Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection

Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection Karen B. Fowler, DrPH, Faye P. McCollister, EdD, Arthur J. Dahle, PhD, Suresh B o p p a n a , MD, William J. Britt, MD, a n d Robert F. Pass, MD From the Department of Pediatrics, University of Alabama at Birmingham School of Medicine, the Department of Special Education, University of Alabama College of Education, Tuscaloosa, and the Department of Biocommunication, University of Alabama at Birmingham

Objective: To determine the prevalence and temporal changes of sensorineural hearing loss (SNHL) among children with clinically inapparent (asymptomatic) congenital cytomegalovirus (CMV) infection identified from a cohort of newborn infants screened for congenital CMV infection. Methods: The study population consisted of 307 children with documented asymptomatic congenital CMV infection, 76 uninfected siblings of children with asymptomatic congenital CMV infection, and 201 children whose neonatal screen for congenital CMV infection showed negative results. Audiologic evaluations were completed for all children to determine their hearing status. Results: SNHL occurred only in children with congenital CMV infection. Of the children with asymptomatic congenital CMV infection, 22 (7.2%; 95% confidence interval, 4.5% to 10.6%) had SNHL. Among the children with hearing loss, further deterioration of hearing occurred in 50.0%, with the median age at first progression at 18 months (range, 2 to 70 months). Delayed-onset SNHL was observed in 18.2% of the children, with the median age of detection at 27 months (range, 25 to 62 months). Fluctuating SNHL was documented in 22.7% of the children with hearing loss. Conclusions: Asymptomatic congenital CMV infection is likely a leading cause of SNHL in young children. The continued deterioration of hearing and delayed onset of SNHL in these children emphasizes the need for continued monitoring of their hearing status. (J Pediatr 1997;130:624-30)

Supported in part by a research grant (5 P01 HD 10699) from the National Institute of Child Health and Human Development, a research grant (5 R01 DC 02139) from the National Institute on Deafness and Other Communication Disorders, and a research grant (5 M01 RR 00032) from the General Clinical Research Center, National Institutes of Health, the Deafness Research Foundation, and the Civitan International Research Center. Submitted for publication June 20, 1996; accepted Sept. 27, 1996. Reprint requests: Karen B. Fowler, DrPH, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave. South, Suite 752, Birmingham, AL 35233. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/21/78377

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Cytomegalovirus is the leading cause of congenital infection in the United States. An estimated 1% of newborn infants are infected with C M V prenatally, a rate that equates to around 40,000 new cases each year. 1 The vast majority, 90% to 95% ABR CI CMV SNHL

Auditory brain-stem response Confidence interval Cytomegalovims Sensorineural hearing loss

of these infected infants, will have no evidence of disease in the newborn period. However, infants with clinically inapparent (asymptomatic) congenital C M V infection may later have central nervous system and sensory impairments, with

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T a b l e I. Characteristics of children with congenital CMV infection, their uninfected siblings, and control children without congenital CMV infection Children with congenital CMV infection (n = 307) Characteristics

Race* Black White Other Sex Female Male Insurance status* Private insurance Medicaid or no insurance Unknown Prenatal care* Private physicians Health department None/unknown Weeks' gestation at delivery <37 Completed wk ->37 Completed wk Sensorineural hearing loss*

Siblings of children with congenital CMV infection (n = 76)

Children without congenital CMV infection (n = 20 I)

No.

(%)

No.

(%)

No.

(%)

233 74 0

(75.9) (24.1)

56 20 0

(73.7) (26.3)

177 23 1

(88.1) (ll.4) (0.5)

149 158

(48.5) (51.5)

43 33

(56.6) (43.4)

111 90

(55.2) (44.8)

67 239 1

(21.8) (77.9) (0.3)

16 60 0

(21.1) (78.9)

8 193 0

(4.0) (96.0)

61 242 4

(19.9) (78.8) (1.3)

18 55 3

(23.7) (72.4) (3.9)

5 196 0

(2.5) (97.5)

51 256 22

(16.6) (83.4) (7.2)

7 69 0

(9.2) (90.8)

