This cross-sectional study assesses the risk factors for hearing loss at birth in newborns with congenital cytomegalovirus.
Key Points
Question
What are the risk factors for hearing loss at birth in newborns with congenital cytomegalovirus (cCMV) infection?
Findings
This cross-sectional study including 1033 newborns with cCMV infection was based on the Flemish CMV registry and identified 3 independent risk factors for congenital hearing loss: petechiae at birth, periventricular cysts on magnetic resonance imaging, and seroconversion in the first trimester of pregnancy.
Meaning
Clinicians may use these risk factors to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss; linking clinical features to hearing loss may provide researchers with new insights into the pathogenesis of cCMV-related hearing loss.
Abstract
Importance
With a prevalence between 0.2% and 6.1% of all live births, congenital cytomegalovirus (cCMV) infection is a major cause of congenital nonhereditary sensorineural hearing loss. Despite the large amount of research on cCMV-related hearing loss, it is still unclear which newborns are at risk of hearing loss.
Objective
To identify independent risk factors for cCMV-related congenital hearing loss and predictors of hearing loss severity at birth.
Design, Setting, and Participants
This cross-sectional study of newborns with cCMV infection used data included in the Flemish CMV registry that was collected from 6 secondary and tertiary hospitals in Flanders, Belgium, over 15 years (January 1, 2007, to February 7, 2022). Data were analyzed March 3 to October 19, 2022. Patients were included in the study after confirmed diagnosis of cCMV infection and known hearing status at birth. Patients who presented with other possible causes of sensorineural hearing loss were excluded.
Main Outcomes and Measures
Primary outcome was hearing status at birth. Clinical, neurological, and laboratory findings along with the timing of seroconversion and blood viral load were separately considered as risk factors. Binary logistic regression was performed to identify independent risk factors for congenital hearing loss in newborns with cCMV. Effect sizes were measured using Hedges g, odds ratio, or Cramer V.
Results
Of the 1033 newborns included in the study (553 of 1024 [54.0%] boys), 416 (40.3%) were diagnosed with symptomatic cCMV infection and 617 (59.7%) with asymptomatic cCMV infection. A total of 15.4% of the patients (n = 159) presented with congenital hearing loss; half of them (n = 80 [50.3%]) had isolated hearing loss. The regression model revealed 3 independent risk factors for congenital hearing loss: petechiae at birth (adjusted odds ratio [aOR], 6.7; 95% CI, 1.9-23.9), periventricular cysts on magnetic resonance imaging (MRI; aOR, 4.6; 95% CI, 1.5-14.1), and seroconversion in the first trimester (aOR, 3.1; 95% CI, 1.1-9.3). Lower viral loads were seen in patients with normal hearing compared with those with congenital hearing loss (median [IQR] viral load, 447.0 [39.3-2345.8] copies per milliliter of sample [copies/mL] vs 1349.5 [234.3-14 393.0] copies/mL; median difference, −397.0 [95% CI, −5058.0 to 174.0] copies/mL).
Conclusions and Relevance
Findings of this cross-sectional study suggest that newborns with cCMV infection and petechiae at birth, periventricular cysts on MRI, or a seroconversion in the first trimester had a higher risk of congenital hearing loss. Clinicians may use these risk factors to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. Moreover, linking clinical features to hearing loss may provide new insights into the pathogenesis of cCMV-related hearing loss. The importance of viral load as a risk factor for congenital hearing loss remains unclear.
