N Newborn hearing screening: Will children with

hearing loss caused by congenital cytomegalovirus

infection be missed?
Karen B. Fowler, DrPH, Arthur J. Dahle, PhD, Suresh B. Boppana, MD, and Robert F. Pass, MD

of those with clinically apparent dis-

Objective: To predict whether universal newborn auditory screening will ease at birth will have SNHL.3-5 Even
identify most infants with sensorineural hearing loss (SNHL) caused by among infants without any clinically
congenital cytomegalovirus (CMV) infection. apparent disease at birth, 8% to 15%
Study design: A cohort of 388 children born between 1980 and 1996 at will have some hearing impairment in
early childhood.6,7
one hospital and identified during the newborn period as having congenital
CMV infection received repeated hearing evaluations to assess whether
ABR Auditory brainstem response
hearing loss had occurred. CMV Cytomegalovirus
Results: SNHL was detected in 5.2% of all infants at birth. Late-onset SNHL Sensorineural hearing loss

SNHL occurred among the children throughout the first 6 years of life. By
the age of 72 months, the cumulative incidence of SNHL was 15.4% in the Onset of SNHL after congenital
cohort. Children with clinically apparent disease at birth had significantly CMV infection may be immediate (at
more SNHL than children without any apparent disease (22.8% vs 4.0% at birth) or delayed, with variability in
3 months and 36.4% vs 11.3% at 72 months of age). the severity of the hearing loss in the
affected children.3,4,6-12 Further dete-
Conclusions: Universal screening of hearing in neonates will detect less
rioration or progression of hearing loss
than half of all SNHL caused by congenital CMV infection. Because most
also occurs in children with congenital
infants with congenital CMV infection are without symptoms at birth, these
CMV infection.6,7,10 Because most
children are unlikely to be recognized as being at risk for SNHL and will children with congenital CMV infec-
not receive further hearing evaluations to detect late-onset hearing loss. A tion have no physical abnormalities
combined approach of universal screening of neonates for hearing, as well suggesting infection, neonatal screen-
as for detection of congenital CMV infection, needs to be considered. ing of hearing based on clinical identi-
(J Pediatr 1999;135:60-4) fication of risk criteria or admission
into the neonatal intensive care unit
has missed these children. In a study
Congenital cytomegalovirus infection Approximately 1% of infants born in by Hicks et al,13 only 14% of the chil-
is the leading infectious cause of sen- the United States have congenital dren with SNHL caused by congenital
sorineural hearing loss in childhood. CMV infection1,2; about 30% to 65% CMV infection were identified by au-
ditory screening of newborns based on
From the Department of Pediatrics, University of Alabama at Birmingham School of Medicine, Birmingham; and the hospital’s risk criteria.
the Department of Biocommunication, University of Alabama at Birmingham, Birmingham. Recognizing the limitations of screen-
Supported in part by research grant number 5 P01 HD 10699 from the National Institute of ing based on risk for identifying infants
Child Health and Human Development, research grant number 5 R01 DC 02139 from the Na- with hearing loss, a National Institutes
tional Institute on Deafness and Other Communication Disorders, research grant number 5
M01 RR 00032 from the General Clinical Research Center, National Institutes of Health and
of Health consensus panel and the
the Civitan International Research Center. Joint Committee on Infant Hearing
Submitted for publication Nov 2, 1998; revision received Mar 19, 1999; accepted Apr 20, 1999. have endorsed a goal of universal de-
Reprint requests: Karen B. Fowler, DrPH, Department of Pediatrics, University of Alabama at tection of infants with hearing loss by 3
Birmingham, 1600 7th Ave South, Suite 752, Birmingham, AL 35233. months of age.14,15 The aims of univer-
Copyright © 1999 by Mosby, Inc. sal hearing screening of newborns are
0022-3476/99/$8.00 + 0 9/21/99423 to identify most or all children with