25 176 0

(12.4) (87.6)

*p <0.05.

sensorineural heating loss being the most commonly observed deficit.2-11 Congenital CMV infection is an important cause of auditory system damage; however, information regarding audiologic findings in children with asymptomatic congenital CMV infection is fimited. To study this hearing loss, we must identify children with infection by virologic tests in the newborn period and continue to monitor them with audiologic evaluations. Previous studies identified children with asymptomatic congenital CMV infection and reported rates and severity of hearing loss in these children. 3-5' 10, 12, 13 However, the rates and severity of hearing loss in these children have varied considerably, reflecting differences in methods of patient selection, types of audiologic evaluation, and small study populations with SNHL. 3-5' 10, 12, 13 Ill addition, many of these studies did not evaluate hearing loss in young infants because improved audiologic methods to allow more precise documentation of auditory function during early infancy were unavailable.3-5, 12, 13 To define the prevalence of hearing impairment and temporal changes in audiologic function in children with asymptomatic congenital CMV infection, we performed serial audiologic examinations o f 307 infected children identified from a cohort screened as neonates for congenital CMV infection. Their audiologic outcomes were compared with those of 201 randomly selected children who had cultures nega-

five for CMV in the newborn period and 76 uninfected siblings of children with asymptomatic congenital CMV infection.

METHODS Study population. The study population consisted of children born between 1980 and December 1995, who were identified by newborn screening for congenital CMV infection at two hospitals in Birmingham, AlaJ 4, 15 Congenital CMV infection was identified by isolation of virus in urine or saliva in the first or second week of life. 16-18 These children were assessed and their medical records were systematicaUy reviewed by study personnel to determine whether any of the following symptoms were observed in the newborn period: microcephaly, thrombocytopenia, petechiae, hepatosplenomegaly, or jaundice with conjugated hyperbilirubinemia. Four hundred twenty-four children met the criteria of no clinically apparent disease (asymptomatic) in the newborn period. No child received antiviral or antiinfiammatory therapy. The children were followed up in a special clinic that provides serial andiologic, psychometric, vision, and medical evaluations. To document progression or fluctuation or both of hearing loss, we included in this study only 307 children with two or more audiologic evaluations. These children did not differ with respect to race, gender, gestational age, birth weight, insurance status, prenatal care loca-

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Table II. Comparison of selected characteristics among Children with asymptomatic congenital CMV infection by SNHL status Characteristic

Black race: No. (%) Male sex: No. (%) Medicaid or no insurance: No. (%) Median No. of heating evaluations (range)* Median age (mo) at first hearing evaluation (range) Median age (too) at last hearing evaluation (range)

Children with Children without SNHL (n = 22) SNHL (n = 285)

17 (77.3) 13 (59.1) 20 (90.9)

216 (75.8) 145 (50.9) 219 (76.8)

8 (4-17)

5 (2-16)

1 (0.5-6)

2 (0.5-57)

63 (12-143)

43 (2-184)

*p <0.05.

tion, or maternal age at delivery from the children with fewer than two audiologic evaluations. Two comparison groups of children were used in this study. The first group comprised 201 children who had no congenital CMV infection and were enrolled as infants. These children were randomly selected weekly by a computer-generated program from a hospital newborn population in which routine neonatal screening for congenital CMV infection occurred.15 The parents of these randomly selected neonates were invited to participate in our study. There were no differences between the newborn infants who enrolled and those who did not with respect to race, gender, socioeconomic status, prenatal care location, and maternal age at delivery. The second group included 76 uninfected siblings of children with asymptomatic congenital CMV infection. The siblings were confn'med not to have congenital CMV infection by a negative CMV culture in the first week of life, seronegative mothers at the time of theft birth, or later serologic tests that showed they were without antibody to CMV. The children were followed up serially for audiologic and psychometric evaluations. Informed consent was obtained from the parents or guardians of the children in the study population. Andiologic assessment. Children with congenital CMV infection routinely received an andiologic evaluation at their first clinic visit at age 3 to 8 weeks, at age 6 and 12 months, and annually thereafter unless results revealed a need for additional testing. Children in the comparison group were seen at one or more of the following: age 3 to 6 weeks, age 16 to 20 months, or age 3, 5, or 7 years. When hearing loss was documented, children were seen more frequently, until the nature and stability of the loss could be established. Testing was accomplished by using auditory hrain-stem response thresholds and developmentally appropriate behavioral techniques for obtaining pure-tone and speech-

