Objective. Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss (SNHL) and neurologic impairment in children. Although the majority of children with symptomatic congenital CMV infection develop hearing loss, many symptomatic infants have normal hearing. The purpose of this study was to identify indicators present in the newborn period that have predictive value for the development of hearing loss in children with symptomatic congenital CMV infection.
Methods. Of the 190 children who had symptomatic congenital CMV infection and were born between 1966 and 1997 and enrolled in a follow-up study, hearing outcome was known for 180 children. Follow-up data were analyzed using univariate and multivariate logistic regression analyses to determine the specific demographic, newborn clinical, and laboratory findings predictive of hearing loss. The amount of infectious CMV in urine was quantified in a subset of 21 children who were born between 1994 and 1998.
Results. The presence of intrauterine growth retardation, petechiae, hepatosplenomegaly, hepatitis, thrombocytopenia, and intracerebral calcifications was associated with the development of hearing loss on univariate analysis. The presence of microcephaly and other neurologic abnormalities was not predictive of hearing loss. Logistic regression analysis revealed that only petechiae and intrauterine growth retardation independently predicted hearing loss. None of the demographic and other newborn findings predicted progressive hearing loss. The children who developed hearing loss had higher urine CMV titers during infancy than those with normal hearing.
Conclusion. In children with symptomatic congenital CMV infection, evidence of disseminated infection with or without the presence of neurologic involvement at birth was predictive of the development of hearing loss. However, it was not possible to identify factors that are independently predictive of the development of progressive hearing loss.
- congenital infection
- symptomatic congenital CMV infection
- sensorineural hearing loss
- predictors of outcome
Congenital cytomegalovirus (CMV) infection is the most common intrauterine infection and affects between 0.4% and 2.3% of live-born infants in the United States.1–3 Approximately 40 000 infants in the United States are born with congenital CMV each year, and the majority of these children have no clinically apparent findings at birth (asymptomatic congenital CMV infection). Only approximately 10% to 15% of the infected infants exhibit clinical evidence of congenital infection at birth (symptomatic congenital CMV infection), but this group is more likely to experience sequelae, including sensorineural hearing loss (SNHL); cognitive, motor, and visual deficits; and seizures.3–7 Previous studies from our laboratory and others have shown that approximately half of the children with symptomatic congenital CMV infection develop hearing loss, and the majority of these children experience continued postnatal deterioration of the deficit.3,8–11
Central nervous system (CNS) involvement in children with symptomatic congenital CMV infection—as evidenced by the presence of microcephaly, seizures, abnormal tone, or chorioretinitis at birth—has been shown to predict the development of cognitive and motor deficits.5,6,12 However, the predictors of hearing loss in children with congenital CMV infection have not been identified. Whether clinical findings at birth are helpful in the identification of infected children who are at risk for the development of hearing loss is not known. In addition, clinical manifestations in the newborn period may provide clues to a better understanding of the pathogenesis of hearing loss in congenital CMV infection. The ability to identify children who have symptomatic congenital CMV infection and are at increased risk for hearing loss will permit careful monitoring of at-risk children, provide a basis for more timely and appropriate counseling for parents, and aid in the formulation of interventional strategies.
Of the 209 children who had symptomatic congenital CMV infection and were born between 1966 and 1997 and evaluated by the investigators at the University of Alabama Hospitals, 190 were enrolled in a prospective follow-up study. Six children died during early infancy after enrollment, and 4 were lost to follow-up. Hearing outcome data were available for the remaining 180 children, and this group constituted the study population. Of the 19 children who were not enrolled in the follow-up study, 14 had died during early infancy.
