immunity (2).
Of the 10–15% of infants with cCMV who are symptomatic at birth, 40–60%
will go on to have permanent sequelae including SNHL, visual deficits, and/
or cognitive delay (1,2). Evidence of central nervous system (CNS) involve-
ment at birth portends a worse outcome (3,4). Among infants with cCMV who
do not have symptoms at birth, between 10% and 15% will develop SNHL or
other permanent sequelae by the time they start school (1,2). Hearing loss from
cCMV can be unilateral or bilateral, vary from mild to profound, be delayed in
onset and can fluctuate, but when present is usually progressive. Overall, two-
thirds of congenitally-infected children who develop permanent sequelae were
asymptomatic at the time of birth.
Methods and indications for cCMV testing
Congenitally-infected infants persistently shed very high levels of CMV in the
saliva and urine (median >12 months) (5–7), and these are therefore the opti-
mal samples to test. CMV polymerase chain reaction (PCR) of saliva or urine
using a validated assay is at least as accurate as urine culture, the historical stan-
dard, and is increasingly used for diagnosis and screening (8). Levels in blood are
much lower than in saliva or urine, which contributes to inadequate sensitivity
(30–80%) of testing dried blood spots collected at birth by PCR (8,9). Saliva is
collected by oral (not throat) swab and is more convenient to obtain than urine.
False-positive CMV PCR results are possible in breastfeeding infants tested by
oral swab and confirmatory testing by urine PCR is required. The high sensitivity
(97–100%) and specificity (99.9%) of saliva PCR testing as a screening method
have been validated in a large population-based cohort study (8).
Definitive diagnosis of cCMV requires direct detection of the virus in infants
before 3 weeks of age (10). The timing of sample collection is important

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Paediatrics & Child Health, 2017, Vol. 22, No. 2
because intrapartum and early postpartum infection is common and does
not result in long-term sequelae. Thus, whenever cCMV is suspected, testing
should be performed as soon after birth as possible. A negative CMV IgG serol-
ogy effectively excludes congenital infection. Antibody testing is not otherwise
useful for diagnosis of cCMV; the presence of CMV IgG does not differentiate
between maternal or infant infection, and CMV IgM is not sufficiently sensi-
tive or specific for congenital infection. Retrospective CMV testing of stored
dried blood spots, if positive, may be helpful when the diagnosis of cCMV is
considered beyond the newborn period, but a negative test does not exclude
the diagnosis (9).
The diagnosis of cCMV is missed for the majority of symptomatic new-
borns when testing depends on clinical suspicion (11,12). Consequently, in the
absence of an alternative explanation, any clinical finding consistent with cCMV
infection (Table  1) should prompt cCMV testing as soon as possible after
birth. Indications for cCMV testing include failing the newborn hearing screen
(13). In most settings, confirmation of SNHL by auditory brainstem-evoked
response (ABR) audiometry does not routinely take place until >3 weeks of
age, which is too late to accurately diagnose cCMV and often beyond the period
when antiviral therapy has proven benefits (see below). Therefore, testing for
cCMV should take place upon hearing screen failure, prior to ABR audiometry.
Algorithms for targeted cCMV screening of high-risk newborns are increas-
ingly being adopted. For example, reflexive cCMV testing of newborns that
fail the hearing screen is now mandated in parts of the USA, including Utah
and Connecticut (14,15), and similar approaches are being piloted in parts
of Canada. Although targeted screening appears cost-effective and improves
cCMV diagnosis (16,17), this strategy by design does not identify asymptom-
atic newborns without hearing loss at birth, and therefore misses the majority
of children who will develop cCMV-related disease (18). In contrast, universal
newborn cCMV screening using urine or saliva PCR would identify virtually
Table 1.  Indications for newborn cCMV testing
•  Suspected or proven primary maternal CMV infection during pregnancy
•  Fetal ultrasound findings consistent with in utero CMV infection
  Intrauterine growth retardation
  Hydrops fetalis
  Brain abnormalities, including calcifications or venticulomegaly
  Hepatomegaly, splenomegaly or visceral calcifications
  Hyperechogenic bowel
  Placental enlargement
•  Maternal HIV infection
•  Placental CMV infection discovered on pathologic examination
•  Symptoms of possible CMV disease in the newborn
  Small for gestational age
  Seizures, microcephaly, cortical atrophy, intracranial calcifications, ventric-
ulomegaly, periventricular cysts, lenticulostriate vasculopathy, cerebellar
hypoplasia, polymicrogyria, or lisencephaly
  Lethargy, hypotonia, or poor feeding
 Thrombocytopenia
  Petechiae or purpura
  Jaundice at birth
  Conjugated hyperbilirubinemia or hepatitis
  Hepatomegaly or splenomegaly
 Pneumonitis
  Chorioretinitis, retinal scarring or optic atrophy
•  Failed hearing screen or proven SNHL
•  Primary immunodeficiency, including positive screen for SCID
CMV Cytomegalovirus; cCMV Congenital CMV infection; HIV Human immunodeficiency
virus; SCID Severe combined immunodeficiency; SNHL Sensorineural hearing loss
73
all infected children. Universal screening has not yet been widely adopted, but
appears to be both beneficial and cost-effective (17,18).
Evaluation of newborns with cCMV infection
Any newborn with cCMV should be evaluated without delay in order to
confirm the diagnosis and determine whether antiviral therapy is indicated.
Parental counseling should be provided to explain the implications of a positive
test. Neonates with confirmed cCMV should be promptly seen by paediatrics,
audiology and ophthalmology and undergo laboratory testing and brain imag-
ing (Table 2). Because the evidence supporting antiviral treatment for cCMV is
largely limited to studies in which therapy is initiated in the first month of life,
every effort should be made to complete the work-up within this period.