60
THE JOURNAL OF PEDIATRICS
VOLUME 135, NUMBER 1
hearing loss and to significantly lower
the age of detection of SNHL in infants
and children so that intervention is
begun by 6 months of age.14,15 Howev-
er, it is uncertain whether universal
hearing screening of newborns will be
more successful than risk criteria–
based auditory screening in identifying
children with hearing loss caused by
congenital CMV infection.
To evaluate when hearing loss occurs
in children with congenital CMV infec-
tion, we have taken a cohort of children
born between 1980 and 1996 at one
hospital who were identified during the
newborn period as having congenital
CMV infection and monitored them
with serial audiological evaluations. On
the basis of the age when hearing loss
occurs, we can define the age-specific
rates of SNHL and predict whether
universal newborn auditory screening
will identify hearing impairment
caused by congenital CMV infection.
METHODS
Study Population
The study population includes chil-
dren born between January 1, 1980,
and December 31, 1996, who were
identified by newborn screening for
congenital CMV infection at one hospi-
tal in Birmingham, Alabama.2 Congeni-
tal CMV infection was identified by iso-
lation of the virus in urine or saliva in
the first or second week of life.16-18 All
children were assessed clinically for dis-
ease in the newborn period. Their med-
ical records were systematically re-
viewed by study personnel to determine
whether any of the following symptoms
were observed in the newborn period:
microcephaly, thrombocytopenia, pe-
techiae, hepatosplenomegaly, or jaun-
dice with conjugated hyperbilirubine-
mia. Children were classified as either
symptomatic (clinically apparent dis-
ease in the newborn period) or asymp-
tomatic (absence of clinically apparent
disease in the newborn period).
Of 443 children identified with con-
genital CMV infection between 1980
and 1996, 407 children (92%) were
enrolled and followed up in a special
clinic that provides serial audiological,
psychometric, sight, and medical eval-
uations. Two children died, and 17
children (4%) were lost to follow-up
and did not receive an audiological
evaluation. The children who did not
enroll in the special clinic and the chil-
dren who were lost to follow-up did
not differ from the remaining 388 chil-
dren with respect to maternal sociode-
mographic factors or sex. However,
those children not followed up or lost
to follow-up were all without symp-
toms at birth, were more likely to be
white and cared for in the well baby
nursery, and had a higher mean birth
weight (3077 ± 517 g) and mean gesta-
tional age (39 ± 2 weeks) at delivery
than the children who received audio-
logical testing. Informed consent was
obtained from the parents or
guardians of the 388 children in the
study population.
Audiological Assessment
Children with congenital CMV in-
fection routinely received an audiolog-
ical evaluation at their first clinic visit
at 3 to 8 weeks of age, at 6 and 12
months of age, and annually thereafter
unless results revealed a need for addi-
tional testing. When hearing loss was
documented, children were seen more
frequently, until the nature and stabili-
ty of the loss could be established.
Testing was accomplished by using
thresholds for auditory brainstem re-
sponses and developmentally appro-
priate behavioral techniques for ob-
taining thresholds for pure tone and
speech detection, tympanograms, and
thresholds for acoustic reflex.19,20
ABR procedures included testing
thresholds by monaural air conduction
click and, when indicated, thresholds
for bone conduction click and 500 and
4000 Hz tone-pip air conduction. Chil-
dren seen for ABR audiometry were
usually sedated with chloral hydrate
according to age and weight. Otoscop-
ic examination was performed before
FOWLER ET AL
each audiometric assessment; children
with evidence of otitis media had test-
ing deferred.
Definition of Hearing Loss
A hearing loss was defined as sen-
sorineural if the air-bone gap was <10
dB. Normal hearing was defined as 0
to 20 dB, with hearing loss defined as
≥21 dB thresholds for the affected fre-
quencies. ABR threshold was defined
as the lowest intensity level at which
wave V could be detected and replicat-
ed. An ABR click threshold >25 dB or
a tone-pip threshold >30 dB was con-
sidered abnormal. A second definition
of SNHL (≥30 dB thresholds in the
500 to 4000 Hz region) was also used
in this cohort because the 1994 Joint
Committee on Infant Hearing has rec-
ommended a ≥30 dB loss as a cutoff in
infant screening programs.15 Fluctuat-
ing hearing loss was defined as a de-
crease in hearing of >10 dB at one or
more frequencies, followed by an im-
provement of >10 dB measured at one
or more times.7 Progressive hearing
loss was defined as a sensorineural de-
crease in hearing of ≥10 dB at any one
frequency or ABR threshold, docu-
mented on 2 separate evaluations.7
Fluctuating and progressive hearing
losses were assigned only if there was
no concurrent middle ear disease that
might influence threshold variation.
High-frequency hearing loss was de-
fined as a decrease in hearing at 4000,
8000, and 12,000 Hz frequencies only
(or a combination of these).7 Children
with conductive hearing impairment
that resolved were not considered to
have hearing loss.
Statistical Analysis
All demographic, medical, and serial
audiometric test data were maintained
in data sets in an SAS for Windows
data management system (SAS Insti-
tute, Cary, NC). The χ2 test, Fisher
exact test, and Student t test were used
when appropriate. Timing of SNHL
was based on the date of the hearing
evaluation when loss was first detect-
61
 FOWLER ET AL THE JOURNAL OF PEDIATRICS
JULY 1999

