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Original Studies

A wider role for congenital cytomegalovirus infection in sensorineural hearing loss


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The Pediatric Infectious Disease Journal: January 2003 - Volume 22 - Issue 1 - p 39-42
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Sensorineural hearing loss (SNHL) strikes ∼1 in 1000 children younger than 10 years and causes serious impairment in the normal development of the child, especially in the field of communication and learning. The causes of SNHL are many, ranging from genetic to infective, both congenitally and postnatally acquired, to pharmacologic. The relative importance of these factors has not been fully assessed, and in about one-third of the cases no cause is found. 1 Incomplete knowledge, delay in diagnosing the hearing loss and late onset of the impairment, even in congenitally acquired cases, may contribute to the incomplete understanding of the etiology of SNHL.

Among the various congenital infections fetal cytomegalovirus (CMV) infection is particularly affected by the above mentioned problems. Follow-up studies in children with congenital CMV infection have shown that SNHL is the most common consequence of this infection, affecting up to 22% of infected children. 2 The impact of congenital CMV in SNHL is ill-defined. Studies performed on deaf children reported frequencies ranging from 2%3 and 3%4, 5 to 18%6 for CMV-attributable cases. These discrepancies are mainly caused by difficulties in diagnosing the infection when the hearing loss is ascertained. In fact the age of identification of SNHL in infants involved in neonatal auditory screenings has a median of 2 months but can be as much as 12.5 months for those identified through behavioral hearing screening. 7 On the other hand the diagnosis of congenital CMV infection requires laboratory tests that must be conducted on neonatal samples collected within the third week of life. The demonstration of CMV DNA in dried blood spots (DBS) on Guthrie cards collected at birth for the screening of metabolic and genetic disorders has proved to be a valuable tool for diagnosing congenital CMV infection. 8 The procedure (DBS test) allows the diagnosis of congenital infection after months or even years of life.

To estimate the impact of congenital CMV infection in SNHL, we retrieved and tested, through the DBS test the Guthrie cards of 130 children diagnosed with SNHL.


Study subjects

One hundred thirty children with a hearing loss above 40 dB hearing loss (dBHL) in the best ear were examined in this study after the parents’ consent was obtained. The availability of the Guthrie card at the regional screening center randomly selected the cases to be studied from a larger group of 210 deaf children. Causes of nonavailability of the cards were: use in a nationwide survey of HIV seroprevalence; inaccurate coding of cases; late (≥10 days of life) collection of neonatal blood; exhaustion of short samples; and the card having been discarded after the conservation period (5 years). The study subjects were divided into 2 groups according to the age at which the diagnosis of hearing loss was established.

Eighty-seven cases (Group A) were the random sample of the 154 children who were sent to UO Neurophysiopathology, Istituti Clinici di Perfezionamento, for the assessment of the level of loss. The infants had been identified in the first 2 months of life (mean age at diagnosis, 40 days) through the audiologic screening protocols performed in some hospitals (nearly 15 000 births/year; 20% of yearly births) of the Regione Lombardia in the years 1995 through 2001. Screening protocols were based on the presence of audiologic risk factors; from 1999 three large third level hospitals (9000 births/year altogether) started a universal screening protocol with otoacoustic emission testing. Of the 87 study subjects 32 were full term babies, with no known audiologic risk factor, who failed the otoacoustic emission test. The risk factors identified in the remaining 55 infants were: syndromes/malformations (n = 25); family history (n = 5); stay in the neonatal intensive care unit (n = 20); congenital CMV infection (n = 5). In this group the cases with a known familial or syndromic cause of deafness made up the control group.

Group B included 43 children (age 1 to 4 years), brought to our attention by reference pediatricians and audiologists, who were asked to report cases of SNHL of unknown cause, together with a few cases of hearing impairment with known etiology as controls. The children had their hearing loss assessed in infancy at a median age of 18 months (range, 3 to 48 months). Controls included 2 children with a familial history of SNHL and 3 who were syndromic.

Auditory brainstem response test

The hearing loss of both Group A and Group B children was assessed using the standard auditory brainstem response test. All children were tested in a quiet room or in a soundproof and faradized booth while sleeping. Surface electrodes of Ag-AgCl were attached in Cz (active), in Fz (ground) and at the ear lobes as reference with a two channel montage. The stimuli were rarefaction clicks delivered monaurally through TDH 39 earphones at a repetition rate of 11.1/s with 10-dB step increases in intensity until the wave V became indistinguishable from the baseline. Responses to 2000 clicks were averaged. For each recording condition trials were conducted at least in duplicate.

Losses varied from monolateral 40 dBHL to bilateral 95 dBHL. A hearing loss above 70 dBHL was recorded in 26 Group A infants (30%) and in 29 Group B children (67%).

DBS test

Guthrie cards were retrieved from the Regione Lombardia screening laboratory after obtaining the parents’ consent. The DBS had been stored under standard conditions.

Extraction of DNA from the DBS and nucleic acid amplification were performed by two investigators (SB and SC) blinded to the characteristics of the cases, as previously described. 8 In brief DNA was extracted from the Guthrie cards by thermal shock. DNA amplification was performed with a nested PCR designed to amplify one region in the gp58 gene. Each sample was punched and tested at least three times. Strict control measures were adopted to avoid carryover and contamination.


With the DBS test congenital CMV infection was diagnosed in 22 deaf children.

The results of the DBS test were evaluated, taking into consideration the accuracy of the test, the percentage of congenital CMV in cases of early and late diagnosed SNHL and the level of hearing impairment in positive vs. negative children.

