Journal of Perinatology (2017) 00, 16

2017 Nature America, Inc., part of Springer Nature. All rights reserved 0743-8346/17
www.nature.com/jp

ORIGINAL ARTICLE
Long-term outcomes of children with symptomatic congenital
cytomegalovirus disease
TM Lanzieri1, J Leung1, AC Caviness2, W Chung3, M Flores2, P Blum4, SR Bialek1, JA Miller4,5, SS Vinson2,4, MR Turcich2,4, RG Voigt2,4,
G Demmler-Harrison2,4 for the Congenital Cytomegalovirus Longitudinal Study Group

OBJECTIVE: To assess long-term outcomes of children with symptomatic congenital cytomegalovirus (CMV) disease detected
at birth.
STUDY DESIGN: We used Cox regression to assess risk factors for intellectual disability (intelligence quotient o 70), sensorineural
hearing loss (SNHL; hearing level 25 dB in any audiometric frequency) and vision impairment (best corrected visual acuity 420 or
based on ophthalmologist report).
RESULTS: Among 76 case-patients followed through median age of 13 (range: 027) years, 56 (74%) had SNHL, 31 (43%, n = 72) had
intellectual disability and 18 (27%, n = 66) had vision impairment; 28 (43%, n = 65) had intellectual disability and SNHL with/without
vision impairment. Microcephaly was signicantly associated with each of the three outcomes. Tissue destruction and dysplastic
growth on head computed tomography scan at birth was signicantly associated with intellectual disability and SNHL.
CONCLUSION: Infants with symptomatic congenital CMV disease may develop moderate to severe impairments that were
associated with presence of microcephaly and brain abnormalities.
Journal of Perinatology advance online publication, 6 April 2017; doi:10.1038/jp.2017.41

INTRODUCTION 3 weeks of life who presented at least one of the following CMV-related
Congenital cytomegalovirus (CMV) infection can cause micro- signs at birth: purpura/petechiae, jaundice, hepatosplenomegaly, micro-
cephaly, unexplained neurological abnormality, elevated liver enzymes
cephaly and result in a spectrum of neurodevelopmental
(alanine aminotransferase 4100 IU), hyperbilirubinemia (total bilirubin
disorders, such as sensorineural hearing loss (SNHL), vision loss 43 mg dl 1), hemolytic anemia or thrombocytopenia (platelet count
and intellectual impairment.1 In the United States, an estimated o75 000/mm3). We did not consider infants who were small for
20 000 (0.5%) children are born with congenital CMV infection gestational age (SGA) or had congenital SNHL in the absence of at least
annually,2,3 of whom 20003000 (1015%) are symptomatic at one of the above signs as having symptomatic congenital CMV disease.16
birth, including 400 (2%) with microcephaly.412 Approximately Seventy-three (95%) case-patients were referrals from several hospitals,
5070% of children with symptomatic CMV disease at birth and 4 (5%) case-patients were identied by routine newborn CMV
develop permanent sequelae.1 Antiviral treatment has been screening at Womens Hospital of Texas (Houston, TX, USA), where the
shown to improve developmental outcomes and reduce progres- observed CMV birth prevalence was 0.4% (135 CMV-positive infants among
sion of SNHL in children with neurologic complications of 32 543 screened during 19821992).19 Ninety-six (71%) CMV-positive
congenital CMV disease at birth.13,14 However, because disease newborns whose parents provided consent were enrolled in the
Congenital CMV Longitudinal Study, 4 (4%) were case-patients included
symptoms at birth may be mild or nonspecic, it is likely that only
in the present analysis and 92 (96%) were asymptomatic at birth for whom
a minority of children with symptomatic congenital CMV disease hearing outcomes have been previously described.19 Case-patients had
are clinically diagnosed in the absence of newborn screening.15 neuroimaging evaluations performed by head computed tomography (CT)
Thus, the full impact of congenital CMV disease throughout the scans within 4 months of age, and were followed with neurodevelop-
course of childhood remains largely unrecognized. Furthermore, mental, hearing and ophthalmologic evaluations during infancy, preschool,
the varying denitions of symptomatic congenital CMV disease elementary, middle and high school years. The institutional review board
complicate comparisons across studies.16,17 In the present study, for Human Subject Research for Baylor College of Medicine and Afliated
we describe neurodevelopmental, hearing and vision outcomes of Hospitals approved the study protocol.
children with symptomatic congenital CMV disease detected at We describe case-patients by demographic characteristics, CMV-related
birth followed through a median age of 13 years. signs at birth and other clinical characteristics, including preterm birth and
SGA. We categorized case-patients as SGA or having microcephaly in two
waysbased on physicians clinical assessment at birth and dening SGA
as birth weight 10th percentile and microcephaly as fronto-occipital
METHODS head circumference 3rd and 10th percentiles, using the Olsens
Our study included 76 children born during 19832005 who were enrolled intrauterine growth curves.20 We classied abnormal head CT ndings in
in the Congenital CMV Longitudinal Study11,18,19 as case-patients with infancy into three broad categories implying (1) tissue destruction
conrmed symptomatic congenital CMV disease, dened as a newborn (calcication, hemorrhage, stroke, encephalomalacia, white matter lucency,
with CMV infection detected by culture of urine samples collected within porencephaly/cysts or atrophy); (2) attenuated growth (immaturity,

