Journal of Infection (2017) 74, S89—S94

www.elsevierhealth.com/journals/jinf

Congenital cytomegalovirus − who, when, what-

with and why to treat?
Yinru Lim a,*, Hermione Lyall a

a Department of Paediatric Infectious Diseases, St Mary’s Hospital, Imperial College NHS Healthcare Trust,
Praed Street, London W2 1NY, UK

Available online 23 June 2017

KEYWORDS Summary Congenital cytomegalovirus (CMV) is the commonest cause of congenital infection
Congenital; worldwide and the leading non-genetic cause of sensorineural hearing loss in children.
Cytomegalovirus; Appropriate investigations and timely decision on treatment is required as studies have
Infection; shown that treatment with antiviral therapy leads to improved hearing and
Antiviral; neurodevelopmental outcomes in the long term when started in the first month of life. This
Ganciclovir; paper outlines the epidemiology, investigations in the diagnosis of congenital CMV infection
Valganciclovir and current evidence surrounding treatment.
Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association.
All rights reserved.

Introduction Around 40% of women of reproductive age are seronegative

Human cytomegalovirus (CMV), a member of the Herpes-
viridae family of viruses, is the commonest cause of
congenital infection worldwide. Congenital CMV infection
can result in serious congenital malformations,
neurodevelopmental delay, and it is the leading non-
genetic cause of sensorineural hearing loss in children.
Epidemiology
CMV is found universally but seroprevalence varies widely
between different geographic locations. Within a
population, CMV’s seroprevalence shows an age-dependent
rise and correlates with race and socioeconomic status. 1
in developed countries and 1-3% of these women can develop
primary CMV infection during pregnancy. Women who are
most at risk include adolescents, women with frequent
contact with young children such as day care workers and
mothers with young children themselves. Transmission rate to
the fetus is 30−40% in primary maternal CMV infection.
Importantly, CMV reactivation or reinfection can occur in
women who are seropositive prior to pregnancy. 2,3 The rate of
CMV transmission is only around 1% after reactivation or
reinfection. However, in populations with high
seroprevalence, there will be more infants with congenital
CMV born to mothers who have had previous CMV infection
than to women with primary seroconversion in pregnancy. 4−6
See Figure 1.

* Corresponding author. NHS Healthcare Trust, London, Praed Street, London W2 1NY, UK. Tel.: +44 (0)203 312 6666.
E-mail addresses: yinrulim@nhs.net (Y. Lim), Hermione.Lyall@imperial.nhs.uk (H. Lyall).