Introduction
Cytomegalovirus (CMV) is a double-stranded DNA virus.1 For infection during pregnancy, intrauterine transmission may cause a congenital cytomegalovirus (cCMV) infection. With a prevalence between 0.2% and 6.1% of all live births, cCMV is the most common congenital infection.2,3,4,5 It might result in sensorineural hearing loss (SNHL) or neurodevelopmental impairment.6,7 As such, cCMV has been a major public health problem worldwide for decades.8
Being a herpesvirus, CMV can establish a lifelong latency with periods of reactivation.9,10 Moreover, different viral strains exist. Consequently, maternal seroconversion can be primary or nonprimary (reactivation of a latent virus or infection with a different strain).1 The risk of intrauterine transmission is considerably lower in a nonprimary infection compared with a primary infection (1% vs 40%).11,12 Once infected, the risk of fetal damage is presumed to be the same.13 A factor contributing to the severity of disease is timing of maternal seroconversion. Most neurodevelopmental sequelae are associated with seroconversion during the first trimester. Sequelae after a second- or third-trimester infection have also been described, albeit with a lower prevalence.14
Congenital CMV infection can be asymptomatic or cause a widespread range of symptoms. Newborns may present with dysmaturity, hepatosplenomegaly, microcephaly, or petechiae.1,14,15 Rarely, retinal or optic nerve abnormalities may be found.16 Laboratory results may show leukopenia or thrombocytopenia. Abnormalities on central imaging (magnetic resonance imaging [MRI] or cranial ultrasonography] may be detected. Striatal vasculopathy, periventricular cysts, ventriculomegaly, hyperintensity of white matter, and cystic periventricular leukomalacia are the most frequently described anomalies.1,14,15 Up to 32% of newborns with cCMV infection will present with hearing loss.17 The characteristics of hearing impairment are highly variable: unilateral or bilateral loss with a severity varying from mild to profound. Hearing loss may present at birth, be isolated or associated with other symptoms, or develop within years. Hearing improvement, deterioration, and fluctuations are known features of cCMV-related hearing loss. Therefore, audiological follow-up in all children with cCMV infection is advised until age 4 years.1,18,19 Vestibular loss associated with cCMV infection seems to exhibit the same variability regarding incidence, onset, evolution, laterality, and severity. However, hearing loss and vestibular loss do not necessarily coexist.20,21
Despite the large amount of research on the occurrence and characteristics of cCMV-related hearing loss, it is still unclear which newborns are at risk of hearing loss at birth.22 Although researchers previously investigated the importance of clinical symptoms and central imaging anomalies as risk factors for hearing loss, uniformity was difficult to reach, mainly due to small sample sizes.23,24,25,26,27,28,29,30 The role of a second- or third-trimester infection and viral load remains contradictory.23,24,31,32,33,34,35 The aim of the study was to identify independent risk factors for cCMV-related congenital hearing loss and predictors of hearing loss severity at birth.
Methods
Data Collection and Neonatal Investigations
This study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Ethical approval was obtained from the Ethical Committee of Ghent University Hospital, and written informed consent was obtained from a parent or caregiver of each participant. In this cross-sectional study, data on newborns collected over 15 years (January 1, 2007, to February 7, 2022) were obtained from a prospective multicenter registry that was set up in Flanders, Belgium, by the Flemish Society of Pediatrics’ Neonatology and Perinatal Epidemiology Working Group in January 2007. Pediatricians and otorhinolaryngologists of 6 secondary and tertiary hospitals (Ghent University Hospital, Antwerp University Hospital, Sint Jan Hospital in Bruges, University Hospitals of Leuven, GZA Sint Augustinus in Antwerp, and GZA Middelheim in Antwerp) reached consensus toward a standardized protocol for diagnosis, treatment, and follow-up of newborns with cCMV. Since 2007, neonatal and audiological data of newborns with cCMV infection have been collected prospectively in the Flemish CMV registry. A digitization was performed in 2013. Details on the neonatal period, such as timing of seroconversion, clinical features at birth, laboratory findings, results of central imaging (cranial ultrasonography or MRI), audiological testing, and ophthalmological investigation were collected. The detailed protocol of patient inclusion and diagnosis of cCMV infection can be found in previous publications.6,14 In this study, the primary outcome was hearing status at birth. Newborns were included in this study after confirmed diagnosis of cCMV and known hearing status at birth. Newborns presenting with other possible causes of SNHL (eg, aplasia of the cochlear nerve) were excluded. For missing data, the medical files were reviewed or the treating physician was contacted.