1
National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA; 2Baylor College of Medicine, Houston, TX, USA;
3
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA; 4Texas Childrens Hospital, Houston, TX, USA and
5
P3S Corporation, San Antonio, TX, USA. Correspondence: Dr TM Lanzieri, National Center for Immunization and Respiratory Diseases, Center for Disease Control and Prevention,
1600 Clifton Road NE, Mail Stop A-34, Atlanta, GA 30333, USA.
E-mail: [email protected]
Received 18 November 2016; revised 20 February 2017; accepted 3 March 2017
 Long-term outcomes of symptomatic congenital CMV
TM Lanzieri et al
2
hypoplasia or underopercularization); and (3) dysplastic growth (migra- SGA based on the Olsens intrauterine growth curves than based
tional abnormalities, such as lissencephaly or pachygyria). Volume loss was on physicians clinical assessment at birth (58% vs 37%). The
inferred by dilatation of cisterns and/or cerebrospinal uid spaces. proportion of case-patients with microcephaly was 41%, based on
Neurodevelopmental evaluations included assessments of physical, physicians clinical assessment at birth. Among 73 case-patients
motor, sensory and cognitive development in infants and young children, with head circumference measurement recorded, 34% had head
and measurement of intelligence quotient or adaptive level of functioning
among older children. Neurodevelopmental evaluation was done using
circumference 3rd and 51% 10th percentile for gestational
one of the following tests: Bayley Scales of Infant Development21 (n = 13), age. The median age at last follow-up visit was 13 (range: 027)
McCarthy Scales of Childrens Abilities22 (n = 4), Wechsler Intelligence Scale years. Eight case-patients died during the follow-up period: 1
for Children3rd edition23 (n = 4), Wechsler Abbreviated Scale of (1.3%) at age 2 months, 2 (2.6%) at 2 years, 3 (3.8%) at 1213 years
Intelligence24 (n = 23), Kaufman Assessment Battery for Children25 (n = 7), and 2 (2.6%) at 20 years. One case-patient who died had a
Leiter International Performance ScaleRevised26 (n = 2), Stanford Binet diagnosis of sudden infant death syndrome, 4 had respiratory
Intelligence Scale27 (n = 2) and Vineland Adaptive Behavior Scales28 failure (1 at age 2 years and 3 at ages 1213 years), 2 had
(n = 18). All tests have scores standardized to a mean of 100 with a s.d. postsurgical complications (ages 2 and 20 years) and 1 had an
of 15 or 16, allowing us to combine the scores from case-patients assessed accidental drug overdose (age 20 years).
at different ages using different instruments. For the 3 case-patients who
received the Bayley Scales of Infant Development at the last evaluation at
42 months of age, we calculated the IQ based on the age-equivalent Head CT scan ndings
scores divided by the age at the time of testing multiplied by 100. We Seventy-three case-patients had a head CT performed within the
categorized case-patients as having intellectual disability, borderline rst 4 months of life, at a median age of 8 days (range
intelligence and normal intelligence when standard scores at last 04 months). A total of 62 (85%) case-patients had abnormal
evaluation were o 70, 7084 and 85, respectively.29
Hearing evaluations included click and tone-burst auditory brainstem
ndings, categorized as tissue destruction in 49 (67%), attenuated
response, behavioral audiometry from 0.25 to 8 kHz and tympanometry. growth in 21 (29%) and dysplastic growth in 6 (8%) (Table 1). The
We dened SNHL as 25 dB hearing level for the click auditory brainstem most common abnormal ndings were intracranial calcications,
response or at any frequency for the corrected tone-burst or pure-tone air ventricular dilatation and white matter lucency, observed in 43
conduction results, in the absence of middle ear disorder. We categorized (59%), 40 (55%), and 20 (27%) case-patients, respectively. Volume
SNHL for each ear as congenital/early-onset when detected in the rst loss was observed in 34 (69%) case-patients with tissue destruc-
auditory brainstem response assessment at age 12 months and tion, in 12 (57%) with growth attenuation and in 5 (83%) with
conrmed in subsequent assessments, or as delayed-onset when detected dysplastic growth. In univariate analyses, microcephaly at birth
after one or more assessments with normal hearing. We also categorized was signicantly associated with tissue destruction and dysplastic
SNHL by laterality and severity, as previously described.19
growth shown by head CT; preterm birth was signicantly
Ophthalmologic evaluations included external ocular exam, indirect
ophthalmoscopy and measurement of best corrected visual acuity (Snellen associated with attenuated growth shown by head CT (P o0.05).
score) in older children or assessment of xation behavior in nonverbal
and preverbal children. We dened an ophthalmic abnormality as any of Neurodevelopmental, hearing and vision outcomes
the following conditions: chorioretinitis, optic nerve atrophy, strabismus Among 72 case-patients with a neurodevelopmental evaluation,
(including esotropia or exotropia), nystagmus, amblyopia or astigmatism.
Based on the last ophthalmologic visit, we categorized case-patients as
the median age at the last evaluation was 10 (range: 0.427) years.
having normal vision (20), mild/moderate vision impairment (2169), low Thirty-one (43%) case-patients had intellectual disability, 12 (17%)
vision (70199) and legal blindness (200), using the Snellen scores in the had borderline intelligence and 29 (40%) had normal intelligence
better eye, or based on the ophthalmologist assessment for nonverbal and (Table 1). Among 31 case-patients with intellectual disability, the
preverbal children.30 median intelligence score was 35 (range: 567) and the median
Using the Cox proportional hazards regression model and the Firth verbal score was 33 (range: 2074). Among 12 case-patients with
method to reduce small sample size bias,31 we calculated hazard ratios borderline intelligence, the median intelligence score was 82
(HRs) and 95% condence intervals (CIs) to assess whether selected clinical (range: 7084) and the median verbal score was 78 (range: 7297).
signs at birth (petechiae/purpura, jaundice or hyperbilirubinemia, hepa- Of 29 case-patients with normal intelligence, the median
tosplenomegaly, microcephaly, SGA or preterm birth) or abnormal head CT
intelligence score was 106 (range: 85122) and the median verbal
ndings (tissue destruction, attenuated growth or dysplastic growth)
within 4 months of birth were predictors for intellectual disability, SNHL, score was 105 (range: 84120).
ophthalmic abnormality or vision impairment. For the models, we dened Among 76 case-patients with an audiologic evaluation, the
microcephaly as head circumference 3rd percentile and SGA as birth median age at rst evaluation was 18 days (range: 4 days to 8
weight 10th percentile. We did not combine clinical signs at birth with years); 75 case-patients were rst evaluated within 10 months of
head CT ndings as predictors in the same model because they were birth. Overall, 56 (74%) case-patients had SNHL (Table 1), among
potentially correlated with each other. We considered results with a P- whom 44 (79%) had congenital/early-onset SNHL and 12 (21%)
value of o0.05 as statistically signicant. For analyses, we used SAS developed delayed-onset SNHL detected at a median age of 3
version 9.3 (SAS Institute, Cary, NC, USA). (range: 0.511) years. Forty-seven (84%) case-patients with SNHL
had bilateral loss, of which 38 (81%) had bilateral loss at rst
diagnosis, and 9 (19%) were initially diagnosed with unilateral loss,
RESULTS
but developed delayed-onset SNHL in the contralateral ear. The
Demographic and clinical characteristics at birth median interval from unilateral to bilateral loss was 3 months
Of the 76 case-patients, 55 (72%) were born during 19831998, (range: 7 days to 5 years) among 5 case-patients who initially
before establishment of the Texas Newborn Hearing Screening presented with unilateral congenital/early-onset SNHL, and 4 years
Program in 1999, and 21 (28%) during 19992005. The majority of (range: 36 years) among 4 case-patients who presented with
case-patients were born to mothers who were o 25 years of age unilateral delayed-onset SNHL.
(62%), non-Hispanic White (57%), married (60%), primipara (52%) Most case-patients with SNHL had moderate to profound SNHL
and who had no other living children at the time of birth (59%). as infancy and SNHL severity worsened with age. At rst
Thirty-ve (46%) case-patients were males and 52 (68%) were assessment, 44% of all case-patients with SNHL and 32% of those
born at term. Fifty-nine (78%) case-patients had urine samples for with bilateral SNHL had profound loss in the poorer- and better-
CMV testing collected within 3 days of life, and 17 (22%) between hearing ears, respectively. At last assessment, 61% of all case-
4 and 21 days of life. The most common CMV-related signs patients with SNHL and 57% of those with bilateral SNHL had
present at birth were petechiae/purpura (72%) and thrombocyto- profound loss in the poorer- and better-hearing ears. Thirty-ve
penia (70%) (Table 1). A greater proportion of case-patients were (63%) of 56 case-patients with SNHL received hearing aids, among

