REVIEW Journal of Bangladesh Perinatal Society

Vol. 1, No. 2, July 2020; Page 75-83

ARTICLE

Updates in Cytomegalovirus Infection in Pregnancy,

Neonates and Infancy: Diagnosis and Treatment 75

Kanij Fatema1, Md Mizanur Rahman2, Shaheen Akhter3

Vol. 1, No. 2, July 2020 BPS journal

................................................................................................................................................
1. Associate Professor, Abstract:
Department of Pediatric
Neurology Congenital cytomegalovirus infection (cCMV) is the most common congenital infection. It is an
Institute of Pediatric important cause of hearing, neurodevelopmental and visual impairment of children particularly
Neurodisorder and in developing countries. There are controversies concerning the diagnosis, treatment modalities
Autism (IPNA), of cCMV infection in infants. There is also debate in treatment of maternal CMV infection. This
Bangabandhu Sheikh
review will highlight the clinical features, investigation protocol and treatment modalities of CMV
Mujib Medical
University (BSMMU). infected neonates, infants and pregnant mothers.
2. Chairman and Most of the cCMV infected neonates are asymptomatic. Among the symptomatic patients the
Professor, important clinical features are microcephaly, hearing loss, chorioretinitis, hepatitis, petechiae etc.
Department of Pediatric Pregnant women usually present with nonspecific viral illness. Viral culture is the gold standard
Neurology
Bangabandhu Sheikh
for diagnosis but it is seldom used for diagnosis, the important investigations for detection is
Mujib Medical PCR for CMV DNA in saliva, serum, urine or CSF.
University (BSMMU). Treatment of infected pregnant mother is not widely recommended and should be individualized.
3. Professor Treatment of moderately or severely symptomatic neonate in 1st month of life with valgancyclovir
Department of Pediatric
for 6 month is widely recommended. There is evidence that public health approaches based on
Neurology
Institute of Pediatric hygiene can dramatically reduce the rate of primary maternal cytomegalovirus infections during
Neurodisorder and pregnancy.
Autism (IPNA)
Key words: congenital Cytomegalovirus (cCMV), neonates, pregnant mother
Bangabandhu Sheikh
Mujib Medical ................................................................................................................................................
University (BSMMU).
Background: congenital CMV (cCMV) infection,
shaheenk33@gmail.com
Address of Cytomegalovirus (CMV) is the most transmission through placenta can occur
Correspondence: common cause of congenital infection during any time of pregnancy. 5-8
Dr. Kanij Fatema worldwide. It is an important cause of Asymptomatic cCMV infection is
FCPS (Pediatric Neurology defined as the presence of CMV in any
and Development), FCPS hearing impairment in children. The
(Pediatrics). disease is asymptomatic in about 85 to secretion within first 3 weeks of life but
Associate Professor
90 percent cases of neonates.1 The the normal clinical, laboratory and
Department of Pediatric
imaging evaluations and symptomatic
Neurology, Institute of symptomatic cases often have signi-
Pediatric Neurodisorder cCMV infection is defined who have
ficant morbidity and mortality.2 The
and Autism (IPNA), clinically evident disease at birth.
Bangabandhu Sheikh children who survive have multiorgan
Mujib Medical University Symptomatic cCMV cases comprise
involvement most importantly neuro-
(BSMMU). only 7-10% of all infected cases.9
Mobile: 01713097751 developmental impairment, hearing
Email: and visual impairment. There are This review will highlight the clinical
mailmonami@gmail.com. features, investigation protocol and
controversies regarding the manage-
ment protocol of infected cases.3,4 treatment modalities of congenital
cytomegalovirus infected neonates,
CMV is a global infection; the infants and pregnant mothers.
prevalence of women of reproductive
age infected with CMV is about 45 to Clinical features:
90%. Transmission of CMV occurs In neonates
through body fluids namely breast CMV is now the leading nongenetic
feeding, sexual activity, blood transfusion, cause of congenital malformations.
organ transplantation and close contact. Most of the infants with cCMV are
Both the primary and secondary asymptomatic at birth. During pregnancy