Infants were classified as symptomatic when they shed CMV and had any of the clinical findings suggestive of congenital infection in the newborn period, including petechiae, jaundice with conjugated hyperbilirubinemia (direct bilirubin >2 mg/dL), hepatosplenomegaly, microcephaly, seizures, and chorioretinitis.4 Demographic data and clinical findings at birth were collected from maternal and newborn hospital records and from parents at the time of initial evaluation of the subjects. Prematurity and extreme prematurity were defined as gestational age <37 completed weeks and <32 completed weeks, respectively. The presence of laboratory abnormalities in the neonatal period—such as elevated alanine aminotransferase (>80 U/mL) or direct bilirubin (>2 mg/dL) and thrombocytopenia (platelet count <100 000/mm3)—and the results of neuroradiographic imaging were obtained from the newborn hospital records. Informed consent was obtained from the parents or legal guardians of the study children.
Sixteen of the 180 study children received ganciclovir as part of a phase II or phase III ganciclovir clinical trial. Hearing loss occurred in nine of these children (56%), and 7 had hearing loss at birth, 2 had delayed onset loss, and 3 had progressive hearing loss. Exclusion of these 16 children from the analysis did not result in any significant changes with respect to the potential risk factors and their relationships to hearing loss. Therefore, the children were included in the analysis of the study group.
The study children were followed in a special interdisciplinary clinic at the University of Alabama at Birmingham (UAB) and were monitored with serial audiologic evaluations using a standard protocol as described previously.11 Audiologic evaluations were administered during the newborn period, then every 6 months until 24 months of age, and followed with annual evaluations thereafter. SNHL was defined as air conduction thresholds >25 decibels (dB) on auditory brainstem response audiometry (ABR) or >20 dB on behavioral audiometric evaluations appropriate for child’s developmental level in conjunction with normal bone conduction thresholds and normal middle ear function.11 Progressive hearing loss was defined as sensorineural decrease in hearing of 10 dB or more at any 1 frequency or ABR threshold, documented on 2 different evaluations, and delayed onset hearing loss was defined as 1 or more hearing evaluations with a normal threshold documented for each ear before SNHL was detected.13
Quantitative Titration of Urine CMV Excretion
Urine samples obtained during the first month of life were available from a subset of 21 children who were born between 1994 and 1997. These samples were analyzed for the amount of infectious CMV by plating 10-fold dilutions of the urine specimens in 24-well plates seeded with human fibroblasts as described previously, and the TCID50 was calculated based on the method of Reed and Muench.14
The demographic data, newborn findings, and serial audiometric data were recorded on standardized case report forms and maintained in SAS for Windows data sets (SAS Institute, Cary, NC). The demographic and newborn characteristics were compared between the groups of children with hearing loss during the follow-up period and those with normal hearing, and statistical significance was determined using χ2, Fisher exact test, or Cochran-Mantel-Haenszel statistics where appropriate. Crude odds ratios (ORs) were calculated from 2 × 2 tables to determine the extent to which various factors were associated with an increased risk for the development of hearing loss, and exact 95% confidence intervals (CIs) were calculated for each OR.15,16 Logistic regression analyses were performed simultaneously to determine the covariates that were independently associated with hearing loss.17 Race, insurance status, intrauterine growth retardation, petechiae, hepatosplenomegaly, microcephaly, jaundice, seizures, thrombocytopenia, and referral status were included in the logistic regression model. Adjusted ORs (aORs) were calculated for each regression covariate, and 95% CIs were determined using the parameter estimates and their respective standard errors. The relationship between hearing loss and the amount of CMV in urine during infancy was analyzed using nonparametric methods, and statistical significance was determined using Wilcoxon rank sum test and χ2 for trend analysis.
Forty-eight percent of the study children (87 of 180) were noted to have hearing loss on follow-up. Of these children, 30% (26 of 87) had delayed-onset hearing loss and 70% (61 of 87) had hearing loss at birth or in the newborn period. Progressive hearing loss was observed in 63% (55 of 87) children. The median age at last hearing evaluation was 69 months, and the median number of hearing evaluations was 8 (range: 1–42).
