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com
ADC-FNN Online First, published on January 18, 2016 as 10.1136/archdischild-2015-308357
1
Department of Pediatrics C,
Schneider Children’s Medical
Center of Israel, Petach Tikva,
Israel
2
Department of Otology, Rabin
Medical Center, Petach Tikva;
both affiliated with Sackler
Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel
3 infection in the first and second trimesters (diagnosed by
Department of Neonatology,
Rabin Medical Center, Petach
Tikva; both affiliated with
Sackler Faculty of Medicine, Tel
Aviv University, Tel Aviv, Israel
4
Departments of Obstetrics and
Gynecology, Rabin Medical
Center, Petach Tikva; both
affiliated with Sackler Faculty
of Medicine, Tel Aviv
University, Tel Aviv, Israel
Correspondence to
Dr Jacob Amir, Department of
Pediatrics C, Schneider
Children’s Medical Center of
Israel, Petach Tikva 49202,
Israel; amirj@clalit.org.il
Received 1 February 2015
Revised 20 December 2015
Accepted 21 December 2015
To cite: Amir J, Atias J,
Linder N, et al. Arch Dis
Child Fetal Neonatal Ed
Published Online First:
[please include Day Month
Year] doi:10.1136/
archdischild-2015-308357
Amir J, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F5. doi:10.1136/archdischild-2015-308357
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Original article
Follow-up of infants with congenital
cytomegalovirus and normal fetal imaging
Jacob Amir,1 Joseph Atias,2 Nechama Linder,3 Joseph Pardo4
ABSTRACT
Objective To evaluate the outcome of infants with
congenital cytomegalovirus (CMV) infection and normal
fetal imaging.
Design Retrospective cohort study.
Setting Tertiary paediatric medical centre.
Patients 98 infants born to mothers with primary CMV
positive amniotic fluid findings) and normal fetal
imaging.
Methods Initial evaluation included confirmatory urine
culture, complete blood count, liver and kidney function
tests, funduscopy, brain ultrasound and hearing test.
Follow-up included periodic neurological and
developmental evaluation, hearing tests until age 5 and
Bayley-III Developmental Scale (in some patients).
Main outcome measures The presence and rate of
sequelae of congenital CMV.
Results 52 (53.1%) infants received early antiviral
treatment for central nervous system symptoms or signs,
mainly lenticulostriatal vasculopathy on postnatal
ultrasonography (88.5%). Sensorineural hearing loss was
found on first examination in 16 infants (25 ears), of
whom 10 also had cranial ultrasound findings; another
five with late-onset hearing loss were also treated. The
median follow-up time was 32 (12–83) months. Most
infants with moderate and severe hearing loss were
infected in the first trimester (10 vs 2, p=0.053). At the
last assessment, eight children (10 ears) still had hearing
loss, including two with bilateral loss who underwent a
cochlear implant. The mean Bayley-III score was 102.6
±10.3 (range 85–127). All 98 children attended regular
educational institutions.
Conclusions Congenital CMV infection acquired from
primary maternal infection with normal fetal imaging is
associated with a high rate of subtle signs and
symptoms after birth. Overall, intermediate-term outcome
is good with a low rate of sequelae.
INTRODUCTION
Cytomegalovirus (CMV) is the most frequent cause
of intrauterine infections, affecting 0.2–2.2% of
live births worldwide.1 2 The risk of primary mater-
nal infection during pregnancy is approximately
2%,3 with intrauterine transmission rates ranging
from 30% to 42% in the first trimester and from
38% to 44% in the second trimester.4–7 Primary
infections are more likely to be associated with
severe fetal damage than recurrent infections. In
one study, 18% of infants exposed to primary
maternal infection were symptomatic at birth com-
pared with almost none exposed to a recurrent
infection.8 Sensorineural hearing loss (SNHL) was
found in 15% of infants born to mothers with a
What is already known on this topic
▸ Twenty-five per cent of infants with congenital
cytomegalovirus (CMV), born to mothers with a
primary infection during the first and second
trimesters, have neurological sequelae.
▸ There are few reports of the outcome of a
subgroup of infants with congenital CMV with
normal fetal imaging.
What this study adds
▸ Fifty per cent of infants (46) with congenital
CMV, born to mothers with primary CMV
infection and who had normal fetal imaging of
ultrasound and fetal MRI, had subtle abnormal
postnatal ultrasound findings.
▸ Eight of 98 children had hearing loss at the last
assessment; two children with bilateral severe
hearing loss who underwent a cochlear
implant; the other six children all had unilateral
hearing loss.