infection of mother can lead to the features may be polyhydramnios,
Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis
oligohydramnios, fetal ascites, intrauterine growth
restriction etc. Fetal demise may occur in utero in
the form of abortion, nonimmune hydrops, intra
uterine death or still birth. In symptomatic neonates
the presenting features are intrauterine growth
restriction, preterm low birth weight, hepatomegaly,
splenomegaly, bleeding manifestations, jaundice,
neonatal seizure, blueberry muffin spots,
microcephaly, intracranial calcification,
ventriculomegaly, hearing loss, chorioretinitis,
etc.10,11 In infancy and childhood they may develop
intellectual disability, hypotonia, cerebral palsy,
epilepsy, failure to thrive, behavioural disorder etc.
Additionally, approximately 15% of initially
asymptomatic CMV-infected newborns develop
long-term neurological sequelae before the age of 5
years. Central nervous system manifestations are
present in about two third of infants of symptomatic
cCMV. Other less frequent features are pneumonia,
osteitis and intracranial hemorrhage.12,13
Table -I: Clinical features of congenital cytomegalo virus
infection.13-15
• Adverse pregnancy outcomes including
stillbirth, neonatal death, intrauterine growth
restriction and preterm birth
• Maternal pregnancy complications such as
preeclampsia
• Fetal injury including
- Sensori-neural hearing loss
- Vision loss, optic atrophy, strabismus and
chorioretinitis
- Hepatomegaly and splenomegaly
Thrombocytopenia
- Petechiae and jaundice
- Microcephaly, seizures and mental disability
Table-II: Definitions of congenital cytomegalovirus
infection and disease16,17
1. Moderate to sever symptomatic congenital
cytomegalo virus disease
• Multiple manifestations attributable to
congenital cytomegalovirus infection:
thrombocytopenia, petechiae, hepatomegaly,
splenomegaly, intrauterine growth
restriction, hepatitis (raised transaminases
or bilirubin), or
Table continued
76
Kanij Fatema et al.
• Central nervous system involvement such
as microcephaly, radiographic abnormalities
76
consistent with cytomegalovirus central
nervous system disease (ventriculomegaly,
Vol. 1, No. 2, July 2020 BPS journal
intracerebral calcifications, periventricular
echogenicity, cortical or cerebellar
malformations), abnormal cerebrospinal
fluid indices for age, chorioretinitis,
sensorineural hearing loss, or the detection
of cytomegalovirus DNA in cerebrospinal
fluid
2. Mild symptomatic congenital cytomegalo virus
disease
• Might occur with one or two isolated
manifestations of congenital cytomegalo-
virus infection that are mild and transient
(eg, mild hepatomegaly or a single
measurement of low platelet count or raised
levels of alanine aminotransferase). These
might overlap with more severe mani-
festations. However, the difference is that
they occur in isolation
3. Asymptomatic congenital cytomegalovirus
infection with isolated sensorineural hearing loss
• No apparent abnormalities to suggest
congenital cytomegalovirus disease, but
sensorineural hearing loss (³21 decibels)
4. Asymptomatic congenital cytomegalovirus
infection
• No apparent abnormalities to suggest
congenital cytomegalovirus disease, and
normal hearing
In Pregnant women:
Symptoms of maternal CMV are nonspecific;
typically there is fever, fatigue and headache. About
25-50% pregnant women are asymptomatic.18 Thus
diagnosis is challenging. Diagnosis is done by IgM
antibody for CMV, seroconversion of previously
seronegative women (IgG or IgM of CMV) or low to
moderate CMV IgG avidity. When these antibodies
are detected using validated assays particularly
before 12–16 weeks of gestation, they indicate a
higher risk for symptomatic congenital infection.
Thus the consensus recommendation is that CMV
serology test should be offered to a pregnant woman
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Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis
when she develops influenza like symptoms not
attributable to another specific infection.19 Moreover,
if the USG or MRI of fetus finding are suggestive of
cCMV infection, serology tests should be done.20,21
Transmission and risk factors for maternal CMV
infection
The infection of fetus is mainly due to the maternal
primary infection. Mother usually acquires the
infection from children who attend day care. Urine