The demographic characteristics were compared between the group of children with normal hearing and those with hearing impairment (Table 1). No significant differences were observed between the 2 groups with respect to the race or gender of the infant. Similarly, the maternal age at delivery was not different between the group of children with hearing loss and those with normal hearing (mean maternal age: 21.8 years vs 21.7 years). Sixty-five percent (117 of 180) of the study children were referred to our clinic from other health care providers, and the remaining children were identified by the newborn virologic screening program at the University of Alabama Hospitals. Referral children were twice as likely to develop hearing loss as those who were identified by newborn screening. The children whose mothers had private health insurance were also twice as likely to develop hearing loss as those whose mothers had Medicaid or no insurance.
Of the 180 children in the study, 117 children (65%) were referred to UAB and the remaining 63 (35%) were identified on newborn virologic screening at the UAB Hospital. There were significant sociodemographic differences between the referral children and those identified by newborn screening. Most children in the screened group were black (75%), were born to single mothers (67%), and had Medicaid or no insurance (83%). In contrast, the majority of children in the referral group were born to white (73%), married women (68%) who had private health insurance (54%). The referral group had significantly higher frequencies of petechiae, jaundice, hepatosplenomegaly, intrauterine growth retardation, thrombocytopenia, and microcephaly than the newborns in the screened group.
A comparison of various newborn clinical findings between children with hearing loss at last follow-up and those with normal hearing at last follow-up is shown in Table 2. The results of univariate analyses showed that children with intrauterine growth retardation, petechiae, or hepatosplenomegaly were at least twice as likely to develop hearing loss as those with normal intrauterine growth and no petechiae or hepatosplenomegaly. The mean gestational age was 38.0 ± 9.5 weeks (range: 29–42 weeks) for children with hearing loss on follow-up and 37.2 ± 3.2 weeks (range: 26–43 weeks) for children with normal hearing on follow-up. The difference between the 2 groups of children with respect to gestational age was not statistically significant.
The presence of clinical neurologic abnormalities at birth, such as microcephaly or seizures, was not associated with an increased risk for hearing loss. The infants for whom the results of laboratory and neuroradiographic imaging (computed tomography) studies were available are shown in Table 3. The presence of thrombocytopenia and hepatitis (alanine aminotransferase >80 IU/mL and/or direct bilirubin >4.0 mg/dL) and the presence of intracerebral calcifications on cranial computed tomography were associated with hearing loss (Table 3). With the exception of thrombocytopenia, laboratory and imaging variables were not included in the logistic regression model of hearing loss because fewer than two thirds of the study children underwent these evaluations.
Logistic regression analyses of the data were performed to adjust for confounders and interaction that may affect the association of specific risk factors and the development of hearing loss (Table 4). Factors independently associated with the development of hearing loss included petechiae (aOR: 2.8; 95% CI: 1.2–6.0), intrauterine growth retardation (aOR: 2.2; 95% CI: 1.1–4.9), and private health insurance (aOR: 2.8; 95% CI: 1.4–6.2). Once the specific factors were adjusted for in the logistic regression model, thrombocytopenia and hepatosplenomegaly were not shown to be independent predictors of hearing loss.
Of the 87 congenitally infected children who developed hearing loss during the study period, progressive hearing loss was observed in 55 children (63%). For this subpopulation, fewer children with intrauterine growth retardation (53%) developed progressive hearing loss than those whose birth weight was appropriate for gestational age (76%; P < .05). Also, fewer microcephalic children (55%) developed progressive hearing loss than those with normal head circumference at birth (75%); however, this difference only approached statistical significance (P = .06). After adjusting for race, referral, insurance status, and microcephaly in a logistic regression model, intrauterine growth retardation was not independently associated with progressive hearing loss (aOR: 0.42; 95% CI: 0.15–1.14).