Journal of Perinatology (2017), 1 6 2017 Nature America, Inc., part of Springer Nature.
 Long-term outcomes of symptomatic congenital CMV
TM Lanzieri et al
3
whom 26 (74%) received bilateral hearing aids. A total of 15 (27%)
Table 1. Clinical characteristics at birth, head CT ndings and
case-patients received cochlear implants, including 10 who
long-term neurodevelopmental, hearing and vision outcomes among
initially used hearing aids. Five (33%) received the rst cochlear
children with symptomatic congenital CMV disease (n = 76)
implant by age 2 years, 6 (40%) between 3 and 7 years and 4
Characteristic n (%) (27%) at 14 years. Five case-patients received cochlear implants
bilaterally, among whom the second implantation was done at a
Clinical signs during neonatal period median of 2 (range: 15) years after the rst.
Petechiae/purpura 55 (72)
Jaundice 30 (39) Among 76 case-patients, 39 (51%) had an ophthalmic
Hepatosplenomegaly 38 (50) abnormality, including 19 (25%) with chorioretinitis and 9 (12%)
Seizures 5 (7) with optic nerve atrophy (Table 1). Overall, among 66 (87%) case-
patients with vision evaluation, 44 (67%) had normal vision, 8
Small for gestational age
Physician clinical assessment at birth 28 (37) (12%) had mild/moderate vision impairment, 4 (6%) had low
Birth weight o 10th percentilea 44 (58) vision and 10 (15%) had legal blindness. Among 41 (54%) case-
patients with a Snellen score for both eyes, including 12 (29%)
Microcephaly with correction, 32 (78%) had normal vision, 8 (20%) had mild/
Physician clinical assessment at birth 31 (41)
Head circumference 3rd percentilea (n = 73) 25 (34) moderate vision impairment and 1 (2%) had low vision. Among 25
Head circumference 10th percentilea (n = 73) 37 (51) (33%) case-patients without a Snellen score in both eyes, 12 (48%)
had normal vision, 3 (12%) had low vision and 10 (40%) had legal
Laboratory abnormalities blindness.
Elevated alanine transaminase (4100 IU) (n = 70) 12 (17)
Thrombocytopenia (platelet count o75 000/mm3) (n = 71) 50 (70) Overall, among 65 (86%) case-patients with neurodevelopmen-
Hyperbilirubinemia (total bilirubin 43 mg dl 1) (n = 74) 28 (38) tal, hearing and vision evaluations, 28 (43%) had intellectual
Hemolytic anemia 3 (4) disability and SNHL with or without vision impairment, 2 (3%) had
Head CT ndings (n = 73)
intellectual disability with normal hearing and vision and 16 (25%)
Intracranial calcications 43 (59) had borderline/normal intelligence with moderate to profound
Ventricular dilatation 40 (55) SNHL in the better-hearing ear (1 of whom had legal blindness
White matter lucency 20 (27) and 2 with mild/moderate vision impairment). The remaining 19
Any abnormal nding 62 (85)
(29%) case-patients had borderline/normal intelligence, of whom
Broad categories 7 had moderate to profound SNHL in the poorer-hearing ear, 2
Tissue destruction 49 (67) had mild/moderate vision impairment and 10 had normal hearing
Attenuated growth 21 (29) and vision.
Dysplastic growth 6 (8)