0163-4453/Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association. All rights reserved
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Figure 1 Illustration of the epidemiology of congenital CMV infection. 9 In the context of the United Kingdom, with 700,000
births per year, there will be 4200 newborn infants with congenital CMV contributed by mothers who are already seropositive
and 1400 to 2000 newborn infants with congenital CMV secondary to primary maternal infection.
Primary and non-primary maternal CMV infection leads
to an overall incidence of congenital CMV of approximately
0.4−0.8% in developed countries.7 Risk of transmission is
higher with later stages of pregnancy but early transmission
is associated with more severe consequences for the fetus. 8
Definitions and clinical features
Approximately 10−15% of infants with congenital CMV present
with symptoms at birth. This is termed symptomatic congenital
CMV infection where the infant presents with signs and symptoms
in utero and/or in the immediate postnatal period. There is no
standard definition for symptomatic CMV infection but studies
have used the presence of one or more of the following to define
symptomatic disease − thrombocytopenia, petechiae,
splenomegaly, hepatomegaly, hepatitis, intrauterine growth
restriction (IUGR), central nervous system involvement such as
microcephaly, intra-cranial calcifications, chorioretinitis,
sensorineural hearing loss, or detection of CMV in cerebrospinal
fluid.10 An example of symptomatic congenital CMV could be an
infant, born at 36 weeks gestation, who had echogenic bowel on
20 week scan, and is noted to have hepatosplenomegaly and
microcephaly with a birth weight of 1.9 kg. Up to two-thirds of
these infants develop long-term neurological sequelae such as
hearing loss, visual impairment and motor or cognitive deficit.8
The remaining 85−90% of newborn infants with congenital
CMV presents with little or no signs and symptoms at birth
and this is termed asymptomatic congenital CMV infection.
However, around 15% of these infants can go on to develop
sequelae, in particular sensorineural hearing loss. 8
Unfortunately, it is not possible to predict which infants will
go on to develop late-onset hearing loss and it is these
children that account for the majority of morbidity associated
with CMV infection.
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Since the advent of newborn hearing screening, more
children have been diagnosed with congenital CMV, and
the difference between ‘symptomatic’ and ‘asymptomatic’
cases has become less clear. Infants previously considered
‘asymptomatic’ may actually be found to have significant
abnormalities on brain MRI, so the clinical paradigm is shifting
as more infants are being detected and investigated.
Additionally, perinatal or postnatal CMV infection in
premature infants can cause severe symptoms. Infection is
acquired during or after birth via the birth canal, breast
milk, or rarely via blood transfusion. 11,12 Whether this can
lead to long-term sequaelae remains uncertain.
Diagnosis
During the antenatal period, diagnosis may be suspected
when signs such as echogenic bowel, IUGR, intracranial
calcification or ventriculomegaly are detected on ultra-
sound scans. However, these are non-specific signs with a
wide differential diagnosis including chromosomal abnor-
malities, cystic fibrosis and other congenital infections like
toxoplasmosis. Maternal serology is only helpful in the case
of a primary infection with detection of IgM or IgG
seroconversion and low avidity IgG. Fetal infection can be
confirmed with detection of CMV DNA through polymerase
chain reaction (PCR) testing via amniocentesis. 13
In the newborn infant, diagnosis of both symptomatic
and asymptomatic CMV infection can be made with
detection of CMV DNA via PCR in body fluids or tissue
samples (saliva, urine, blood, CSF and placenta) that were
obtained before Day 21 of life. Dried blood spots from
Guthrie cards can be used to detect CMV DNA by PCR
retrospectively with variable sensitivity up to 80%. 14
Perinatal/postnatal CMV infection diagnosis is more
difficult as it requires demonstration of a negative sample
Congenital cytomegalovirus
taken before day 21 of life and a positive sample taken
after day 21 of life.
Screening
Routine CMV screening in pregnancy remains matter of
debate. Maternal screening to identify primary CMV infection
in pregnancy may allow for early identification of infected
infants and such screening programmes have previously been
carried out, or are being carried out in certain European
countries (e.g. Italy, Belgium, France, Germany and Sweden)
and in Israel.15,16 However, difficulties in accurate diagnosis,
absence of effective interventions in preventing transmission
of CMV from mothers with primary CMV infection to their
infant, possibility of reinfection or reactivation, and the
challenges in providing definite prognosis to an individual
mother means that universal screening of pregnant women is
not currently recommended in most countries including the
UK and North America.17,18
Screening of newborn infants to detect congenital CMV,
whether all infants, or only those who fail the newborn
hearing screening test has also been controversial. Recent
evidence from the USA suggests that both could be cost
effective, and national newborn screening programmes
will need to review this for their own populations. 19,20
Further investigations to stage end-
organ disease
With detection of CMV DNA and therefore confirmation of
congenital CMV infection, it is important for guiding
management to document clinical symptoms and carry out
further investigations looking for evidence of end-organ
disease.21,22 These investigations include:
• Blood
− Full blood count −thrombocytopenia (<100,000/mm3)
or neutropenia (<1.0 x 109/L)
− Liver function test − transaminitis often with
conjugated hyperbilirubinaemia
− CMV viral load
• Imaging
− MRI − evidence of white or grey matter changes,
including cysts, and migration defects such as poly-
microgyria
− Cranial ultrasound − calcification or
ventriculomegaly
• Ophthalmology
− Chorioretinitis, optic atrophy, cataracts
• Hearing test
− Auditory brainstem response − senorineural hearing
loss
Congenital CMV treatment
Who to treat?
Infants with symptomatic congenital CMV (i.e. <21 days of
age, positive CMV PCR and evidence of significant end
organ disease in particular, or any central nervous system
(CNS) disease, including sensorineural hearing loss) should
be considered for treatment. However, for infants who are
asymptomatic or mildly symptomatic with no CNS disease
(i.e. isolated IUGR, hepatomegaly with normal
S91
liver enzymes, isolated elevation of liver enzymes or mild
or transient thrombocytopenia), treatment is usually not
recommended.
So far, studies for treatment has been in infants above 32
weeks of gestation and over 1800 grams in weight, and
therefore further studies are required to verify benefit of
treatment in infants below this gestational age and weight.
Why to treat?
Kimberlin et al have shown in initial studies that treatment of
infants with symptomatic congenital CMV infection involving
the CNS with intravenous ganciclovir for 6 weeks prevents
hearing deterioration at 12 months, and infants who had
received treatment were found to have improved
developmental delay at both 6 and 12 months when compared
to infants who did not receive treatment. 23,24
More recently, the results of a randomised controlled trial
comparing 6 weeks versus 6 months of oral valganciclovir in
infants with symptomatic congenital CMV was reported. This
study found that when compared to 6 weeks of treatment, 6
months treatment with valganciclovir did not improve hearing
at 6 months, but did improve hearing and neurodevelopment
in the long term (at 24 months). The Bayley Scales of Infant
and Toddler Development (Bayley
III) was used for measurement of neurodevelopmental
outcomes and statistically significant improvement was
demonstrated in language and receptive-communication
scales.10 Table 1 summarises the results from the National
Institute of Allergy and Infectious Diseases Collaborative
Antiviral Study Group (CASG).
However, it is important to bear in mind the potential
risk of treatment and families should be fully counselled
and informed of the potential toxicities associated with
valganciclovir treatment. Short-term side effects include
neutropenia, thrombocytopenia and hepatotoxicity and
occurrence may require interruption of treatment and,
occasionally, treatment with granulocyte-colony
stimulating factor for neutropenia. Side effects can occur
throughout treatment and therefore, regular monitoring of
full blood count, liver and renal function whilst on
treatment is essential. Long-term toxicity associated with
treatment is unknown but concerns have been raised
about potential effects on fertility and carcinogenicity. 10,23
When and for how long to treat?
Treatment should start in the first month of life and the
current recommended length of treatment is 6 months of
oral valganciclovir.
Currently, benefit of treatment after the first month of
life is unclear due to lack to studies. A Phase II
randomized controlled study (NCT01649869) on the use of
valganciclovir in infants and children with congenital CMV
infection and hearing loss from the age of 1 month up to 4
years of age in currently underway. 25
What treatment?
Intravenous ganciclovir or its oral prodrug valganciclovir is
used for treatment. These antiviral drugs inhibit CMV
replication by disrupting viral DNA synthesis. Pharmacokinetic
S92 Y. Lim, H. Lyall