detection thresholds, tympanograms, and acoustic reflex thresholds. 19'2° ABR procedures included monaural airconduction click thresholds and, when indicated, bone-conduction crick thresholds and 500 and 4000 Hz tone-pip airconduction thresholds. Children seen for ABR andiometry were usually sedated with chloral hydrate according to their age and weight. Otoscopic examination was performed before each audiometric assessment; children with evidence of otitis media had testing deferred. Classification of hearing loss. A modification of the Davis classification of degree of hearing impairment was used to categorize audiologic results for children who gave conditioned responses. 21 Normal heating was defined as 0 to 20 dB, with heating loss defined as one of the following: mild loss, 21 to 45 dB; moderate loss, 46 to 70 dB; severe loss, 71 to 90 dB; and profound loss, greater than 90 dB. When hearing loss was present but the pure-tone average (average of 500, 1000, and 2000 Hz) threshold was less than 21 dB, the thresholds for the affected frequencies determined the classification for degree of heating impairment. The ABR threshold was defined as the lowest intensity level at which wave V could be detected and replicated. An ABR click threshold greater than 25 dB or a tone-pip threshold greater than 30 dB was considered abnormal. A hearing loss was defined as sensorineural if the air-bone gap was less than 10 dB. Progressive hearing loss was defined as sensorineural decrease in hearing of 10 dB or more at any one frequency or ABR threshold, documented on two separate evaluations. Fluctuating hearing loss was defined as a decrease in hearing of greater than 10 dB at one or more frequencies, followed by an improvement of greater than 10 dB measured at one or more times. Progressive and fluctuating hearing losses were assigned only if there was no concurrent middle ear disease that might influence threshold variation, resulting in an incorrect definition of progression or fluctuation or both. Other criteria for fluctuating hearingloss assignment included good test reliability and agreement between two audiologists that fluctuation had occurred. High-frequency hearing loss was defined as a decrease in hearing at 4000, 8000, and 12,000 Hz frequencies only (or a combination of these). Delayed or late-onset hearing loss was defined as one or more heating evaluations with a normal threshold documented for each ear before onset of SNHL. Children with conductive heating impairment that resolved were not considered as having hearing loss. Statistical analysis. All demographic, medical, and serial audiometric test data were maintained in datasets in an SAS for Windows data management system (SAS Institute, Cary, N.C.). Contingency tables were obtained for the characteristics of interest according to the children's hearing-loss status. To determine statistical significance, we used routine methods for calculating the chi-square or Fisher exact test,

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Table III. Severity of SNHL in 22 children with asymptomatic congenital CMV infection Bilateral loss*

Unilateral loss

No.

Degree of hearing loss

Mild, 2145 dB Moderate, 46-70 dB Severe, 71-90 dB Profoufid, >90 dB High-frequency loss~

0 1 0 5 5

(%)

(4.5) (22.7) (22.7)

No.

(%)

1 1 4 3 2

(4.5) (4.5) (18.2) (13.6) (9.1)

*Based On better ear. ?High-frequencyloss is defined as decrease in hearing sensitivityat 4000, 8000, and 12,000 Hz frequenciesonly or a combinationof these.

Table IV. Characteristics of SNHL in 22 children with asymptomatic congenital CMV infection Bilateral loss (n = 1 I) Characteristic

Delayed or late onset of loss Yes No Uncertain Progression of loss Yes No Fluctuating loss Yes No High-frequency loss* Yes No

Unilateral loss (n = 1 I)

Total loss (n = 22)

No.

(%)

No.

(%)

No.