Neurodevelopmental outcomes (n = 72) Predictors of intellectual disability, SNHL, ophthalmic

Intellectual disability 31 (43) abnormalities and vision impairment
Borderline intelligence 12 (17)
Normal intelligence 29 (40) In multivariate analysis of clinical signs at birth, microcephaly was
signicantly associated with intellectual disability (HR: 3.4, 95% CI:
Hearing outcomes 1.57.6), SNHL (HR: 2.6, 95% CI: 1.45.0), ophthalmic abnormality
SNHL 56 (74)
Normal hearing 20 (26) (HR: 2.7, 95% CI: 1.26.0) and vision impairment (HR: 6.4, 95% CI:
1.626.4) (Table 2). Petechiae/purpura were associated with
SNHL onset (n = 56) decreased risk of SNHL (HR: 0.4, 95% CI: 0.20.8), whereas
Congenital/early-onset SNHL 44 (79) hepatosplenomegaly was associated with increased risk of SNHL
Delayed-onset SNHL 12 (21)
(HR: 3.4, 95% CI: 1.67.3). Jaundice was associated with a
Laterality (n = 56) decreased risk of vision impairment (HR: 0.2, 95% CI: 0.10.8). In
Bilateral SNHL 47 (84) multivariate analyses of head CT ndings, tissue destruction was
Unilateral SNHL 9 (16)
signicantly associated with intellectual disability (HR: 4.2, 95% CI:
Severity (n = 47) b 1.116.1) and SNHL (HR: 2.2, 95% CI: 1.14.3). Dysplastic growth
25 dB in isolated frequency 1 (2) was signicantly associated with intellectual disability (HR: 4.4,
Slight (1625 dB) 5 (11) 95% CI: 1.711.5), SNHL (HR: 2.4, 95% CI: 1.05.8), ophthalmic
Mild (2640 dB) 2 (4)
Moderate (4155 dB) 4 (9) abnormalities (HR: 6.1, 95% CI: 2.316.6) and vision impairment
Moderately severe (5670 dB) 1 (2) (HR: 10.4, 95% CI: 2.937.7). Neither preterm birth nor attenuated
Severe (7190 dB) 7 (15) growth shown by head CT were signicantly associated with
Profound (490 dB) 27 (57) intellectual disability, SNHL, ophthalmic abnormalities or vision
Ophthalmic abnormalities impairment (P40.05).
Astigmatism 22 (29)
Strabismus 19 (25)
Nystagmus 11 (14) DISCUSSION
Amblyopia 3 (4)
Chorioretinitis 19 (25) In this longitudinal study of children with conrmed symptomatic
Optic nerve atrophy 9 (12) congenital CMV disease, the majority of whom were clinically
Any ophthalmic abnormality 39 (51) referred, we observed a high proportion of case-patients with
microcephaly, intellectual disability, SNHL, ophthalmic abnormal-
Vision outcomes (n = 66)
Normal vision 44 (67) ities and vision impairment. Among case-patients with intellectual
Mild/moderate vision impairment 8 (12) disability, the median intelligence score was in the severe to
Low vision 4 (6) profound range, suggesting that a substantial proportion of these
Legal blindness 10 (15) children likely require daily supervision, help with self-care
Abbreviations: CMV, cytomegalovirus; CT, computed tomography; SNHL, activities and special education, in addition to long-term
sensorineural hearing loss. aBased on Olsens intrauterine growth charts. monitoring and health interventions. It is likely that a greater
b
Better-hearing ear at the last assessment. proportion of children with symptomatic congenital CMV disease
identied through referrals have more severe manifestations at

2017 Nature America, Inc., part of Springer Nature. Journal of Perinatology (2017), 1 6
 Long-term outcomes of symptomatic congenital CMV
TM Lanzieri et al
4
Table 2. Multivariate Cox proportional hazards regression analysis of CMV-related clinical signs at birth and head computed tomography scan
ndings and neurodevelopmental outcomes, hearing loss, ophthalmic abnormalities and vision impairment

Intellectual disability Sensorineural hearing Ophthalmic abnormality Vision impairment

loss

HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value

Model 1 (clinical signs at birth) (n = 65) (n = 70) (n = 70) (n = 61)

Petechiae/purpura 1.2 (0.43.5) 0.690 0.4 (0.20.8) 0.011 1.2 (0.53.1) 0.697 1.6 (0.47.3) 0.523
Jaundice or hyperbilirubinemia 0.6 (0.31.4) 0.289 1.0 (0.51.8) 0.987 0.6 (0.31.2) 0.140 0.2 (0.10.8) 0.024
Hepatosplenomegaly 1.8 (0.74.4) 0.218 3.4 (1.67.3) 0.002 1.2 (0.52.9) 0.618 0.7 (0.22.4) 0.593
Microcephaly at birtha 3.4 (1.57.6) 0.003 2.6 (1.45.0) 0.004 2.7 (1.26.0) 0.019 6.4 (1.626.4) 0.010
Small for gestational ageb 1.5 (0.63.5) 0.386 1.1 (0.62.2) 0.759 1.6 (0.73.6) 0.290 1.9 (0.57.5) 0.373
Preterm birthc 1.3 (0.63.0) 0.498 1.0 (0.51.7) 0.902 1.7 (0.83.6) 0.136 2.1 (0.67.1) 0.241