Table I. Characteristics of study population of 388 children with congenital CMV ing before hospital discharge included
infection suspected congenital CMV infection
Children with congenital CMV infection (70.1%), aminoglycoside use in the
nursery (25.4%), and family history of
Characteristic No. % hearing loss (4.5%). None of the in-
Race/Ethnicity fants with CMV infection and a family
Black 337 86.9 history of hearing loss have had SNHL
White 50 12.9 identified. One CMV-positive infant
Hispanic 1 0.2 who was given aminoglycoside thera-
Sex py in the nursery had SNHL detected,
Female 189 48.7 and 8 other infants with CMV infec-
Male 199 51.3 tion who received an auditory screen
Prenatal care because of suspected congenital CMV
Private physicians 18 4.6 infection also had SNHL detected by
Health Department 358 92.3 the newborn screening test. The other
None 12 3.1 CMV-positive newborns were missed
Maternal age at delivery by the risk criteria–based auditory
<20 y 200 51.6 screening used by the hospital during
≥20 y 188 48.4 the study period. The mean age of last
Marital status of mother hearing evaluation for the cohort was
Single 314 80.9 55 ± 45 months, and a median of 5
Married 74 19.1 (range, 1 to 21 months) audiological
Insurance status evaluations per child were completed
Private insurance 38 9.8 during the study period. Approximate-
Medicaid or no insurance 350 90.2 ly 48% of the children with both
Clinically apparent disease at birth SNHL at birth and late-onset SNHL
Symptomatic 53 13.7 had further deterioration or progres-
Asymptomatic 335 86.3 sion of their hearing loss. Fluctuating
Nursery hearing loss occurred in 35% of the
Well baby 308 79.4 children with SNHL. Approximately
Neonatal intensive care 80 20.6 17% of the children with SNHL had
high-frequency hearing loss only.
Timing and definition of hearing loss
in children with congenital CMV infec-
ed. The Kaplan-Meier method was RESULTS tion is shown in Table II. Hearing loss
used to estimate time of hearing loss of >20 dB thresholds was detected in
(in months) in the cohort and to adjust The study population (Table I) was a 5.2% of all newborns with congenital
for those children who either did not predominantly black, urban population CMV infection within the first month of
complete follow-up or were younger with the majority of infants showing no life. Approximately 6.5% of infants had
than 72 months of age at completion of symptoms of congenital CMV infection SNHL detected by 3 months of age.
the study.21 Because it is known that at birth. The median length for a new- Hearing loss continued to occur, with
sequelae including hearing loss are born hospital stay was 3 days (range, 1 8.4% of the children having SNHL by
more likely to occur after a sympto- to 96 days), and infants with symptoms the end of their first year of life. Late-
matic congenital CMV infection, eval- had significantly longer hospital stays onset SNHL was observed each year in
uation of time to hearing loss was also than infants without symptoms. The the children with congenital CMV in-
analyzed for symptomatic and asymp- mean gestational age was 38 ± 3 weeks, fection. By the age of 72 months, ap-
tomatic congenital infections separate- and the mean birth weight was 2895 ± proximately 15% of children with con-
ly. The association between SNHL 722 g for the study population. genital CMV infection had documented
and whether the child had sympto- Only 17% of the infants had screen- SNHL. Three children were not includ-
matic or asymptomatic infection at ing of hearing before being discharged ed in the estimates of cumulative inci-
birth was assessed with Kaplan-Meier from the hospital nurseries. Risk fac- dence of SNHL because their hearing
survival curves, compared by means of tors initially identified for CMV-posi- loss was identified after 72 months of
a log-rank test.21 tive infants who had screening of hear- age. For 2 of these children, the age of