(%)

1 8 2

(9.1) (72.7) (18.2)

3 8 0

(27.3) (72.7)

4 16 2

(18.2) (72.7) (9.1)

3 8

(27.3) (72.7)

8 3

(72.7) (27.3)

11 11

(50.0) (50.0)

2 9

(18.2) (81.8)

3 8

(27.3) (72.7)

5 17

(22.7) (77.3)

5 6

(45.4) (54.6)

2 9

( t 8.2) (81.8)

7 15

(31.8) (68.2)

*High-frequencyloss is defined as decrease in heating sensitivityat 4000, 8000, and 12,000 Hz frequenciesonly or a combinationof these.

and Wilcoxon rank-sum tests were used where appropriate. Confidence intervals were calculated by exact methods based on the binomial distribution.

RESULTS There were 584 children in the study population who had audiologic evaluations to assess SNHL. The children were divided into three groups: 307 children with congenital CMV infection, 76 uninfected siblings of children with asymptomatic congenital infection, and 201 randomly selected control children. Characteristics for each group of children are shown in Table I. The CMV-negative group was more likely to be black, have Medicaid or no insurance, and receive prenatal care at the health department, in comparison with the children with congenital CMV infection and their siblings (p <0.05). In all three groups of children, preterm delivery occurred in about 9% to 17% of the births. SNHL occurred only among the children with congenital CMV infection. The prevalence of SNHL was 7.2% (95% CI, 4.5 to 10.6) for children with asymptomatic congenital CMV infection. Other possible origins of or risk factors for

hearing impairment, such as family history of hearing loss, birth weight of less than 1500 gin, ototoxic medications for longer than 5 days, asphyxia, mechanical ventilation for 10 days or longer, bacterial meningitis, and craniofacial or auditory anomalies, were reviewed for children with and without SNHL. None of the children with SNHL had any other identifiable cause of hearing loss, although 8% of children without SNHL had the presence of other hearing risk factors, including a family history of hearing impairment. Bacterial meningitis was not observed in any of the children in the study population. Two children in the group without SNHL had conductive hearing impairment related to structural abnormalities, including a congenital anomaly of the right ear and a cholesteatoma. As seen in Table II, children with asymptomatic congenital CMV infection who had SNHL and those without hearing loss did not differ with respect to race, gender, or insurance status. Children with heating impairment had a greater number of hearing evaluations compared with children without SNHL (p <0.05). Children with SNHL and those without hearing loss had a median age of 1 versus 2 months

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Fowler et al.

at first hearing evaluation (p >0.05). Children with SNHL had a median age at last heating evaluation that was slightly higher than did the children without heating loss (p = 0.12). The severity of SNHL in the 22 children with asymptomatic congenital CMV infection varied from mild unilateral los s to profound bilateral loss (Table llI). Of the 22 children, 11 (50.0%) had bilateral loss. Profound bilateral hearing loss occurred in 22.7% of children with SNHL. High-frequency hearing loss (loss at 4000, 8000, and 12,000 Hz frequencies, or a combination of these) was observed in 7 children (31.8%), 3 children had bilateral high-frequency loss, and 2 children had only unilateral high-frequency loss. The other 2 children had high-frequency hearing loss in the better ear, with the other ear having an overall hearing threshold of greater than 90 dB. Among children with SNHL, 18.2% had delayed-onset SNHL (Table IV). There was no significant difference in the percentages of late-onset heating loss between children with bilateral and unilateral loss, although more children with unilateral loss had delayed-onset loss. The median age for detection of SNHL among children with late-onset SNHL was 27 months (range, 25 to 62 months). Further deterioration of hearing occurred in 50% of all the children with SNHL. Although not statistically significant, progression of heating loss occurred more often among children with unilateral loss (72.7%) than among those with bilateral loss (27.3%). The median age at first progression of hearing loss was 18 months (range, 2 to 70 months). Fluctuating heating loss also was observed in 22.7% of the children with SNHL. Fluctuating loss occurred in 5 children, 3 (27.3%) with unilateral loss and 2 (18.2%) with bilateral loss. Of the 5 children with fluctuating SNHL, 3 had further deterioration of heating loss and 2 had some improvement of hearing loss from initial or previous evaluations.