Model 2 (head computed tomography scan ndings (n = 68) (n = 73) (n = 73) (n = 64)
within 4 months of age)
Tissue destruction 4.2 (1.116.1) 0.036 2.2 (1.14.3) 0.024 2.1 (0.94.8) 0.077 15.7 (0.8303.1) 0.068
Attenuated growth 1.0 (0.42.1) 0.914 1.6 (0.82.9) 0.154 1.6 (0.83.3) 0.165 1.9 (0.65.9) 0.237
Dysplastic growth 4.4 (1.711.5) 0.002 2.4 (1.05.8) 0.042 6.1 (2.316.6) o0.001 10.4 (2.937.7) o0.001
Abbreviations: CI, condence interval; CMV, cytomegalovirus; HR, hazard ratio. aMicrocephaly dened as head circumference o3rd percentile for
gestational age. bSmall for gestational age dened as birth weight 10th percentile. cPreterm birth dened as birth before 37 weeks of gestational age.

birth and disabilities than those who would be identied through radiation may affect the developing human brain. More recently,
newborn screening.32 Thus, our data should not be generalized to neuroimaging using magnetic resonance, which was not available
all infants with congenital CMV infection, among whom only for our cohort, and ultrasound have been recommended for the
1015% present with symptomatic disease of varying degree of diagnosis and categorization of brain developmental disorders
severity at birth. We found the prevalence of moderate to severe and white matter disease, including for children with asympto-
outcomes was 71% among our case-patients in contrast to the matic congenital CMV infection.3638 Severe brain abnormalities
32% found among infants with symptomatic congenital CMV very similar to those of our case-patients with symptomatic
disease identied in 2 large population-based newborn screening congenital CMV disease have been recently reported in cases of
studies.33 We did not include congenital SNHL as a dening microcephaly associated with congenital Zika virus infection.39
condition for symptomatic congenital CMV disease that, if we had, Development of standard clinical and diagnostic protocols,
would have resulted in a greater number of infants classied as including neuroimaging evaluations, would be needed should
having symptomatic disease and a lower estimate of the newborn screening for congenital CMV infection be implemented.
proportion with intellectual disability. Our ndings from head CT suggest that tissue destruction or
We found microcephaly was signicantly associated with dysplastic growth shown by magnetic resonance or ultrasound
abnormal head CT ndings indicative of tissue destruction and would be useful to inform prognosis of affected children.
dysplastic growth, as well as intellectual disability, SNHL, In our study, the majority of case-patients had moderate to
ophthalmic abnormalities and vision impairment. Our ndings profound SNHL since early infancy and received hearing device
expand on a previous analysis of 41 case-patients from our cohort, interventions, including hearing aids and cochlear implants. The
reinforcing the specicity of microcephaly as a predictor of poor rst cochlear implantation among our case-patients was per-
cognitive outcome.34 None of the case-patients in our study with formed in 1998. Twice as many children who received cochlear
normal intelligence, hearing and vision had microcephaly at birth. implants in our study would likely have met the current candidacy
In newborn screening studies, the proportion of children with criteria for cochlear implantation. Data from small studies have
symptomatic congenital CMV disease who have microcephaly shown that children with congenital CMV-related SNHL may
ranges between 7 and 40%.412 Many of these studies used the benet from cochlear implantation but perform less well than a
10th percentile as a cutoff for microcephaly, and hence the comparable group of children with implants who do not have
prevalence of microcephaly may have been overestimated. In our congenital CMV infection; this lag may be related to the degree of
study, using the 3rd percentile for head circumference adjusted CMV-related motor or cognitive disabilities.4043 Children who
for gestational age at birth, we found 34% of case-patients had receive cochlear implants require ongoing audiological and
microcephaly, lower than the 40% classied by physician report. otolaryngological follow-up, as well as training/rehabilitation to
Using standardized methods to assess microcephaly in infants develop a wide range of listening skills for optimal benet from
with congenital CMV infection is important, not only to allow their devices.44 More data on quality of life, language skills and
comparability across studies, but to accurately inform clinical educational achievement following cochlear implantation in
management decisions and inform prognosis. children with congenital CMV-related SNHL will be useful to
Although head CT abnormalities have been associated with document potential benets and provide realistic expectations to
impairments/disabilities in children with symptomatic congenital patients and parents considering this intervention.
CMV disease, the types of abnormalities that predict adverse Vision impairment in children with symptomatic congenital
outcomes have not been assessed.35 We found that tissue CMV disease may be caused by cortical, optic nerve and/or retinal
destruction and dysplastic growth were signicantly associated abnormalities.45 Data on long-term vision outcomes for children
with microcephaly at birth, intellectual disability and SNHL. with congenital CMV infection are limited.1 Overall, 21% of our
Dysplastic growth was also associated with ophthalmic abnorm- case-patients had low vision or legal blindness. In our study, half of
alities and vision impairment. Currently, it is recommended that case-patients had an ophthalmic abnormality; 25% had chorior-
CT be limited to selected cases because exposure to ionizing etinitis, not much higher than in previous reports.32 Among case-