Antiviral treatment for cCMV infection
Strong evidence from two NIH-sponsored randomized controlled trials sup-
ports antiviral treatment of symptomatic cCMV with neurologic involvement
(19,20). In the earlier study, intravenous ganciclovir for 6 weeks, initiated
within 1  month of birth, was shown to reduce progression of hearing loss at
6 months of age in children with baseline neurologic, ophthalmologic or hear-
ing impairment (19). More recently, a randomized placebo-controlled trial of 6
weeks versus 6 months of valganciclovir given to newborns with symptomatic
cCMV found that the longer treatment duration was associated with modestly
better hearing at 12 and 24 months of age after adjusting for CNS involvement
(20). Neurodevelopmental outcomes, including Bailey-III language-composite
and higher receptive communication scale scores at 24 months of age were also
Table 2.  Suggested evaluation of congenital cytomegalovirus infection
Type of evaluation Comments
Audiology Diagnostic ABR testing for all CMV positive newborns
that failed the hearing screen should be performed as
early as possible.*
Paediatrics Paediatric evaluation, including a complete history and
physical exam with anthropometrics
Laboratory** Urine CMV viral isolation or PCR to confirm diagnosis
Complete blood count with differential
Liver function tests
BUN and serum creatinine
Consider quantitative serum CMV PCR***
Consider CSF protein, cell count and CMV PCR†
Brain imaging Cranial ultrasound
Consider CT or MRI††
Ophthalmology Fundoscopic exam
Otolaryngology Indicated for those infants with confirmed SNHL
Parental counseling Families should be counseled about the natural history
and standard precautions for prevention of CMV
transmission to pregnant women or
immunocomprised people.
ABR Auditory brainstem-evoked response; BUN Blood urea nitrogen; CSF Cerebrospinal
fluid; CT Computed tomography; PCR Polymerase chain reaction; MRI Magnetic resonance
imaging; SNHL Sensorineural hearing loss
*All evaluations should be completed as quickly as feasible so that antiviral therapy
may be initiated at <1  month of age if cCMV-related disease is confirmed; **For infants
that receive 6 months of valganciclovir treatment, laboratory monitoring is recommended
weekly × 4 weeks, then every 2 weeks × 8 weeks, then every month × 3 months, with a
complete blood count with differential, liver function tests, and BUN and serum creatinine
(20); ***CMV levels in blood may have prognostic value (7,27); †Some experts recommend
lumbar puncture as part of the evaluation of cCMV central nervous system disease (28);
††
Brain imaging with CT or MRI should be considered for abnormal findings on neurologic
exam or cranial ultrasound. Some experts recommend CT or MRI on all infected infants.
74
higher in the longer treatment group after adjustment for CNS involvement,
prematurity, and age of starting treatment.
Based on these data, the standard treatment for symptomatic cCMV is val-
ganciclovir 16 mg/kg/dose twice daily for 6 months (10); at this time, there is
no evidence for longer treatment. There is equipoise among experts regarding
treatment of newborns with milder disease, for example isolated SNHL, mild
thrombocytopenia or slight intrauterine growth retardation (21,22). However,
newborns with clear symptoms of cCMV, especially CNS involvement, should
be treated (10,21,22). Starting antiviral therapy at >30 days of life is of uncer-
tain benefit although case series suggest efficacy (23,24), and controlled trials
of late-onset disease are ongoing. Currently, there are no data to support anti-
viral therapy to prevent late-onset disease in infants with asymptomatic cCMV.
The major risk of ganciclovir is reversible neutropenia, but thrombocy-
topenia and hepatotoxicity are also reported (25). Neutropenia appears less
common with valganciclovir, and treatment discontinuation is rarely needed
(19,25). Laboratory monitoring of complete blood cell counts and renal and
liver function in infants treated with valganciclovir is nevertheless required
(20) (Table 2). The potential for adverse reproductive effects and carcinogenic-
ity based on animal studies should be acknowledged, but these have not been
observed in humans. Because of these complexities, treatment of cCMV should
be discussed with a specialist in paediatric infectious diseases.
Follow-up care of cCMV-infected infants
All infants with cCMV should have close audiologic follow-up, to monitor for
progression or development of SNHL for 6 years (26), or longer in consulta-
tion with an audiologist (13). Monitoring for developmental delay and learn-
ing disability is also important. Follow-up of infants for specific complications
of cCMV should be individualized based on severity and other factors by the
relevant specialty services (e.g., otolaryngology, ophthalmology, developmen-
tal paediatrics). Infection control issues should be addressed with families of
children with cCMV infection (10). These children do not require isolation if
hospitalized or restrictions on childcare attendance. However, due to prolonged
CMV shedding by infected children, hand hygiene is recommended and avoid-
ance of contact with saliva and urine are advised for pregnant women or immu-
nocompromised individuals.
Conclusions
cCMV is common and causes substantial morbidity. Prompt identification
and treatment can improve hearing and cognitive outcomes. The diagnosis is
made by CMV PCR or culture from saliva or urine collected prior to 3 weeks
of age. Because clinical suspicion of infection is insensitive, targeted or univer-
sal newborn screening programs should be encouraged (29). All children with
cCMV need close follow-up to monitor for hearing loss or other neurocognitive
sequelae. Family practitioners, paediatricians and infectious disease specialists
should be familiar with cCMV in order to facilitate the diagnosis and manage-
ment of infected children.
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