Imaging findings were considered abnormal in the setting of typical cCMV-related anomalies (eg, calcifications, ventriculomegaly, intraventricular adhesions, periventricular cysts, or cystic periventricular leukomalacia) on cranial ultrasonography or MRI.14 Laboratory findings were considered to be aberrant in the setting of a white blood cell count lower than 5000/μL or a platelet level lower than 50 000/μL (to convert white blood cell count and platelet level to ×109 L, multiply by 0.001). Ophthalmological evaluation was performed by fundoscopy. In the first 3 weeks of life, blood samples were taken for a quantitative CMV polymerase chain reaction test to assess viral load at birth.36 Viral load was expressed as the number of copies per milliliter of sample (copies/mL). Only the results of viral load measurements performed at Ghent University Hospital were analyzed. If the CMV load was below the analytical limit of detection, the exact value was retrieved retrospectively. The result of the universal neonatal hearing screening (every newborn in Flanders) or auditory brainstem response within the first month of life was considered the initial hearing status.7,37 The audiological protocol was previously described by Goderis et al.7 Details of hearing status were collected for both ears separately.
Definition of Symptomatic cCMV
All newborns included in the registry were reclassified in 2018 according to the European consensus statement on cCMV.38 However, in this study, newborns were subdivided into 4 categories depending on the presence of congenital hearing loss and other symptoms at birth (clinical, neurological, or laboratory abnormalities) (Figure). Newborns with cCMV and isolated SNHL (without symptoms other than SNHL) were considered symptomatic.
Figure. Categorization of the Study Population.
cCMV indicates congenital cytomegalovirus.
Statistical Analysis
Analyses were performed March 3 to October 19, 2022, using IBM SPSS, version 28 (IBM Corp). The baseline characteristics were compared using χ2, Fisher exact, Mann-Whitney U, or Kruskal-Wallis tests as appropriate. All continuous variables were nonparametrically distributed. The same univariate tests were performed to assess whether baseline and clinical characteristics were risk factors for congenital hearing loss. Effect sizes were measured using Hedges g (continuous variables), odds ratio (OR) (categorical variables with 2 subcategories), or Cramer V (categorical variables with more than 2 subcategories).39 Median difference and 95% CIs were calculated using the Hodges-Lehmann estimator.
To identify variables independently associated with congenital hearing loss, variables with significant results (univariate test, P < .05) were added to a binary logistic regression analysis using a forward stepwise selection process. The adjusted OR (aOR) was used to express the relative risk of congenital hearing loss, assuming the other variables to be constant. To identify risk factors for hearing loss severity, univariate tests (Mann-Whitney U test or Spearman rank correlation coefficient) were performed to assess ears with hearing loss (decibels above the normal adult hearing level).
A clinical prediction risk model for congenital hearing loss was created based on the presence of 1 or more risk factors. Points were assigned based on the relative values for the aORs as follows: 2 points for petechiae at birth, 1 point for periventricular cysts on MRI, and 1 point for seroconversion in the first trimester. A total score between 0 and 4 for the risk of congenital hearing loss was calculated for each child.
All statistical tests were 2-tailed, and the significance level was set at P < .05. Bonferroni correction was applied as appropriate.
Results
Baseline Characteristics
A total of 1033 newborns were included (553 of 1024 boys [54.0%] and 471 of 1024 girls [46.0%]; data on sex were missing for 9 newborns) in the analysis; 416 newborns (40.3%) had symptomatic cCMV and 617 (59.7%) had asymptomatic cCMV. The timing of diagnosis of cCMV infection ranged between 1 day and 59 months. A retrospective diagnosis was mainly made by dried blood spot because of etiological evaluation of hearing loss. An overview of the baseline characteristics can be found in Table 1 and eTable 1 in Supplement 1.