Journal of Perinatology (2017), 1 6 2017 Nature America, Inc., part of Springer Nature.
 Long-term outcomes of symptomatic congenital CMV
TM Lanzieri et al
5
patients with vision evaluation, 55% of those with chorioretinitis term outcomes of congenital CMV infection not included in this report. The
and/or optic nerve atrophy had at least mild/moderate vision remaining authors declare no conict of interest.
impairment, consistent with the 58% reported in another study.46
The evidence suggests that infants with symptomatic congenital
CMV disease should receive careful ophthalmologic screening and ACKNOWLEDGEMENTS
regular follow-up examinations to allow for early intervention.45,47 We thank all the children who participated in the study, their families and physicians
for their lifetime of dedication and support for this study, and Kim Van Naarden Braun
Our study had some limitations. Clinical data for CMV-positive
for careful review of the manuscript. The study was supported, in part, by the CMV
newborns that were identied by routine CMV screening but not
Research Fund Donors at Baylor College of Medicine; the Womans Hospital of Texas
enrolled in the study were not available. Although we estimate Research Foundation; the Ofce of Research Resources and the General Clinical
only 23 of these newborns would have presented with Research Center for Children at Texas Childrens Hospital and Baylor College of
symptomatic disease at birth, those who died in the neonatal Medicine (NIH 5M0I RR00188-33); the Mental Retardation Research Center at Baylor
period would not have had the opportunity to be enrolled in the College of Medicine (NIH-CHHD 5 P30 HD24064P); the Research to Prevent Blindness,
study. In our cohort, the cumulative mortality rate within 2 years of New York, NY; the Deafness Foundation, Houston, TX; the Vale Ashe Foundation,
life was 4%, comparable to that of 56% reported in previous Houston, TX; the Maddies Mission Foundation, Katy, TX; the Naymola Foundation,
studies.1,32 Although a few case-patients were born preterm, we Beaumont, TX; the American Pediatric Society-Society for Pediatric Research Summer
found no signicant association of preterm birth or head CT Student Research Program (NIH-CHHD); and the Centers for Disease Control and
ndings suggesting prematurity with any of the severe outcomes. Prevention (Cooperative Agreement FOA IP 10-006).
Because case-patients were born over the course of 2 decades, the The Congenital CMV Longitudinal Study Group through the years has included:
available diagnostic procedures, treatment and interventions Shahzad Ahmed, Hanna Baer, Amit R Bhatt, Peggy Blum and Texas Children's Hospital
Audiology, Frank Brown, Francis Catlin, Alison C Caviness, David K Coats, Jane C
evolved over time. We did not investigate all clinically important
Edmonds, Marily Flores, Daniel Franklin, Cindy Gandaria, Jewel Greer, Carol Griesser,
outcomes, including outcomes such as cerebral palsy and
Mohamed A. Hussein, Isabella Iovino, Allison Istas, Haoxing (Douglas) Jin, Mary K
nutritional status, or interventions that these children required Kelinske, Joseph T Klingen, Antone Laurente, Thomas Littman, Mary Murphy, Jerry
or received, such as orthopedic surgeries, assistive devices and Miller, Christopher Nelson, Daniel Noyola, Evelyn A Paysse, Alan Percy, Sara Reis, Ann
physical, occupational, speech and language therapies. In addi- Reynolds, Judith Rozelle, OBrien Smith, Paul Steinkuller, Marie Turcich, Sherry Sellers
tion, we were unable to report on the impact on quality of life of Vinson, Robert G Voigt, Bethann Walmus, Jill Williams, Daniel Williamson, Kimberly G
affected children and families that should be included for more Yen, Martha D Yow and Gail J Demmler-Harrison.
complete assessment of burden of disease and its economic
impact.
Determining the burden of disease associated with congenital DISCLAIMER
CMV infection is critical to assess the cost effectiveness of The ndings and conclusions in this article are those of the authors and do not
newborn screening for congenital CMV infection. The severity of necessarily represent the ofcial position of the Centers for Disease Control and
outcomes vary widely and the data available on the range of Prevention.
disabilities among affected children are limited.16,48,49 Our study
provides detailed outcome data for a subset of congenitally
infected infants who were diagnosed at birth and likely over- AUTHOR CONTRIBUTIONS
estimates the burden of disease among all children with TML conceptualized and conducted analysis contained in this report,
congenital CMV infection who are symptomatic at birth. More interpreted the data, led the writing of the initial manuscript and revised
data on the prevalence and spectrum of long-term outcomes versions and approved the nal version; JL conducted analysis contained in this
among both symptomatic and asymptomatic infants are needed report, interpreted the data, revised the manuscript and approved the nal
to estimate the potential benet and assess the cost effectiveness version; WC conceptualized the analysis contained in this report, reviewed and
of newborn screening for congenital CMV infection. interpreted individual audiological data, revised the manuscript and approved
In the United States, symptomatic congenital CMV disease is the nal version; MF and JAM assisted with data management and quality
estimated to affect 20003000 newborns annually. An additional control for the Longitudinal Congenital CMV Study, revised the manuscript and
900 infants with asymptomatic congenital CMV infection are approved the nal version; PB conceptualized and provided audiological
estimated to have SNHL within 8 weeks of life, although nearly follow-up in the Longitudinal Congenital CMV Study, revised the manuscript
half of these infants are likely missed by newborn hearing and approved the nal version; ACC was the co-Principal Investigator for the
screening.50 Children with delayed-onset SNHL occurring during Longitudinal Congenital CMV Study, revised individual clinical, laboratory and
the rst 9 months of age are likely to benet from early head computed tomography data, conducted analysis contained in this report,
intervention.16 By age 5 years, 360 (2%) of children with
revised the manuscript and approved the nal version; SRB conceptualized the
asymptomatic congenital CMV infection are estimated to have
analysis contained in this report, interpreted the data, revised the manuscript
severe enough bilateral SNHL to potentially meet candidacy
and approved the nal version; SSV, MRT and RGV conducted the
criteria for cochlear implantation.19 A laboratory-conrmed
neurodevelopmental evaluations, revised the manuscript and approved the
diagnosis of congenital CMV disease in the rst month of life is
nal version; GD-H was the Principal Investigator for the Longitudinal
critical for implementing appropriate clinical management,
Congenital CMV Study, provided patient follow-up, conceptualized the
including administration of antivirals for eligible infants.13,14 Most
cases of symptomatic congenital CMV disease likely remain analysis contained in this report, interpreted the data, revised the manuscript
undiagnosed because they present with mild or nonspecic and approved the nal version.
signs.15,51 Although congenital CMV infection meets some of the
criteria for inclusion in the newborn screening panel, more
REFERENCES
research is needed to develop a screening test appropriate for
1 Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological
large scale implementation, inform guidelines for treating and
and sensory sequelae and mortality associated with congenital cytomegalovirus
monitoring children with congenital CMV infection and assess the infection. Rev Med Virol 2007; 17(5): 355363.
cost benet or cost effectiveness of CMV screening.52,53 2 Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG et al.
Saliva polymerase-chain-reaction assay for cytomegalovirus screening in
newborns. N Engl J Med 2011; 364(22): 21112118.
CONFLICT OF INTEREST 3 Boppana SB, Ross SA, Novak Z, Shimamura M, Tolan RW Jr, Palmer AL et al. Dried
Dr Demmler-Harrisons institution received funding from Merck Sharpe & Dohme blood spot real-time polymerase chain reaction assays to screen newborns for
Corporation since July 2016 to assist with salary support for further analysis on long- congenital cytomegalovirus infection. JAMA 2010; 303(14): 13751382.