Table 1 Summary of results from the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
(CASG).
Study Study Details Main findings
Treatment of cCMV • Randomised controlled trial Improved or maintained normal hearing between
involving central nervous • IV ganciclovir (GCV) vs no treatment (i) Baseline and 6 months
system • 6 weeks treatment 84% GCV vs 58% controls (p=0.06)
• 100 patients recruited, only 44 evaluable (ii) Baseline and 12 months
(CASG 102 79% GCV vs 32% controls (p=0.133)
Kimberlin et al. 200323) Worsening of hearing between
(i) Baseline and 6 months
0% GCV vs 41% controls (p<0.01)
(ii) Baseline and 12 months
21% GCV vs 68% controls (p<0.01)
Neuro-developmental • Denver developmental tests at 6 weeks, Average number of delays

outcomes 6 months and 12 months (i) 6 weeks

• Number of milestones not met = ‘delay’ 1.5 GCV vs 2.05 controls (p=0.11)
(Follow on study from determined for each child (ii) 6 months
CASG 102 4.46 GCV vs 7.51 controls (p=0.02)
Oliver et al. 200924) (iii) 12 months
10.06 GCV vs 17.14 controls (p=0.007)
6 months vs 6 weeks • Randomised, placebo-controlled trial Improved or normal total ear hearing (6 months