▸ Developmental outcome was good; all children
attended regular educational institutions.
▸ Bayley-III Scale scores were normally distributed
in a subgroup of patients assessed.
primary infection, which was severe and bilateral in
approximately 50% of infants.8 9 However, in the
USA, only 25% of infants with congenital CMV
infection were attributable to primary maternal
infection; 75% were born to mothers with non-
primary infections (reactivation or reinfection with
different viral strains).10 In a recent population-
based prediction model, it was estimated that non-
primary infections account for the majority of
CMV-related hearing losses.11
In the past, owing to the perceived high rate of
neurological sequelae in children infected with
CMV in utero, most women in Israel preferred to
terminate their pregnancy if the virus was isolated
from the amniotic fluid after a primary infection.
During the last decade, however, improvements in
serological assays,12 13 fetal brain ultrasound and
fetal brain MRI14–17 have led to earlier and more
accurate intrauterine detection of fetal brain
damage. Therefore, in Israel today, when all fetal
imaging studies are normal, some women opt to
continue their pregnancy even in the presence of
positive CMV findings in the amniotic fluid.
F1
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Original article
The aim of this study was to compare the short-term and
intermediate-term outcomes of infants with a maternal CMV
infection in the first trimester versus the second trimester with
normal fetal imaging.
PATIENTS AND METHODS
The electronic records of a tertiary paediatric medical centre
were searched for all infants born during 2007–2013 to
mothers who had had a primary maternal CMV infection in the
first or second trimester with positive findings in the amniotic
fluid. Only those with normal fetal imaging who were older
than 1 year on 1 January 2014 were included in the follow-up
analysis. Background, clinical and imaging data at diagnosis and
follow-up were recorded. The findings were compared between
infants infected in the first trimester or the second trimester.
In Israel, many women undergo serological screening for
CMV before or during the first trimester. Those who are sero-
negative are reassessed during pregnancy. The diagnosis of
primary CMV infection is based on the following criteria: sero-
conversion of IgG from negative to positive during pregnancy,
low IgG with low avidity in the presence of specific IgM and a
significant rise in IgG and avidity at a later date. The timing of
the maternal infection is determined by the serological and clin-
ical data. These data are further examined to identify cases of
periconceptional infection (4 weeks before the last reported
menstrual period and up to 3 weeks of gestation).
Amniocentesis to detect fetal CMV is performed after 21 com-
pleted weeks of gestation and at least 7 weeks after the assumed
date of infection. Fetal CMV infection is diagnosed when the
virus is detected in the amniotic fluid by both PCR amplification
and rapid shell-vial culture. Follow-up fetal imaging includes
repeated detailed transabdominal and transvaginal ultrasound
and fetal brain MRI at 33–34 weeks of gestation.
All infants undergo confirmatory urine culture (shell-vial)
during the first 2 weeks of life. Clinical and laboratory studies
performed immediately after birth include complete blood
count, liver and kidney function tests, funduscopy and ultrason-
ography over the anterior and posterior fontanels ( performed
by a paediatric radiologist). Small head circumference is defined
as less than the second centile (<2 SD) and microcephaly as <3
SD. Full physical examination and neurological and develop-
mental assessments are performed during the neonatal period; a
second examination is performed within the first 3 months of
life and every 3–6 months thereafter. In addition, hearing is
evaluated by brainstem evoked response audiometry (BERA)
during the first 2 weeks of life and again every 3–6 months until
Table 1 Postnatal signs and symptoms in infants with congenital
CMV infection (n=98) by trimester of infection
First trimester Second trimester
Signs and symptoms n=52 (%) n=46 (%)
Abnormal brain ultrasound* 25 (48.1) 21 (45.7)
Small head circumference 4 (7.7) 2 (4.4)
Thrombocytopaenia 3 (5.6) 1 (2.2)
Elevated liver enzymes 2 (3.9) 2 (4.4)
Chorioretinitis 1 (1.9) 0 (0)
Splenomegaly 9 (17.3) 9 (19.6)
SNHL (ears) 16 (15.4) 9 (9.8)
*In 44 cases, the abnormal ultrasound showed LSV.
CMV, cytomegalovirus; LSV, lenticulostriatal vasculopathy; SNHL, sensorineural
hearing loss.