Table 1. Baseline Characteristics of Newborns With Symptomatic and Asymptomatic cCMV.
| Characteristic | Newborns, No./total No. (%) | ||
|---|---|---|---|
| With cCMV | With symptomatic cCMVa | With asymptomatic cCMVb | |
| Sexc | |||
| Male | 553/1024 (54.0) | 214/411 (52.1) | 339/613 (55.3) |
| Female | 471/1024 (46.0) | 197/411 (47.9) | 274/613 (44.7) |
| Timing of seroconversion | |||
| First trimester (0-13 wk) | 277/609 (45.5) | 148/247 (59.9) | 129/362 (35.6) |
| Second trimester (14-27 wk) | 211/609 (34.6) | 74/247 (30.0) | 137/362 (37.8) |
| Third trimester (>27 wk) | 121/609 (19.9) | 25/247 (10.1) | 96/362 (26.5) |
| Prematurity (<37 wk) | 82/852 (9.6) | 48/378 (12.7) | 34/474 (7.2) |
| Birth weight, median (IQR), g | 3285.0 (2920.0-3616.3) | 3180.0 (2767.5-3517.5) | 3350.0 (3060.0-3667.5) |
| Birth length, median (IQR), cm | 50.0 (48.0-51.0) | 49.0 (47.0-51.0) | 50.0 (49.00-51.0) |
| Head circumference, median (IQR), cm | 34.0 (33.0-35.0) | 34.0 (33.0-35.0) | 34.0 (33.0-35.0) |
| Method of diagnosis | |||
| Polymerase chain reaction on saliva | 23/1020 (2.3) | 9/412 (2.2) | 14/608 (2.3) |
| Polymerase chain reaction on urine | 236/1020 (23.1) | 97/412 (23.5) | 139/608 (22.9) |
| Virus isolation in saliva | 19/1020 (1.9) | 9/412 (2.2) | 10/608 (1.6) |
| Virus isolation in urine | 682/1020 (66.9) | 255/412 (61.9) | 427/608 (70.2) |
| Dried blood spot | 60/1020 (5.9) | 42/412 (10.2) | 18/608 (3.0) |
| Viral load, median (IQR), copies/mLd | 467.0 (41.8-2373.8) | 445.0 (32.5-2293.0) | 513.0 (141.0-2447.5) |
Abbreviation: cCMV, congenital cytomegalovirus.
The group with symptomatic cCMV consists of newborns with hearing loss and with other symptoms, newborns without hearing loss and with other symptoms, and newborns with hearing loss and without other symptoms.
The group with asymptomatic cCMV consists of newborns without hearing loss and without other symptoms.
Data on sex were missing for 9 newborns.
As a standardized test to detect blood viral load across laboratories is lacking, results were limited to 1 center to prevent analytical bias.
The clinical characteristics of the cohort can be found in Table 2 and Table 3. For this study, newborns with cCMV were classified into 4 groups. The majority of newborns (n = 617 [59.7%]) were in the asymptomatic group (without congenital hearing loss or other symptoms), whereas 257 newborns (24.9%) were in the group without congenital hearing loss but with other symptoms, 79 (7.6%) in the group with congenital hearing loss and other symptoms, and 80 (7.7%) in the group with congenital hearing loss but without other symptoms. None of the newborns showed symptoms of cataract, convulsions, or cortical atrophy on ultrasonography. One hundred fifty-nine newborns (15.4%) had hearing loss at birth; half of them (n = 80 [50.3%]) had isolated hearing loss (eTable 2 in Supplement 1). For the group with hearing loss and with other symptoms, 44.6% (50 of 112) of the newborns experienced profound hearing loss vs 52.4% (54 of 103) of newborns in the group with hearing loss and without other symptoms (eFigure in Supplement 1).