The DBS test showed good clinical specificity. Negative results were obtained in infants and children with genetic or syndromal risk factors (30 from Group A and 5 from Group B) whereas indications of possible congenital infection were found in 12 DBS test-positive cases. In fact the test identified 9 cases in whom a congenital CMV infection had either been confirmed by virologic tests at birth (2 cases in Group A and 1 in Group B) or had indication for but was not identified at birth (3 cases in Group A and 3 in Group B). Virologically confirmed cases were 3 babies with signs of congenital CMV disease 2 at birth: petechiae and neurologic abnormalities in one; hyperbilirubinemia and hepatomegaly, low platelets counts and elevated ALT in a baby who was small for gestational age; hyperbilirubinemia and hepatomegaly in the third case. No viral examination was performed at birth in 1 case with hyperbilirubinemia and in 5 cases with maternal CMV IgM or seroconversion in pregnancy. In three additional children (2 in Group A and 1 in Group B) the congenital infection might have been the cause of their preterm birth. 9, 10 In the remaining positive cases clinical data were inconclusive or unavailable.

The proportion of CMV-positive cases was 10% (9 of 87) in Group A and 30% (13 of 43) in Group B (Table 1). The higher percentage of CMV-positive cases found in Group B than in Group A is related to the different composition of the groups, the cases with no known cause of SNHL being the majority (88%; 38 of 43) in Group B. After eliminating the cases with a known familial or syndromic cause of deafness, 30 from Group A and 5 from Group B, the percentages of congenital CMV related cases rose to 15.8% (9 of 57) in the former group and to 34.2% in the latter one.

Results of the ascertainment of congenital CMV infection through the DBS test

In Group A the rate of positive cases in children identified after an universal audiologic screening (12.5%; 4 of 32) was not statistically different from the rate in those examined for the presence of audiologic risk factors (9%; 5 of 55) (P = 0.72, Fisher’s exact test).

From the audiologic point of view, no difference was found in acuity between CMV-positive and CMV-negative cases in Group A infants. In Group B all positive cases but one had documented severe to profound hearing loss; this means that 42.7% (12 of 28) of the children with a hearing impairment of unknown cause and needing rehabilitation had deafness resulting from congenital CMV infection.


Estimating the burden of congenital CMV infection in sensorineural hearing loss is no easy task. In fact the infection is largely (90%) asymptomatic at birth, the standard virologic diagnosis is restricted to the first 3 weeks of life and the deafness is present at birth in only one-third to one-half of the cases that will develop the sequelae in infancy. 11 As a consequence the evaluation of the role of congenital CMV can be attained only by retrospective studies employing innovative tests for the late diagnosis of the infection. The methodology used in this study is very sensitive and has been previously shown to work well for this purpose. Both the nature of the sample and the characteristics of the test favor the performance of retrospective studies. In the present survey the accuracy of the test was supported by the absence of positives among the cases with a known cause and by the fact that nearly one-half of the positive cases had clinical or laboratory indications of a possible congenital infection. The good performance of the test suggests that it could be used in assessing or discounting congenital CMV infection as the cause of SNHL in previously undefined cases. In a recent report in which congenital CMV infection could be determined in only 4 cases of 168, 3 the DBS test could have given an answer in 41 patients (24%).

The results obtained in the two groups of children give indications of the burden of congenital CMV infection in SNHL. In relation to the 10% of infants positive in Group A and the data of Fowler et al. 11 showing that only 50% of the congenitally infected babies who develop SNHL are actually identified in the neonatal period, one might infer that the impact of congenital CMV in SNHL could be as high as 20%. This is in agreement with the 18% (21 of 114) reported in a study by Ohlms et al. 6 whose data came from routine screening for congenital CMV. The results obtained from Group B indicate congenital CMV as the cause of 34% of the cases of unknown etiology. A similar rate (31.6%) is obtained from Group A results when cases of known etiology are eliminated and the indications of Fowler et al. 11 are followed. Interestingly this is the estimated percentage of cases attributable to all congenital infections. 4

The different criteria adopted in the audiologic screening protocol in Group A did not result in a significant difference in the frequency of CMV-positive cases. It cannot be excluded that this depends on the fact that the cases examined were selected casually depending on the availability of DBS within the regional screening center. If the presence of risk factors was the screening criterion, the probability of missing deafness cases caused by congenital CMV would be higher than that proposed by Fowler et al. 11 for universal audiologic screening. This is because congenital CMV infections are largely asymptomatic and the identification of cases of infection either at birth or prenatally is not routinely conducted.

Finally further data showing the relevance of congenital CMV in SNHL derives from the observation that >40% of children requiring rehabilitation because of a hearing impairment of unknown cause result positive for CMV.

In conclusion these results suggest that congenital CMV infection plays a wider role in the etiology of SNHL than was previously thought. The availability of a test permitting diagnosis of the congenital infection even after years of life was decisive. Confirmation of these data will stress the advisability of preventive interventions both primarily through anti-CMV vaccination and secondarily by means of neonatal screening for congenital infection aimed at early detection and correction of possible hearing impairments.

We gratefully acknowledge the excellent technical assistance of Valeria Primache. We also thank Drs. A. Del Prete (“Manzoni” Hospital, Lecco, Italy), P. Guidotti (“S. Anna” Hospital, Como, Italy), R. Tornaghi (“Sacco” Hospital, Milan, Italy) and B. Zapparoli (“S. Gerardo” Hospital, Monza, Italy) for referral of some of the cases.

This study was partly supported by a grant from the University of Milan (FIRST 2000).


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Cytomegalovirus; congenital infection; hearing loss; Guthrie card; polymerase chain reaction

© 2003 Lippincott Williams & Wilkins, Inc.