DISCUSSION Our study found a prevalence of SNHL of 7.2% (95% CI, 4.5% to 10.6%) for children with asymptomatic congenital CMV infection. Approximately haft of the children with SNHL had bilateral hearing loss. The severity of loss ranged from mild high-frequency loss to profound loss, with further deterioration of hearing occurring in 50% of the children with SNHL. Late-onset hearing loss occurred in about 20% of the children with SNHL. Neither the siblings nor the children whose test results were negative for CMV had any SNHL documented. Our findings are similar to those of Williamson et al., 10 although the Houston study had a smaller study population (9 children with SNHL; 59 children with asymptomatic congenital CMV infection) and a shorter follow-up period.I° Williamson et al. found that 15.2% of the children with

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asymptomatic congenital CMV infection (95% CI, 7.2% to 30.0%) had SNHL and 55.5% had further progression of hearing loss. The prevalence of hearing loss among children with congenital CMV infection was slightly higher in their study than in our study, although a similar percentage of children had further deterioration of hearing in both studies. The selection of children included in the studies or possible differences in the underlying populations or both may account for the observed differences in the prevalence (7.2% vs 15.2%) of hearing loss among children with asymptomatic congenital CMV infection. Late-onset heating loss was observed in 1 child (11.1%) in the Williamson study, in comparison with 18.2% in our study. Moreover, neither the Williamson study nor our study documented any SNHL in the control groups of children monitored. Both studies would likely identify more children with delayed-onset hearing loss with further follow-up of study participants. In our study the children without hearing loss were followed up for a shorter time than the children with SNHL. Because late-onset loss was observed in some children aged 60 months and older, it is likely that more lateonset SNHL will occur in this symptom-free cohort with their increasing age. Other findings of interest are the fluctuating and highfrequency SNHL documented in 20% to 30% of the children with hearing loss. Although progressive heating loss in children with asymptornatic congenital CMV infection has been described before, less is known about fluctuating hearing loss after asymptomatic congenital CMV infection.I°, 13,22,23 The mechanism of CMV hearing loss in human congenital infection is not known. It is possible that progression or fluctuation of hearing loss or both are related to virus reactivation and replication or host immunologic response to infection. Studies have suggested that both the host's inflammatory response and the cytopathic effect of virus in the inner ear may cause hearing deterioration. 24 Other studies in guinea pigs infected with CMV support the hypothesis of immune-mediated damage of the inner ear structures. 25, 26 However, further investigations are needed to evaluate viral and immunologic changes and their relation to subsequent hearing status in children with asymptomatic congenital CMV infection. Congenital CMV infection can be definitively diagnosed only in the newborn period, so many of these infections remain undetected. Newborn auditory screening programs that depend on the presence of clinical abnormalities to identify neonates also will miss most of the infants with asymptomatic congenital CMV infection. A study by Hicks et al. 27 found that only 20% of children with congenital CMV infection are identified by neonatal high-risk hearing-loss