Table 2. Risk Factors for Congenital Hearing Loss in Newborns With Clinical, Neurological, or Laboratory Abnormalities With and Without Hearing Loss at Birth.
| Risk Factor | Patients, No. (%) | Difference between groups with congenital hearing loss and normal hearing, test type, result (95% CI) | P value | |
|---|---|---|---|---|
| With hearing loss and with other symptoms | Without hearing loss and with other symptoms | |||
| Timing of seroconversion | ||||
| First trimester (0-13 wk) | 34/42 (81.0) | 88/175 (50.3) | Cramer V, 0.24 (0.14 to 0.36)a | <.001 |
| Second trimester (14-27 wk) | 6/42 (14.3) | 65/175 (37.1) | ||
| Third trimester (>27 wk) | 2/42 (4.8) | 22/175 (12.6) | ||
| Prematurity | 12/72 (16.7) | 31/243 (12.8) | OR, 1.37 (0.67 to 2.83) | .40 |
| Birth weight | ||||
| No. | 72 | 242 | ||
| Median (IQR), g | 2915.0 (2558.8-3345.0) | 3245.0 (2773.8-3572.5) | Hedges g, 0.43 (0.16 to 0.69)a | <.001 |
| Birth length | ||||
| No. | 60 | 211 | ||
| Median (IQR), cm | 48.0 (47.0-50.8) | 50.0 (48.0-51.0) | Hedges g, 0.33 (0.05 to 0.62)a | .04 |
| Head circumference | ||||
| No. | 55 | 196 | ||
| Median (IQR), cm | 33.0 (31.0-34.0) | 34.0 (33.0-35.0) | Hedges g, 0.57 (0.27 to 0.88)a | <.001 |
| Viral load | ||||
| No. | 8 | 83 | ||
| Median (IQR), copies/mL | 1350.0 (314.8-22 523.0) | 444.0 (13.0-2073.0) | Hedges g, −0.91 (−1.64 to −0.18) | .09 |
| Clinical examination at birth | ||||
| Dysmaturity | 10/79 (12.7) | 20/257 (7.8) | OR, 1.72 (0.77 to 3.84) | .18 |
| Hepatomegaly | 10/79 (12.7) | 8/257 (3.1) | OR, 4.51 (1.72 to 11.87)a | .003 |
| Splenomegaly | 8/79 (10.1) | 7/257 (2.7) | OR, 4.02 (1.41 to 11.48)a | .01 |
| Microcephaly | 3/79 (3.8) | 5/257 (1.9) | OR, 1.99 (0.47 to 8.52) | .40 |
| Petechiae | 12/79 (15.2) | 14/257 (5.4) | OR, 3.11 (1.37 to 7.04)a | .005 |
| Laboratory findings at birth | ||||
| Abnormal white blood cell count | 1/57 (1.8) | 3/208 (1.4) | OR, 1.22 (0.13 to 11.96) | >.99 |
| Abnormal platelet count | 4/57 (7.0) | 7/208 (3.4) | OR, 2.18 (0.62 to 7.72) | .26 |
| Cranial ultrasound | ||||
| Cystic periventricular leukomalacia | 4/67 (6.0) | 12/249 (4.8) | OR, 1.25 (0.39 to 4.02) | .75 |
| Intraventricular adhesions | 1/67 (1.5) | 3/249 (1.2) | OR, 1.24 (0.13 to 12.14) | >.99 |
| Periventricular cysts | 16/67 (23.9) | 38/249 (15.3) | OR, 1.74 (0.90 to 3.37) | .10 |
| Striatal vasculopathy | 28/67 (41.8) | 73/249 (29.3) | OR, 1.73 (0.99 to 3.02) | .05 |
| Calcifications | 4/67 (6.0) | 14/249 (5.6) | OR, 1.07 (0.34 to 3.35) | >.99 |
| Vermis hypoplasia | 0/67 | 1/249 (0.4) | NA | >.99 |
| Hyperechogenic caudal pit | 6/67 (9.0) | 8/249 (3.2) | OR, 2.96 (0.99 to 8.86) | .09 |
| Ventriculomegaly | 9/67 (13.4) | 23/249 (9.2) | OR, 1.53 (0.67 to 3.47) | .31 |