Valganciclovir in cCMV • 6 months vs 6 weeks of valganciclovir group vs 6 weeks group) at

involving central nervous • 96 recruited (i) 6 months
system • Hearing outcomes and neurodevelopmental 63% vs 55% (p=0.2)
outcomes (ii)12 months
(CASG 112 73% vs 57% (p=0.01)
Kimberlin et al. 201510) (iii) 24 months
77% vs 64% (p=0.04)
6 month group had better neurodevelopmental
scores at 24 months on
(i) language-composite component (p=0.004)
(ii) Receptive-communication scale (p=0.003)

studies have shown oral valganciclovir to be of comparable
efficacy to intravenous ganciclovir with less short-term
side effects.26 Therefore, intravenous ganciclovir is now
only recommended when the infant is not enterally fed
with switch to oral valganciclovir recommended once
established on enteral feeds.
Doses are:23,26
• 6 mg/kg/dose of intravenous ganciclovir twice daily or
• 16 mg/kg/dose of oral valganciclovir twice daily
Treated infants should be followed up with regular
audiology review recommended until the age of 6 years
and ophthalmology review till the age of 5 years.
Parents of all children with congenital CMV should be
recommended to consent to enter their children into
national registries, so that cohort data can be
accumulated regarding outcomes, and toxicities.
International cohort collaboration via the European
Congenital CMV Initiative is currently in progress and will
further contribute important case based information.
Postnatal CMV in premature infants
As discussed briefly above, CMV infection may occur during
the perinatal or postnatal period and in premature and
extremely low birth weight (ELBW) infants, this can lead
to asymptomatic infection or severe sepsis-like syndrome.
A major route of postnatal transmission in ELBW infants is
via maternal expressed breast milk (EBM). In a meta-analysis
by Lanzieri et al. on premature babies <32 weeks gestation or
birth weight <1500 grams, 19% (95% CI 11−32%) of infants that
were fed fresh EBM from CMV positive mothers acquired CMV
and 4% (95% CI 2−7%) developed CMV sepsis like syndrome.
Infants who were fed frozen EBM from CMV positive mothers
had lower rates of acquiring CMV at 13% (95% CI 7−24%) but
rates of developing CMV sepsis like syndrome was similar at 5%
(95% CI 2−12%).27
However, breast milk is known to be extremely beneficial
in premature infants and at this point the benefits of
receiving EBM outweigh the risk of developing breast-milk
acquired CMV infection. Moreover, the long-term follow up
data is currently limited. A prospective study that was carried
out on 50 premature ELBW infants with postnatal CMV
infection found that at the age of 4 or more years, there was
no difference in prevalence of cerebral palsy when compared
to matched pair controls. There was however a signifi cantly
lower cognitive outcome in the infants with postnatally
acquired CMV infection, raising the possibility of an
adverse impact on intellectual development. However,
Congenital cytomegalovirus
larger studies are required to further investigate the
significance of this.11
More importantly, there is still little data on the
pharma-cokinetic and pharmacodynamics of ganciclovir in
premature infants. A study (NCT01602614) on its use in
infants born at less than 32 weeks is currently underway.
Peer support
Diagnosis with congenital CMV can be difficult for families
and it is important that families are given adequate
support from the multi-disciplinary team involved in the
care of their child. In addition, parent-led organisations
are available to enlist guidance and peer support for
families (e.g. CMV Action − cmvaction.org.uk).
Unanswered questions
There is a need for further research and pooling of infor
ma-tion on a central registry and the European Congenital
CMV Initiative is currently in progress.
Other important questions that warrant further investi-
gations include:
• Management of infants who presents after 30 days of life
− Is there a case for treatment?
• Is there a benefit in treating infants with mild or
asymptomatic congenital CMV infection?
• What are the long-term effects of treatment with
ganciclovir and valganciclovir?
• Is there a case for screening for congenital CMV in term
or in preterm infants?
• Management of premature infants
− When is it appropriate to treat?
− What is appropriate treatment?
− Short and long-term outcomes with and without
treatment?
• Is there a case for developing maternal vaccination to
prevent CMV infection?
• What are the best strategies to prevent maternal infec-
tion or re-infection in pregnancy?
Conclusion
CMV is the major infectious cause of congenital
abnormalities and hearing loss in infants. Some progress
has been made in terms of treatment for infants with
symptomatic congenital CMV infection. However, the
majority of maternal infection and transmission is
clinically silent. This, along with the absence of initial
symptoms in many infants who later develop complications
such as hearing loss, has resulted in some neglect of the
problem. The scale and scope of congenital CMV infection
needs to be raised internationally and further research
undertaken into effective prevention and management.
Conflict of interest
The authors declare no conflict of interest
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