F2
age 2; behavioural hearing tests are performed between ages 2
and 5 years. Patients with abnormal findings on behavioural
tests undergo further testing with BERA. Evoked potentials are
measured using Bio-Logic (Bio-Logic Systems Corp.,
Mundelein, Illinois, USA). Tympanometry is performed in
patients with an abnormal BERA test and suspected conduction
problems. If middle ear dysfunction is found, BERA is repeated
after a few weeks, and only the bone-conduction results are
used. BERA results are categorised according to a modification
of the threshold definition used in the University of Alabama
studies18 and the Grundfast and Siparsky19 method,: <25 dB—
normal hearing; 25–44 dB—mild SNHL; 45–69 dB—moderate
SNHL; ≥70 dB—severe SNHL.
For the present study, we also recorded scores on the Bayley
Scales of Infant and Toddler Development, 3rd Edition
(Bayley-III),20 which was administered to a subgroup of patients
at ages 1–3 years by a clinical psychologist well trained in the
use of this instrument.
All infants with a hearing loss or abnormal cranial ultrasound
findings are treated using one of two clinical protocols: (a) up
to 2011, intravenous ganciclovir 5 mg/kg twice a day for
6 weeks followed by oral valganciclovir 17 mg/kg/dose in two
daily doses for 6 weeks followed by one daily dose for 9 months
was given21 and (b) since 2011, the protocol used oral valganci-
clovir 17 mg/kg/dose in two daily doses for 12 weeks followed
by one daily dose for 9 months.
Groups were compared by the χ2 test or the Fisher’s exact
test (two-tailed) for categorical variables and the Mann–
Whitney test for continuous non-parametric variables
(follow-up time). p<0.05 was considered significant.
RESULTS
One hundred and one mothers met the study criteria: preg-
nancy during 2007–2013; primary CMV infection in the first or
second trimester; positive CMV findings in the amniotic fluid
and normal findings on fetal imaging by both ultrasound and
MRI; in three cases, there were suspected abnormal findings in
the brain white matter seen only on the MRI. After a review of
the MRI scans, they were reported as normal; therefore, no case
was excluded from the study due to a normal ultrasound and
abnormal MRI. There was a steady increase over time in the
number of women with positive amniotic fluid findings who
opted to continue the pregnancy and gave birth: 4 during 2007
and 6, 12, 19, 32 and 28 during 2008–2012, respectively. The
rate of termination of pregnancy due to CMV detection in the
amniotic fluid decreased from approximately 90% in 2007 to
30% in 2012, in our centre.
The final study group consisted of 98 of these infants with
congenital CMV infection. The other three were lost to
follow-up. Diagnosis was confirmed by a positive urine culture
for CMV (shell-vial) during the first 2 weeks of life. Fifty-two
infants (53.1%) acquired the infection in the first trimester and
p Value 46 (46.9%) in the second trimester (p=0.544). There was no
difference in sex distribution by time of infection (61.5% and
0.671 56.5% males, respectively, p=0.544). Ninety-one infants
0.542 (92.9%) were born at term and seven (7.1%) at near-term/pre-
0.442 maturely (34–36 weeks). Of the premature infants, six (11.5%
0.885 of the cohort) were infected in the first trimester and one
0.557 (2.2%) in the second trimester ( p=0.063). Birth weight was
0.769 within the normal range in 94 infants (95.9%). The other four
0.240 were small for gestational age, two (3.9%) infected in the first
trimester and two (4.4%) in the second trimester ( p=0.664).
Sixty infants (61.2%) exhibited early postnatal signs or symp-
toms possibly related to congenital CMV infection according to
Amir J, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F5. doi:10.1136/archdischild-2015-308357
 Downloaded from http://fn.bmj.com/ on January 19, 2016 - Published by group.bmj.com
our definition. Abnormal cranial ultrasound findings were
observed in 46 (46.9%), mostly (44/46, 95.7%) lenticulostriatal
vasculopathy (LSV). One infant each (2.1%) had periventricular
hyperechoic foci and a single small calcification. Head circum-
ference was below the second centile in six infants (6.1%).
There were four cases each of elevated liver enzyme levels and
thrombocytopaenia. None of the infants had a petechial rash.
Splenomegaly was the most common non-central nervous
system (CNS) sign found in 18 infants (18.4%). Of the 46
infants with an abnormal cranial ultrasound, 10 had SNHL, 12
splenomegaly, 4 a small head circumference, 3 thrombocyto-
paenia and 1 chorioretinitis. Nine of the 10 infants with an
abnormal ultrasound and SNHL had only LSV. The distribution
of the signs and symptoms by time of infection is shown in
table 1.