62
THE JOURNAL OF PEDIATRICS FOWLER ET AL
VOLUME 135, NUMBER 1

onset of SNHL could not be deter-

mined because of incomplete hearing
evaluations. The other child had moder-
ate unilateral SNHL documented when
tested at 82 months of age, after a prior
evaluation indicated normal hearing at
70 months of age.
For hearing loss of ≥30 dB thresholds
(at 500 to 4000 Hz), approximately 3.9%
of newborns with congenital CMV infec-
tion had SNHL in the first month of life
(Table II). By 3 months of age, 5.3% of
infants had SNHL. Late-onset SNHL
continued, and by 72 months of age,
8.3% of children with CMV infection
had SNHL identified. Although some Figure. Cumulative SNHL >20 dB thresholds in children with congenital CMV infection according
SNHL did continue to occur until 72 to symptomatic and asymptomatic status at birth (P < .0001).
months of age, most late-onset SNHL of
≥30 dB thresholds had occurred by 36
Table II. Cumulative incidence of SNHL in 388 children with congenital CMV infection
months of age in the cohort.
The cumulative incidence of all hear- Cumulative incidence Cumulative incidence
ing loss for children with symptomatic Age of child of all SNHL (%)*† of SNHL (%)*‡
and asymptomatic infections is shown
<1 mo 5.2 3.9
in the Figure. Children with sympto-
3 mo 6.5 5.3
matic congenital CMV infection have
12 mo 8.4 6.8
more SNHL than children with asymp-
24 mo 9.9 7.2
tomatic infection (P < .0001). Children
36 mo 10.8 7.6
with symptomatic infection have 16.5%
48 mo 11.3 7.6
SNHL in the first month of life com-
60 mo 12.4 7.6
pared with 2.9% in children with
72 mo 15.4 8.3
asymptomatic infection. By 3 months of
age, the cumulative incidence of SNHL *Estimates are based on Kaplan-Meier methods.
†Includes any hearing loss >20 dB thresholds.
is 22.8% and 4.0% in infants with ‡Includes only hearing loss ≥30 dB thresholds at 500 to 4000 Hz.
symptomatic and asymptomatic infec-
tion, respectively. Hearing loss after a
symptomatic infection occurs earlier, SNHL was identified in another 3.2% Children with symptomatic infection
but delayed-onset SNHL continues to of children with CMV infection by 12 have hearing loss at an earlier age and
occur throughout the first years of life months of age and another 7% of the with greater severity than children with
both in children with symptomatic in- children by 72 months of age. Because asymptomatic infection. Previous re-
fection and those with asymptomatic delayed-onset SNHL followed congen- search has already shown that more fre-
infection. By 72 months of age, 36.4% ital CMV infection, about two thirds of quent and severe sequelae, including
of children with symptomatic infection SNHL (>20 dB thresholds) caused by SNHL, follow symptomatic infections
and 11.3% of those with asymptomatic congenital CMV infection would not compared with asymptomatic infec-
infection have SNHL. have been identified by universal tions.1,3-7 Most SNHL after both symp-
screening of newborns for hearing in tomatic and asymptomatic congenital
this population. Similarly, if the recom- CMV infections occurred after the new-
DISCUSSION mended definition of hearing loss for born period in our study population.
newborn screening were used,15 ap- Infants with clinically apparent dis-
Our findings indicate only 5.2% of all proximately one half of SNHL that ease at birth are more likely to be identi-
infants with congenital CMV infection may impair speech and language devel- fied and have appropriate virologic test-
had hearing loss at birth and therefore opment in a child would not have been ing for congenital CMV infection in the
would be identified by universal new- identified by newborn auditory screen- newborn period. These infants will like-
born hearing screening. Late-onset ing in this CMV-positive population. ly have a hearing evaluation completed