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criteria. Of the children with asymptomatic congenital CMV infection, only 8.0% had an auditory screen based on recognition of congenital CMV infection as the risk factor. All the other neonates with asymptomatic congenital CMV infection who had auditory screening were tested because of risk criteria other than CMV infection. Retrospective studies of SNHL in children have underestimated the role of CMV in SNHL origin, because retrospective methods are more likely to detect causes of hearing loss in children if clinically apparent conditions or infections are present. 28-34However, evidence from cohort studies has identified congenital CMV infection as a significantcause of SNHL in young children. A study in Sweden that included screening of more than 10,000 newborn infants both for CMV infection and for hearing loss found that congenital CMV infection was the leading cause of SNHL, accounting for 40% of the hearing loss. 35 Hicks et al.27 found 14 cases of congenital CMV infection with SNHL in 12,371 neonates screened for CMV, a rate of approximately 1.1 per 1000 live births; when only cases involving bilateral loss of 50 dB or greater were considered, the rate was 0.6 per 1000. 27 Comparison of this rate of hearing loss caused by CMV infection with estimates of the overall rates of childhood hearing impairment suggests that the infection may account for at least a third of SNHL in young children.27 Asymptomatic congenital CMV infection occurs in more than 90% of the 40,000 infants born each year with congenital CMV infection in the United States. On the basis of the prevalence of 7.2% reported here, about 2600 children (95% CI, 1650 to 3850 children) with asymptomatic congenital CMV infection may be expected to have SNHL each year. Of these children, it can be expected that 600 young children (95% CI, 380 to 885 children) will have profound SNHL bilaterally because of asymptomatic congenital CMV infection every year. The continued deterioration of hearing and the late onset of SNHL in children with asymptomatic congenital CMV infection, occurring even after age 6 years, emphasize the need for continued monitoring of hearing loss in these children. Because clinically inapparent infection can result in SNHL, it will be important to identify these children in the newborn period, when infection can still be documented. Laboratory procedures now available make it possible to screen infants for CMV rapidly and at relatively low cost.17' 18Clearly all children with congenital CMV infection should be screened for hearing loss. Because their hearing status can deteriorate with advancing age, even when the initial evaluation reveals no abnormalities, repeated auditory evaluation, especially during the first 3 years of life, is strongly recommended. During the early years of life, progressive or late-onset hearing loss is more likely to appear,

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and undetected hearing loss can be detrimental to normal acquisition of speech and language skills. REFERENCES

1. Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control: summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991;13:315-29. 2. Reynolds DW, Stagno S, Stubbs KG, et al. Inapparent congenital cytomegalovirus infection with elevated cord IgM levels: causal relationshipwith auditoryand mental deficiency.N Engl J Med 1974;209:291-6. 3. Hanshaw JB, Scheiner AP, Moxley AW, Gaev L, Abel V, Scheiner B. School failure and deafness after "silent" congenital cytomegalovirusinfection.N Engl J Med 1976;295:468-70. 4. Saigal S, Luynk O, Larke B, Chernesky MA. The outcome in children with congenital cytomegalovirusinfection: a longitudinal follow-up study. Am J Dis Child 1982;136:896-901. 5.. Kumar ML, Nankervis GM, Jacobs IB, et al. Congenital and postnatally acquired cytomegalovirus infections: long-term follow-up. J Pediatr 1984;104:674-9. 6. Preece PM, Pearl KN, Peckham CS. Congenital cytomegalovirus infection. Arch Dis Child 1984;59:1120-6. 7. Pearl KN, Preece PM, Ades A, Peckham CS. Neurodevelopmental assessment after congenital cytomegalovirusinfection. Arch Dis Child 1986;62:323-6. 8. Conboy TJ, Pass RF, Stagno S, et al. Intellectual development in school-agedchildren with asymptomaticcongenitalcytome: galovirus infection. Pediatrics 1986;77:801-6. 9. Williamson WD, Percy AK, Yow MD, et al. Asymptomatic congenital cytomegalovirus infection. Am J Dis Child 1990; 144:1365-8. 10. Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in infants with asymptomatic congenital eytomegalovirus infection. Pediatrics 1992;90:862-6. 11. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirusinfection in relation to maternal antibody status.N Engl J Med 1992;326:663-7. 12. Stagno S, Reynolds DW, Amos CS, et al. Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections. Pediatrics 1977;59:669-78. 13. Dahle AJ, McCollister FP, Stagno S, Reynolds DW, Hoffman HE. Progressive heating impairment in children with congenital cytomegalovims infection. J Speech Hear Disord 1979; 44:220-9. 14. Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus, and clinical outcome. JAMA 1986;256:1904-8. 15. Fowler KB, Stagno S, Pass RF. Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990. J Infect Dis 1993;168:552-6. 16. Reynolds DW, Stagno S, Hosty TS, Tiller M, Alford CA. Maternal cytomegalovirus 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 fluorescent antibody assay for rapid detection of human cytomegalovirus infections. J Clin Microbiol 1992; 30:721-3. 18. Balcarek KB, Warren W, Smith RJ, Lyon MD, Pass RF. Neo-

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