2017 Nature America, Inc., part of Springer Nature. Journal of Perinatology (2017), 1 6
 Long-term outcomes of symptomatic congenital CMV
TM Lanzieri et al
6
4 Ahlfors K, Ivarsson SA, Harris S. Report on a long-term study of maternal and Surveillance Program (MADDSP) Case Denitions. [cited 30 September 2016.]
congenital cytomegalovirus infection in Sweden. Review of prospective studies Available from http://www.cdc.gov/ncbddd/developmentaldisabilities/case
available in the literature. Scand J Infect Dis 1999; 31(5): 443457. denitions.html#vision.
5 Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital 31 King G, Zeng L. Logistic regression in rare events data. Pol Anal 2001; 9: 137163.
cytomegalovirus infection in infants born to mothers with preexisting immunity 32 Dreher AM, Arora N, Fowler KB, Novak Z, Britt WJ, Boppana SB et al. Spectrum of
to cytomegalovirus. Pediatrics 1999; 104(1 Pt 1): 5560. disease and outcome in children with symptomatic congenital cytomegalovirus
6 Melish ME, Hanshaw JB. Congenital cytomegalovirus infection. Developmental infection. J Pediatr 2014; 164(4): 855859.
progress of infants detected by routine screening. Am J Dis Child 1973; 126(2): 33 Townsend CL, Forsgren M, Ahlfors K, Ivarsson SA, Tookey PA, Peckham CS.
190194. Long-term outcomes of congenital cytomegalovirus infection in Sweden and the
7 Numazaki K, Fujikawa T. Chronological changes of incidence and prognosis of United Kingdom. Clin Infect Dis 2013; 56(9): 12321239.
children with asymptomatic congenital cytomegalovirus infection in 34 Noyola DE, Demmler GJ, Nelson CT, Griesser C, Williamson WD, Atkins JT et al.
Sapporo, Japan. BMC Infect Dis 2004; 4: 22. Early predictors of neurodevelopmental outcome in symptomatic congenital
8 Peckham CS, Chin KS, Coleman JC, Henderson K, Hurley R, Preece PM. Cytome- cytomegalovirus infection. J Pediatr 2001; 138(3): 325331.
galovirus infection in pregnancy: preliminary ndings from a prospective study. 35 Boppana SB, Fowler KB, Vaid Y, Hedlund G, Stagno S, Britt WJ et al. Neuroradio-
Lancet 1983; 1(8338): 13521355. graphic ndings in the newborn period and long-term outcome in children with
9 Saigal S, Lunyk O, Larke RP, Chernesky MA. The outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 1997; 99(3):
congenital cytomegalovirus infection. A longitudinal follow-up study. Am J Dis 409414.
Child 1982; 136(10): 896901. 36 Alarcon A, Martinez-Biarge M, Cabanas F, Quero J, Garcia-Alix A. A prognostic
10 Starr JG, Bart RD Jr, Gold E. Inapparent congenital cytomegalovirus infection. neonatal neuroimaging scale for symptomatic congenital cytomegalovirus
Clinical and epidemiologic characteristics in early infancy. N Engl J Med 1970; 282 infection. Neonatology 2016; 110(4): 277285.
(19): 10751078. 37 van der Knaap MS, Vermeulen G, Barkhof F, Hart AA, Loeber JG, Weel JF. Pattern
11 Yow MD, Williamson DW, Leeds LJ, Thompson P, Woodward RM, Walmus BF et al. of white matter abnormalities at MR imaging: use of polymerase chain reaction
Epidemiologic characteristics of cytomegalovirus infection in mothers and their testing of Guthrie cards to link pattern with congenital cytomegalovirus infection.
infants. Am J Obstet Gynecol 1988; 158(5): 11891195. Radiology 2004; 230(2): 529536.
12 Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y et al. Screening for 38 Lanari M, Capretti MG, Lazzarotto T, Gabrielli L, Rizzollo S, Mostert M et al.
congenital cytomegalovirus infection using newborn urine samples collected on Neuroimaging in CMV congenital infected neonates: how and when. Early Hum
lter paper: feasibility and outcomes from a multicentre study. BMJ Open 2011; 1 Dev 2012; 88(Suppl 2): S3S5.
(1): e000118. 39 Hazin AN, Poretti A, Di Cavalcanti Souza Cruz D, Tenorio M, van der Linden A,
13 Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG et al.
Pena LJ et al. Computed Tomographic Findings in Microcephaly Associated with
Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med
Zika Virus. N Engl J Med 2016; 374(22): 21932195.
2015; 372(10): 933943.
40 Malik V, Bruce IA, Broomeld SJ, Henderson L, Green KM, Ramsden RT. Outcome
14 Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M et al. Effect
of cochlear implantation in asymptomatic congenital cytomegalovirus deafened
of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus
children. Laryngoscope 2011; 121(8): 17801784.
disease involving the central nervous system: a randomized, controlled trial.
41 Viccaro M, Filipo R, Bosco E, Nicastri M, Mancini P. Long-term follow-up of
J Pediatr 2003; 143(1): 1625.
implanted children with cytomegalovirus-related deafness. Audiol Neurootol 2012;
15 Lanzieri TM, Bialek SR, Bennett MV, Gould JB. Cytomegalovirus infection among
17(6): 395399.