Urine specimens obtained during the first month of life from a subset of 21 children who were born between 1994 and 1997 were analyzed for the amount of infectious CMV. The mean duration of follow-up for this group of 21 children was 42.5 ± 19.9 months, and the median number of hearing evaluations was 8 (range: 2–17). On follow-up, 9 of these 21 children (43%) had developed hearing loss. Although the group of children who developed hearing loss shed more CMV in urine at birth than those with normal hearing, this difference only approached statistical significance (P = .06). A significant association between urine CMV titers during infancy and the development of hearing loss on follow-up was observed when the data were analyzed using χ2 for trend analysis (P = .01). None of the 6 children with urine titers <5 × 103 pfu/mL developed hearing loss, whereas 4 of 8 children (50%) with titers between 5 × 103 and 5 × 104 pfu/mL and 5 of 7 infants (57%) with urine CMV titers >5 × 104 pfu/mL had hearing impairment (Fig 1).
The results of this long-term follow-up study of children with symptomatic congenital CMV infection during the past 30 years demonstrates that disseminated disease at birth—as evidenced by petechiae, hepatosplenomegaly, intrauterine growth retardation, thrombocytopenia, or hepatitis—is predictive of hearing loss (Tables 2 and 3). In contrast, clinical evidence of CNS involvement at birth is not associated with an increased likelihood of developing hearing loss. Petechiae and intrauterine growth retardation are shown to be independent risk factors for hearing loss in the study population (Table 4). These results reveal that infants with petechiae are 3 times more likely to develop hearing loss than those without petechiae at birth. Also, children with intrauterine growth retardation are twice as likely to have hearing impairment as those with normal intrauterine growth.
Previous studies from our laboratory and others have demonstrated that evidence of CNS involvement at birth is a strong predictor of cognitive and motor deficits in children with symptomatic congenital CMV infection.5,6,12 Although a significant proportion of infants with microcephaly at birth develop hearing loss, this finding was not predictive of hearing loss in our study. In fact, infants with microcephaly were less likely to develop progressive hearing loss compared with those with normal head circumference; however, this difference only approached statistical significance. These observations suggest that symptomatic infants with disseminated CMV infection at birth—as evidenced by the presence of intrauterine growth retardation, petechiae, hepatitis, or thrombocytopenia with or without neurologic abnormalities—are at an increased risk for developing hearing loss. The association between the amount of urinary excretion of CMV at birth and the proportion of children with hearing loss further supports our hypothesis that in symptomatic infants, disseminated disease at birth may be more important in the development of hearing loss than isolated neurologic involvement (Fig 1).
The finding that disseminated disease at birth is predictive of hearing loss, together with the observation that isolated CNS involvement does not predict hearing loss, is helpful in providing more accurate counseling for the parents of congenitally infected symptomatic infants. On the basis of the results of our study, it is prudent to recommend that all children with symptomatic congenital CMV infection, not just those with neurologic abnormalities at birth, be monitored closely for the development of hearing loss. The results of this study also suggest that the pathogenic mechanisms that contribute to the development of hearing loss in children with symptomatic congenital CMV infection are different from those that lead to cognitive and motor deficits. The observation that CNS disease at birth has no predictive value for hearing loss in the study population suggests that future studies of antiviral therapy for symptomatic CMV should include children with disseminated disease regardless of whether they have CNS involvement.18
More children who were referred to the UAB developed hearing loss than those who were identified by the newborn virologic screening program. An increased frequency of hearing loss in the referral group is probably attributable to the fact that these children had more clinically apparent or disseminated disease at birth compared with those who were identified by the newborn virologic screening program. The majority of children in the referral group had private health insurance compared with only 17% of the children in the screened group. Thus, the association between private health insurance and the development of hearing loss is probably attributable to the selection bias whereby more infants who had symptomatic congenital infection with disseminated disease and had private health insurance were detected by the health care providers and referred to us for enrollment in our study. Although an association between intrauterine growth retardation and hearing loss exists, no statistically significant association between prematurity and hearing loss was observed in the study population. One explanation for this difference may be that most fetal weight gain occurs during the third trimester of pregnancy; therefore, intrauterine growth retardation may be a marker of disseminated CMV infection in the fetus during later gestation. This observation further supports our hypothesis that children with symptomatic congenital infection with evidence of disseminated CMV infection at birth are at an increased risk for hearing loss.