SNHL was detected on initial assessment in 16/98 infants
(16.3%) with 25 affected ears (12.8% of total 196 ears): mild
in 13 ears, moderate in 9 and severe in 3. Although not reaching
statistical significance, there were more cases of moderate and
severe hearing loss among infants infected in the first trimester
than infants infected in the second trimester (10 vs 2,
p=0.053).
Fifty-two infants (53.1%) were treated with an antiviral agent
starting in the first month of life. The main indication for treat-
ment was an abnormal cranial ultrasound finding in 46 infants
(88.5% of treated patients). Of the 16 infants with early SNHL,
10 also had an abnormal ultrasound finding and the other 6
were treated only for the hearing loss. An additional five
patients were treated at a later period for SNHL, making a total
of 57 treated patients in the cohort (58.2%).
The median duration of follow-up was 32 (12–83) months.
Infants infected during the first trimester were followed for sig-
nificantly less time than those infected during the second trimes-
ter (27 (12–83) versus 45 (12–77), p<0.001). Of the six
patients with a small head circumference on initial examination
(table 1), four measured above the second centile at the last
follow-up and two remained below.
The findings on hearing tests are shown in table 2.
Reassessment of the 16 children (25 ears) with hearing loss at
the first examination revealed that of the 13 ears with mild
hearing loss, 9 showed an improvement and 4, no change. Of
the nine ears with moderate hearing loss, six showed an
improvement and one deteriorated to severe hearing loss. None
of the three ears with initially severe hearing loss showed any
change by the last visit. An additional five patients (10 ears)
were found to have late-onset SNHL at age 5–14 months. All
improved to normal hearing after treatment. Thus, of the 98
children in the cohort, eight children (10 ears) had hearing loss
at the last assessment. Analysis by the best-ear approach18
yielded two children with bilateral severe hearing loss who
Table 2 Initial and last assessments of hearing levels in 98 infants (196 ears) with congenital CMV infection by trimester of infection*
First trimester
Initial test Last test
N (ears)=104 N (ears)=92
Normal 88 (84.6) 95 (91.4)
Mild SNHL 6 (5.8) 3 (2.9)
Moderate SNHL 7 (6.7) 2 (1.9)
Severe SNHL 3 (2.9) 4 (3.9)
*The median duration of follow-up is 32 (12–83) months.
CMV, cytomegalovirus; SNHL, sensorineural hearing loss.
Amir J, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F5. doi:10.1136/archdischild-2015-308357
Original article
underwent a cochlear implant; the other six children all had
unilateral hearing loss: moderate in two, mild in four.
The patient with chorioretinitis (table 1) had normal vision
with a small retinal scar. Motor development was assessed
approximately every 6 months. Two children experienced mild
motor delays (started walking independently at 18 and 19
months); both were diagnosed with benign hypotonia. One also
had a small head circumference. The other had a brother who
exhibited the same motor skills pattern. The rest of the cohort
achieved normal motor milestones.
Developmental assessment by the Bayley-III was performed
during 2010–2011 in a subgroup of 27 patients. The mean
mental developmental index was 102.6±10.3 (range 85–127).
None of the patients showed any cognitive delay.
At the end of this study, all 98 children were attending
regular educational institutions. Five were in first or second
grade, 40 in kindergarten and 53 in day-care centres.
DISCUSSION
In Israel, screening for CMV infection is frequently performed
before or during the first trimester of pregnancy. Amniocentesis
is performed in mothers with a primary infection to detect fetal
infection. Over the study period, there was an increase in
patients with primary CMV infection and normal fetal ultra-
sound who continued the pregnancy. The numbers have been
steadily increasing, as demonstrated in the present study.
The neurodevelopmental impact of intrauterine CMV ranges
from no adverse long-term effects to severe damage and even
fetal death. The present study describes the short-term and
intermediate-term outcomes of infants with congenital CMV
infection diagnosed in utero by positive amniotic fluid (PCR)
with normal fetal imaging (ultrasound and MRI) results. All
were infected in the first or second trimester. Three cohort
studies in the literature reported a good short-term prognosis
for infants with these characteristics.17 22 23
Accordingly, most of the 98 infants in our study were born at
term with normal birth weight. However, 61% exhibited subtle
signs and symptoms of congenital CMV infection undetected on
fetal imaging (table 1). About 50% had abnormal postnatal
ultrasound findings, mostly LSV.