infants in California neonatal intensive care units, 2005-2010. J Perinat Med 2014;
42 Ciorba A, Bovo R, Trevisi P, Bianchini C, Arboretti R, Martini A. Rehabilitation and
42(3): 393399.
outcome of severe profound deafness in a group of 16 infants affected by
16 Cannon MJ, Grifths PD, Aston V, Rawlinson WD. Universal newborn screening for
congenital cytomegalovirus infection. Eur Arch Otorhinolaryngol 2009; 266(10):
congenital CMV infection: what is the evidence of potential benet? Rev Med Virol
15391546.
2014; 24(5): 291307.
43 Matsui T, Ogawa H, Yamada N, Baba Y, Suzuki Y, Nomoto M et al. Outcome of
17 Lanzieri TM, Dollard SC, Bialek SR, Grosse SD. Systematic review of the birth
cochlear implantation in children with congenital cytomegalovirus infection or
prevalence of congenital cytomegalovirus infection in developing countries.
GJB2 mutation. Acta Otolaryngol 2012; 132(6): 597602.
Int J Infect Dis 2014; 22: 4448.
44 American Academy of Audiology. Cochlear Implants in Children. Cited 23 March
18 Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in
infants with asymptomatic congenital cytomegalovirus infection. Pediatrics 1992; 2017. Available from http://www.audiology.org/publications-resources/docu
90(6): 862866. ment-library/cochlear-implants-children.
19 Lanzieri TM, Chung W, Flores M, Blum P, Caviness AC, Bialek SR et al. Hearing loss 45 Ghekiere S, Allegaert K, Cossey V, Van Ranst M, Cassiman C, Casteels I. Ophthal-
in children with asymptomatic congenital cytomegalovirus infection. Pediatrics mological ndings in congenital cytomegalovirus infection: when to screen, when
2017 (e-pub ahead of print 16 February 2017; doi:10.1542/peds.2016-2610). to treat? J Pediatr Ophthalmol Strabismus 2012; 49(5): 274282.
20 Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth 46 Anderson KS, Amos CS, Boppana S, Pass R. Ocular abnormalities in congenital
curves based on United States data. Pediatrics 2010; 125(2): e214e224. cytomegalovirus infection. J Am Optom Assoc 1996; 67(5): 273278.
21 Bayley N. Bayley Scales of Infant Development. Psychological Corporation: 47 Coats DK, Demmler GJ, Paysse EA, Du LT, Libby C. Ophthalmologic ndings in
3San Antonio, TX, 1969. children with congenital cytomegalovirus infection. J AAPOS 2000; 4(2): 110116.
22 McCarthy D. McCarthy Scale of Children's Abilities. Psychological Corp: New York, 48 Gantt S, Dionne F, Kozak FK, Goshen O, Goldfarb DM, Park AH et al. Cost-
1972. effectiveness of universal and targeted newborn screening for congenital cyto-
23 Wechsler D. Wechsler Intelligence Scale for Children, 3rd edn. The Psychological megalovirus infection. JAMA Pediatr 2016; 170(12): 11731180.
Corporation: San Antonio, TX, 1991. 49 Grosse SD, Ross DS, Dollard SC. Congenital cytomegalovirus (CMV) infection as a
24 Wechsler D. Wechsler Abbreviated Scale of Intelligence. The Psychological cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol
Corporation: San Antonio, TX, USA, 1999. 2008; 41(2): 5762.
25 Kaufman AS, Kaufman NL. Kaufman Assessment Battery for Children. American 50 Fowler KB, McCollister FP, Sabo DL, Shoup AG, Owen KE, Woodruff JL et al.
Guidance Service: Circle Pines, MN, 1983. A targeted approach for congenital cytomegalovirus screening within newborn
26 Roid G, Miller L. Leiter International Performance Scale-Revised: Examiners Manual. hearing screening. Pediatrics 2017 (e-pub ahead of print 3 January 2017;
Stoelting: Wood Dale, IL, 1997. doi:10.1542/peds.2016-2128).
27 Thorndike RHE, Sattler J. The Stanford-Binet Intelligence Scale Fourth Edition Guide 51 Townsend CL, Peckham CS, Tookey PA. Surveillance of congenital cytomegalo-
for Administering And Scoring. Riverside Pub: Chicago, IL, 1986, p 192. virus in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 2011; 96(6):
28 Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behavior ScalesInterview F398F403.
Edition Survey Form. American Guidance Service: Circle Pines, MN, 1984. 52 Grosse SD, Dollard S, Ross DS, Cannon M. Newborn screening for congenital
29 Sampath V, Bowen J, Gibson F. Risk factors for adverse neurodevelopment in cytomegalovirus: Options for hospital-based and public health programs. J Clin
extremely low birth weight infants with normal neonatal cranial ultrasound. Virol 2009; 46(Suppl 4): S32S36.
J Perinatol 2005; 25(3): 210215. 53 Dollard SC, Schleiss MR, Grosse SD. Public health and laboratory considerations
30 National Center on Birth Defects and Developmental Disabilities, Centers for regarding newborn screening for congenital cytomegalovirus. J Inherit Metab Dis
Disease Control and Prevention. Metropolitan Atlanta Developmental Disabilities 2010; 33(Suppl 2): S249S254.

Journal of Perinatology (2017), 1 6 2017 Nature America, Inc., part of Springer Nature.