or saliva of these children is the main source of
infection. Moreover, a seronegative mother can
acquire the infection from her partner by sexual
intercourse or saliva. 22-25 In addition to that, the
women who are seropositive before conception can
be infected again with reactivation of latent virus
infection or reinfection. 26-28
Diagnosis of cCMV in neonates and infants:
The diagnosis of cCMV infection in neonate is based
on clinical features along with demonstration of the
virus by isolation from urine, blood, saliva or CSF.
The identification is done by detection of CMV-DNA
by polymerase chain reaction (PCR). It has high
sensitivity (>97%) and specificity (99%). 16 For
confirmation of cCMV it is important that virus is
detected before 3 weeks of age. In can also be
detected by CMV IgM in blood, however, only 70%
of cCMV infected neonates have IgM antibody at
birth. Sensitivity of IgM CMV ELISA in relation to
viral culture is 63.2% and the specificity is 85%.29
IgG antibodies are maternally transmitted mostly.30
The CMV-IgG avidity test is an important test which
can detect the time of primary infection. It is a
measure of the binding capacity of CMV-IgG
antibodies. Low avidity IgG indicates antibody-
production induced by acute or recent primary CMV
infection, whereas high avidity IgG indicates no
current or recent primary infection. But this test is
unavailable in most of the laboratories.31-33
However, the gold standard for the diagnosis of
congenital CMV infection in newborns has
traditionally been viral culture of urine or saliva
specimens. But this method is expensive and
laborious, and, even with use of rapid culture assays,
results may be delayed several days. Thus it is not
practiced widely.34 In this respect, the consensus
recommendation is that the diagnosis of cCMV
infection in neonates should include real-time PCR
of saliva, urine, or both, as soon as possible after birth
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Kanij Fatema et al.
but within the 1st 3 weeks of life, with saliva as the
preferred sample.16
77
Diagnosis of maternal cytomegalovirus
infection:
Vol. 1, No. 2, July 2020 BPS journal
Routine screening of CMV of all pregnant women is
not recommended by national public health bodies
in any country. However, selective testing of
pregnant women is done. It is here to mention that
women who are seropositive of CMV before
pregnancy can give birth to cCMV infected infants
(non-primary maternal CMV infection). Estimates
suggest that more than two-thirds (about 75%) of all
congenital cytomegalovirus cases in the USA (and
by implication in other developed countries) occur
in infants born to women with non-primary
cytomegalovirus infection, presumably due to
reactivation of latent virus, reinfection with a new
cytomegalovirus strain, or both. Moreover, there is
increasing evidence that the risk of symptomatic
infection, especially that resulting in hearing loss, is
similar after maternal primary or non-primary
cytomegalovirus infection. Thus there is minimal use
of screening of pregnant women to diagnose primary
CMV infection and it is not recommended by most
of the authorities. Investigation to diagnose the
infection in mother are the following:
1. IgG seroconversion (appearance of virus-specific
IgG in the serum of a pregnant woman who was
previously seronegative)
2. Presence of anti-CMV IgM and IgG antibodies,
3. Anti-CMV IgG avidity test. Seroconversion of
CMV IgG between two serum samples obtained
in 2-3 weeks distance provides the most reliable
diagnosis of primary infection. When there is
presence of CMV-IgM in blood it suggests a
recent or ongoing infection, however it has a low
specificity.16,36,37,38
Role of other modalities of investigations in
diagnosis:
Neuroimaging is an important mode of diagnosis of
cCMV. In CT brain the changes are as follows:
intracranial calcifications, white matter low density
regions, ventriculomegaly, cerebral atrophy,
neuronal migration disorders. Calcification is the
most frequent feature here, the calcification is
particularly thick and chunky in germinal matrix and
periventricular regions with faint and punctate basal
ganglia calcifications. In MRI the features are
ventriculomegaly, hydrocephalus, delayed
77
Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis Kanij Fatema et al.