63
 FOWLER ET AL
at the time of diagnosis. However, in-
fants with milder symptoms may not be
recognized as being at increased risk for
SNHL. In fact, only 44% of the infants
with symptomatic infection in our popu-
lation received a hearing evaluation be-
fore being discharged from the hospital.
The 1994 Joint Committee on Infant
Hearing15 has recognized that addi-
tional hearing evaluations after univer-
sal newborn screening will be needed
for children with conditions associated
with late-onset SNHL. However,
CMV-infected newborns with milder
symptoms and those without any
symptoms will not be clinically identi-
fied during the perinatal period. Few
hospitals routinely screen infants for
congenital CMV infection, and without
virologic confirmation within the first
weeks of life, congenital CMV infection
cannot be diagnosed definitively.16-18
Children with undiagnosed congenital
CMV infection are not likely to receive
future hearing evaluations routinely
because they will not be known to have
an increased risk of SNHL.
The goal of universal screening of
hearing is to detect hearing loss as early
as possible so that infants can receive in-
tervention promptly.15 As indicated by
our findings, universal auditory screen-
ing at birth will not detect most SNHL
caused by congenital CMV infection be-
cause children with congenital CMV in-
fection continue to have hearing loss
occur throughout childhood. A different
approach is needed to detect hearing
loss as early as possible for these chil-
dren. Newborn hearing screening com-
bined with detection of congenital CMV
infection in the newborn period could be
effective in identifying children at risk
for hearing loss caused by congenital
CMV infection. Laboratory procedures
now available make it possible to screen
infants for CMV rapidly and at relative-
ly low cost.17,18
Because of effective vaccinations,
rubella and Haemophilus influenzae type
b meningitis have been virtually elimi-
nated as causes of SNHL in children.
This leaves congenital CMV infection
64
as the probable leading non-genetic
cause of SNHL in childhood. Until
CMV vaccines are available to prevent
or ameliorate sequelae after congenital
CMV infection, each year more chil-
dren will continue to have SNHL
caused by congenital CMV infection.
Although universal newborn hearing
screening may lower the age of detec-
tion and intervention for hearing loss in
some infants, each year approximately
1200 (3%) children older than 3 months
of age will go on to have late-onset hear-
ing loss caused by congenital CMV in-
fection that could affect development of
speech and language. These children
who are at increased risk for SNHL
need early detection and intervention.
REFERENCES
1. Demmler GJ. Infectious Diseases So-
ciety of America and Centers for Dis-
ease Control. Summary of a workshop
on surveillance for congenital cy-
tomegalovirus disease. Rev Infect Dis
1991;13:315-29.
2. Fowler KB, Stagno S, Pass RF. Mater-
nal age and congenital cytomegalovirus
infection: screening of two diverse
newborn populations, 1980-1990. J In-
fect Dis 1993;168:552-6.
3. Pass RF, Stagno S, Myers GJ, Alford
CA. Outcome of symptomatic congen-
ital CMV infection: results of long-
term longitudinal follow-up. Pediatrics