A significant proportion of congenitally infected children with hearing loss will experience continued postnatal deterioration of hearing.11,13,19 In this study, 55 (63%) of 87 of the study children who developed hearing loss were noted to have further deterioration of their hearing. The pathogenesis of hearing loss and the continued postnatal deterioration of hearing function in children with congenital CMV infection has not been elucidated. In a recent study of 85 children with congenital CMV infection, we demonstrated that increased virus burden in early infancy as evidenced by greater CMV excretion in urine and high peripheral blood viral load was predictive of hearing loss.20 However, the role of virus burden in the development of progressive hearing loss could not be defined in that study because of the small number of children who developed hearing loss during the study period. The demonstration of a significant association between the amount of CMV in urine and the proportion of children who develop hearing loss further supports the notion that increased virus burden contributes to hearing loss (Fig 1). A recent study by Noyola et al21 showed that significantly more children who excreted CMV for <4 years developed hearing loss and progressive hearing loss compared with children who excreted CMV for >4 years. The authors of that study suggested that host immune responses that lead to cessation of virus shedding may play a role in the pathogenesis of progressive hearing loss.
Although this study demonstrates that the presence of petechiae and intrauterine growth retardation are independently associated with hearing loss among children with symptomatic congenital CMV infection, no predictors of the development of progressive hearing loss were identified. It is therefore essential that all symptomatic children be monitored carefully to detect the occurrence of hearing loss and also the possible further deterioration of hearing deficit as currently recommended for children at increased risk for hearing loss.22 Our study did not examine indicators that may exist for the development of hearing loss among children with asymptomatic congenital CMV infection; however, adequate follow-up is needed to detect subsequent development of hearing loss in these children as well.22 Additional studies to elucidate the risk factors and mechanisms underlying progressive hearing loss in children with symptomatic and asymptomatic congenital CMV infection are needed for accurately identifying these children early and for formulating strategies for effective intervention.
This work was supported in part by grants from the National Institutes of Health, the National Institute of Child Health and Human Development (P01 HD10699), the National Institute of Allergy and Infectious Diseases (P01 AI43681), the National Institute on Deafness and Other Communication Disorders (R01 DC04163 and R01 DC02139), and the General Clinical Research Center (M01 R00032).
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- ↵Bale JF, Blackman JA, Sato Y. Outcome in children with symptomatic congenital cytomegalovirus infection. J Child Neurol.1990;5 :131– 136
- ↵Stagno S, Reynolds DW, Amos CS, et al. Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections. Pediatrics.1977;59 :669– 678
- ↵Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. Am J Hygiene.1938;27 :493– 497
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- ↵Kimberlin DW, Lin CY, Sanchez P, et al. Ganciclovir (GCV) treatment of symptomatic congenital cytomegalovirus (CMV) infections. Results of a phase III randomized trial. 40th Interscience Conference on Antimicrobials and Chemotherapy; September 17–20, 2000; Toronto, Canada
- ↵Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection. Pediatrics.1992;90 :862– 866
- ↵Boppana SB, Rivera LB, Fowler KB, Yang J, Britt WJ. Viral load in infancy predicts outcome in children with congenital CMV infection. 41st Interscience Conference on Antimicrobials Agents and Chemotherapy; December 16–19, 2001; Chicago, IL
- ↵American Academy of Pediatrics, Joint Committee on Infant Hearing. Year 2000 position statement: principles and guidelines for early hearing detection and intervention programs [special article]. Pediatrics.2000;106 :798– 817
- Copyright © 2002 by the American Academy of Pediatrics