Table-III: Diagnostic methods available for the diagnosis of maternal, fetal and neonatal CMV infection.35

Type of patient Diagnostic method Comments 78

Maternal infection 1. IgG seroconversion Two consecutive maternal blood
(appearance of virus- samples need to be collected 2-3 weeks

Vol. 1, No. 2, July 2020 BPS journal

specific IgG in the serum
of a pregnant woman who
was previously
seronegative)
2. Presence of anti-CMV
IgM and IgG antibodies
3. Anti-CMV IgG avidity
test
apart. IgM can be detected in:
• reactivations or reinfections;
• until more than one year after
CMV primary infection;
• interference due to
rheumatoid factor of the IgM
class or cellular antigen;
• false positive during other
viral infections (B19 Virus,
Epstein Barr Virus, etc.).

Low avidity means recent maternal

infection, but threshold differs
between virological methods.
Fetal infection Amniocentesis to assess • Perform the test after the 21st
the presence of CMV by week of gestation and after 5-6
PCR weeks from the estimated
onset of infection.

• Indications are: woman with

Neonatal infection
Culture or CMV-DNA
testing by PCR in urine,
blood, throat and CSF.
compatible clinical signs of
primary CMV infection;
compatible ultrasound
abnormalities; serologic
suspicion of a recent maternal
infection.
If infection is confirmed, classify as
symptomatic or asymptomatic and
follow-up at 1, 3, 6 and 12 months and
annually until school age in order to
detect sequelae with delayed onset.

myelination, periventricular and temporal pole cysts,
migrational abnormalities like lissencephaly,
pachygyria, cortical dysplasia, polymicrogyria,
schizencephaly etc.39 (Figure 1, B, C)
Ophthalmological evaluation is important in cCMV
infected cases. The ophthalmological features are
cortical visual impairment, strabismus, optic atrophy,
chorioretinal patch, retinal detachment, nystagmus,
refractive error. Ophthalmological manifestations are
not progressive. (Figure 1, D) However, progressive
hearing loss is common in symptomatic cCMV. The
prevalence of Sensory neural hearing loss (SNHL)
caused by cCMV infection (symptomatic and
asymptomatic) at birth is 5.2% and late-onset hearing
loss at 6 years is 15.4%. SNHL is the most frequent
long-term consequence and is not manifested
invariably at birth or in the neonatal period. Thus
formal audiological and visual assessment should be
done in all patients of cCMV. 40,41
Treatment of cCMV infected neonates
Most of the researchers suggest treatment with
antiviral to moderate and severe symptomatic cCMV
infected neonates. Breastfeeding is encouraged.42
However, some authors suggest treatment in the
following cases:
1. Evidence of central nervous system
involvement, including SNHL and develo-
pmental delay.

78 Vol. 1 | No. 2 | July 2020

Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis Kanij Fatema et al.

79

Vol. 1, No. 2, July 2020 BPS journal

Fig.-1: A. Microcephaly in a cCMV infected infant; B. CT scan of brain showing calcification in the periventricular
areas; C. CT scan of brain showing lissencephaly and agyria (neuronal migration defect ) in cCMV infected case; D.
Chorioretinitis of cCMV infection.

2. Chorioretinitis (virus clearance 93% in VGCV and 80% in GCV

3. Critically ill preterm infant with life threatening
CMV infection manifested by pneumonitis,
hepatitis or encephalitis.43 Timing of treatment
is very important. Most of the authorities suggest
tostart the treatment within first month of life.16
However, in some studies treatment was
commenced beyond one month, up to 1 year of
age.43
Among currently available antivirals, intravenous
ganciclovir (GCV) and oral valganciclovir (VGCV)
have been studied for the treatment of infants with
cCMV infection. Result from a study done by Kanij
et al.44 showed that there was no statistical difference
in virus clearance in VGCV and GCV treated infants
treated infants). Although the side effects of GCV
treated infants were more that the VGCV treated
infants. Here treatment was given for a period of 6
weeks in both groups.
Currently VGCV is the drug of choice by most of the
researchers. The dose of VGCV is 16mg/kg/dose 12
hourly. Based upon the fact that infants with cCMV
demonstrates prolonged viral shedding and delayed
or progressive sequelae, recent recommendations are
in support of longer duration of treatment. The
collaborative antiviral study group (CASG)
conducted a randomized, placebo-controlled trial
comparing 6 week oral VGCV therapy with 6 month
VGCV therapy in cCMV infants. There was
improved outcome of hearing and neuro-