Is LSV a true sign of CNS involvement caused by CMV infec-
tion? Researchers have no definitive answer. However, in our
published experience24 and a recent larger cohort study (submit-
ted for publication), we showed that LSV is a common finding
in infants with congenital CMV infection and may serve as a
marker of high risk for SNHL. In the present study, 12.8% of
ears had hearing loss on the first BERA. Most cases were mild,
although moderate and severe hearing losses were associated
more often with first-trimester infection rather than second-
trimester infection ( p=0.053). All infants with abnormal
Second trimester
Initial test Last test
p Value n (ears)=104 n (ears)=92 p Value
0.249 83 (90.2) 91 (98.9) 0.02
7 (7.6) 1(1.1)
2 (2.2) 0 (0.0)
0 (0.0) 0 (0.0)
F3
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Original article
ultrasound findings or SNHL were treated with ganciclovir/val-
ganciclovir. By the last hearing assessment, six children had uni-
lateral residual hearing loss (no hearing aid); only two required
cochlear implants for severe bilateral hearing loss.
Small head circumference was detected on initial examination
in six infants (6%). In two of them, the findings normalised at
the following clinical visit, suggesting that the abnormalities had
been due either to moulding of the skull or to error. In the
other four patients, head circumference remained on the second
centile in two and below the second centile in two (2 SD below
the mean) at the last follow-up examination. In all these cases,
head circumference had been reported as normal on fetal ultra-
sound examination. This discrepancy may have been due to dif-
ferent definitions of abnormal head circumference among
paediatricians (less than the second centile or <2 SD below the
mean)25 and ultrasound guidelines for fetal microcephaly (3 SD
below the mean).26 Accordingly, others described three infants
diagnosed on follow-up with microcephaly and developmental
delay in which fetal ultrasound findings had been considered
normal.27 We suggest that the relationship between fetal ultra-
sound head circumference measurements and postnatal clinical
findings needs to be reassessed.
The developmental outcome of our cohort was good, with all
patients attending regular educational institutions at the end of
the study. In the subgroup of patients assessed with the
Bayley-III Scale, scores were normally distributed. These results
may reflect our selection of patients with normal fetal imaging
findings, although the antiviral therapy may also have contribu-
ted, as reported by others.28 29 Indeed, the rate of antiviral
treatment was high (57/98 cases, 58.2%) because we treated the
infants with LSV. There are no reliable data on the treatment
rate of infants who were born to mothers with primary CMV
infection and normal fetal imaging findings. Most studies have
included mainly symptomatic patients without brain ultrasound
studies. Our report is a large cohort describing this unique
patient group. The results also support the relative safety of the
approach used in our centre in pregnancies complicated by
primary maternal CMV infection during the first and second
trimesters.
The main limitations of this study were the relatively short
follow-up of the infants infected during the first trimester, the
absence of a control group of untreated infants with a sole
abnormal finding of LSV on ultrasound and the small number of
patients formally assessed for developmental delay. Although
postnatal antiviral therapy is now common practice in many
medical centres worldwide, the presented therapy protocol is
more extensive than used in most centres treating congenital
CMV. Our protocol was not studied in controlled trials;
however, recent data have implied that longer treatment seems
better.29 Moreover, no controlled studies have specifically
assessed the benefit of treating babies with only subtle signs on
cranial ultrasound or isolated SNHL or in late-onset hearing
loss. Improvement in these groups may therefore be due to
hearing threshold fluctuations known to occur in congenital
CMV.30
In conclusion, this study demonstrates that infants with con-
genital CMV infection acquired from primary maternal infec-
tion during the first and second trimesters of pregnancy with
normal findings on fetal imaging may have a high rate of subtle
postnatal signs and symptoms. First trimester infection is asso-
ciated with a trend towards more severe hearing loss than
second trimester infection. Overall, the outcome of these infants
is good, with a low rate of sequelae on short-term follow-up
and intermediate-term follow-up.
F4 Amir J, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F5. doi:10.1136/archdischild-2015-308357
Acknowledgements The authors thank Mrs Phyllis Curchack Kornspan for her
editorial services and Mrs Tamar Elazar for her secretarial services.
Contributors JA: designed the study, collected all follow-up data and wrote the
manuscript. JA: responsible for collecting and analysing the hearing studies. NL:
collected and analysed the short-term data of the newborn with congenital CMV. JP:
collected and analysed the data relating to the pregnant women and contributed in
interpretation of the data.
Competing interests None declared.
Ethics approval The study protocol was approved by the Rabin Medical Center’s
ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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Amir J, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F5. doi:10.1136/archdischild-2015-308357 F5

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Follow-up of infants with congenital

cytomegalovirus and normal fetal imaging
Jacob Amir, Joseph Atias, Nechama Linder and Joseph Pardo

Arch Dis Child Fetal Neonatal Ed published online January 18, 2016

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