1980;66:758-62.
4. Williamson WD, Desmond MM,
LaFevers N, Taber LH, Catlin FI,
Weaver TG. Symptomatic congenital
cytomegalovirus: disorders of lan-
guage, learning and hearing. Am J Dis
Child 1982;136:902-5.
5. Pass RF, Fowler KB, Boppana S. Clin-
ical importance of cytomegalovirus in-
fection: an overview. In: Landini MP,
editor. Progress in cytomegalovirus re-
search. New York: Elsevier Science
Publishers; 1991. p. 3-10.
6. Williamson WD, Demmler GJ, Percy
AK, Catlin FI. Progressive hearing
loss in infants with asymptomatic con-
genital cytomegalovirus infection. Pe-
diatrics 1992;90:862-6.
7. Fowler KB, McCollister FP, Dahle AJ,
Boppana S, Britt WJ, Pass RF. Pro-
gressive and fluctuating sensorineural
hearing loss in children with asympto-
matic congenital cytomegalovirus in-
fection. J Pediatr 1997;130:624-30.
THE JOURNAL OF PEDIATRICS
JULY 1999
8. Hanshaw JB, Scheiner AP, Moxley
AW, Gaev L, Abel V, Scheiner B. School
failure and deafness after “silent” con-
genital cytomegalovirus infection. N
Engl J Med 1976;295:468-70.
9. Stagno S, Reynolds DW, Amos CS,
Dahle AJ, McCollister FP, Mohindra I,
et al. Auditory and visual defects result-
ing from symptomatic and subclinical
congenital cytomegaloviral and toxoplas-
ma infections. Pediatrics 1977;59:669-78.
10. Dahle AJ, McCollister FP, Stagno S,
Reynolds DW, Hoffman HE. Progres-
sive hearing impairment in children with
congenital cytomegalovirus infection. J
Speech Hear Disord 1979;44:220-9.
11. Saigal S, Luynk O, Larke B, Cher-
nesky MA. The outcome in children
with congenital cytomegalovirus infec-
tion: a longitudinal follow-up study.
Am J Dis Child 1982;136:896-901.
12. Kumar ML, Nankervis GM, Jacobs
IB, Ernhart CB, Glasson CE, McMil-
lan PM, et al. Congenital and postna-
tally acquired cytomegalovirus infec-
tions: long term follow-up. J Pediatr
1984;104:674-9.
13. Hicks T, Fowler K, Richardson M,
Dahle A, Adams L, Pass R. Congenital
cytomegalovirus infection and neona-
tal auditory screening. J Pediatr 1993;
123:779-82.
14. National Institutes of Health. Early
identification of hearing impairments
in infants and young children. NIH
Consensus Statement 1993;11:1-24.
15. Joint Committee on Infant Hearing.
1994 Position Statement. Pediatrics
1995;95:152-6.
16. Reynolds DW, Stagno S, Hosty TS,
Tiller M, Alford CA. Maternal cy-
tomegalovirus excretion and perinatal
infection. N Engl J Med 1973;289:1-5.
17. Boppana SB, Smith R, Stagno S, Britt
WJ. Evaluation of a microtiter plate flu-
orescent antibody assay for rapid detec-
tion of human cytomegalovirus infec-
tions. J Clin Microbiol 1992;30:721-3.
18. Balcarek KB, Warren W, Smith RJ,
Lyon MD, Pass RF. Neonatal screen-
ing for congenital cytomegalovirus in-
fection by detection of virus in saliva.
J Infect Dis 1993;167:1433-6.
19. Marlowe JA. Hearing in infancy: the
development of auditory skills and the
audiological evaluation. Semin Speech
Lang Hear 1982;3:28-44.
20. Dahle AJ, McCollister FP. Considera-
tions for evaluating hearing. In:
Mencher GT, Gerber SE, editors. The
multiply handicapped hearing im-
paired child. New York: Grune &
Stratton; 1983. p. 171-205.
21. Matthews DE, Farewell VT. Using
and understanding medical statistics,
2nd ed. London: Karger; 1988.