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Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis
developmental parameters in 6 month group.17
Prolonged VGCV treatment was associated with
neutropenia, although the incidence was markedly
lower than previously observed with intravenous
GCV. Thus, VGCV treatment for 6 months is
recommended for congenitally infected neonates.
Currently, there is no definitive evidence about the
potential benefit of antiviral for treatment of mildly
symptomatic or asymptomatic infants with isolated
sensorineural hearing loss, so they should not
routinely be given antiviral therapy.16,17,44
VGCV and GCV provides similar systemic exposure.
Dose of GCV is 5-6 mg/kg/dose 12 hourly. GCV is
associated with a number of drug toxicities. The
adverse effects are myelosuppression (such a
granulocytopenia, anemia, thrombocytopenia) ,
raised liver enzymes, hypokalemia and renal
impairment. For GCV-induced neutropenia, it has
been demonstrated that Granulocyte Colony
Stimulating Factor could be used to increase the
absolute neutrophil count, while continuing long-
term GCV therapy. Another challenge is maintaining
the intravenous access. All these side effects are
reversible after stopping the drug for 3-7 days or
decreasing the dose of the drug.35 Toxicity of VGCV
is similar to that of GCV. About 38% of the patients
develop neutropenia in VGCV treated cases while
63% of that of GCV treated cases.45
Table-IV: Hygiene precautions and behavioural
interventions that could prevent cytomegalovirus
infection in pregnant women. 46-48
1. Do not share food, drinks, or utensils used by
young children
2. Do not put a child’s dummy/soother/pacifier
in your mouth
3. Avoid contact with saliva when kissing a child
4. Thoroughly wash hands with soap and water
for 15–20 seconds, especially after changing
nappies/ diapers, feeding a young child, or
wiping a young child’s nose or saliva
5. Other precautions that can be considered, but
are likely to less frequently prevent infection,
include clean toys, countertops, and other
surfaces that come into contact with children’s
urine or saliva, and not sharing a toothbrush
with a young child.
80
Kanij Fatema et al.
Treatment of pregnant mother, intervention to treat
fetal CMV:
Currently there is no approved treatment for fetal 80
CMV infection. Several studies have been done on
CMV Human immunoglobulin (HIG) and antivirals
Vol. 1, No. 2, July 2020 BPS journal
(VGCV) to pregnant women with primary CMV
infection. But no randomized, placebo-controlled
clinical trials have established the efficacy of
potential prenatal treatments for fetal CMV infection.
Thus antenatal treatment is not widely
recommended. If treatment is recommended to a
patient, it should be accompanied by forthright
explanation regarding the level of certainty (or
uncertainty) of benefit or adverse effects. Some
experts recommend that such interventions be
confined to clinical trials and is individualized.
Further study in this field is needed.49,50
Prevention of infection of pregnant mother:
Preventing CMV infections in pregnant women is
an important public health concern. Till date no CMV
vaccine is in practice. Two important form of
exposure is contact with young children and sexual
contact. Avoiding both the modalities are difficult.
Thus only way of prevention is to maintain proper
hygiene by regular hand washing, particularly after
changing diapers. Hygiene education of mother
plays important role. Studies of hygiene education
to decrease maternal CMV infection rates during
pregnancy have had promising results. In one study
there was a statistically significant decrease in CMV
infection rate from 42% to 6% when women who
were pregnant got hygiene education. The
information can be given by video, in writing,
pictorial teaching, demonstrations to group etc. 46-48
Follow up cCMV infected neonates:
It is important to identify all infants with cCMV
infection so that appropriate developmental
interventions and long-term follow-up can be
established. Once diagnosed they should be tested
for hearing impairment every 6 months for 3 years
and then yearly for at least 1-2 years. The
interventions suggested are physical therapy,
occupational therapy, hearing aids, cochlear implants
according to the problem status. 17
Conclusion:
Cytomegalovirus remains the major infectious cause
of fetus and infants. This review summarizes the
clinical features, diagnosis, treatment protocol of
cCMV infected fetus and infants along with pregnant
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Updates in Cytomegalovirus Infection in Pregnancy, Neonates and Infancy: Diagnosis
mothers with updated information. It may thus help
to develop a protocol to manage pregnant women
with infection, manage fetus and infants with
congenitally acquired infection and thus prevent the
sequelae of this infection particularly hearing and
neurodevelopmental deficit.
Table-V: Recommended treatment regimen and
monitoring of the congenitally cytomegalovirus-infected
neonate.16
1. Who to treat
• Neonates with moderately to severely
symptomatic congenital cytomegalovirus
disease
2. When to treat
• Within the first month of life
3. What to treat with
• Oral valganciclovir 16 mg/kg per dose
orally, twice a day
4. How long to treat
• Treatment duration for the goal of
improving audiological or developmental
outcomes should not exceed 6 months
5. Monitoring during treatment
• Absolute neutrophil counts should be
followed weekly for 6 weeks, then at week
8, then monthly for the duration of therapy
• Levels of transaminases should be followed
monthly throughout therapy
6. Follow up -An ophthalmological examination
should be done early in the course of treatment,
with follow-up eye examinations as suggested
by the ophthalmologist -Audiological testing
should be done at 6-month intervals for the first
3 years of life, and annually thereafter through
adolescence (ages 10–19).
- Developmental assessments beginning at
the first year of life might be helpful in some
children with symptomatic congenital
cytomegalovirus disease, and should be
employed on a case-by-case basis
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