| MRI | ||||
| Cortical atrophy | 1/68 (1.5) | 2/206 (1.0) | OR, 1.52 (0.14 to 17.06) | >.99 |
| Cystic periventricular leukomalacia | 5/68 (7.4) | 9/206 (4.4) | OR, 1.74 (0.56 to 5.38) | .35 |
| Intraventricular adhesions | 3/68 (4.4) | 10/206 (4.9) | OR, 0.91 (0.24 to 3.39) | >.99 |
| Periventricular cysts | 14/68 (20.6) | 19/206 (9.2) | OR, 2.55 (1.20 to 5.42)a | .01 |
| Gyration disorders | 8/68 (11.8) | 8/206 (3.9) | OR, 3.30 (1.19 to 9.17)a | .03 |
| Calcifications | 7/68 (10.3) | 7/206 (3.4) | OR, 3.26 (1.10 to 9.67)a | .049 |
| Vermis hypoplasia | 3/68 (4.4) | 1/206 (0.5) | OR, 9.46 (0.97 to 92.53)a | .048 |
| Hyperintensity white matter | 32/68 (47.1) | 126/206 (61.2) | OR, 0.56 (0.33 to 0.98)a | .04 |
| Ventriculomegaly | 13/68 (19.1) | 20/206 (9.7) | OR, 2.20 (1.03 to 4.70)a | .04 |
| Ophthalmology | ||||
| Abnormal ophthalmological findings | 0/77 | 1/247 (0.4) | NA | >.99 |
Abbreviations: MRI, magnetic resonance imaging; NA, not applicable; OR, odds ratio.
Significant difference at P < .05; the variable was added to the binary logistic regression.
Table 3. Risk Factors for Congenital Hearing Loss in Newborns Without Clinical, Neurological, or Laboratory Abnormalities With and Without Hearing Loss at Birth.
| Risk factor | Patients, No./total No. (%) | Difference between groups with congenital hearing loss and normal hearing, test type, results (95% CI) | P value | |
|---|---|---|---|---|
| With hearing loss and without other symptoms | Without hearing loss and without other symptoms | |||
| Timing of seroconversion | ||||
| First trimester (0-13 wk) | 26/30 (86.7) | 129/362 (35.6) | Cramer V, 0.28 (0.20 to 0.36)a | <.001 |
| Second trimester (14-27 wk) | 3/30 (10.0) | 137/362 (37.8) | ||
| Third trimester (>27 wk) | 1/30 (3.3) | 96/362 (26.5) | ||
| Prematurity | 5/63 (7.9) | 34/474 (7.2) | Odds ratio, 1.11 (0.42 to 2.97) | .80 |
| Birth weight | ||||
| No. | 56 | 468 | ||
| Median (IQR), g | 3317.5 (2877.5-3621.3) | 3350.0 (3060.0-3667.5) | Hedges g, 0.15 (−0.12 to 0.43) | .32 |
| Birth length | ||||
| No. | 46 | 407 | ||
| Median (IQR), cm | 49.0 (47.8-51.0) | 50.0 (49.0-51.0) | Hedges g, 0.30 (−0.01 to 0.60) | .07 |
| Head circumference | ||||
| No. | 35 | 365 | ||
| Median (IQR), cm | 33.0 (33.0-35.0) | 34.0 (33.0-35.0) | Hedges g, 0.38 (0.03 to 0.72)a | .048 |
| Viral load | ||||
| No. | 2 | 113 | ||
| Median, copies/mL | 2622.0 | 513.0 (IQR, 141.0-2447.5) | Hedges g, 0.06 (−1.33 to 1.44) | .86 |
Significant difference at P < .05; variable added to the binary logistic regression.
Risk Factors for Congenital Hearing Loss in the Group With Other Symptoms
To identify risk factors for congenital hearing loss in patients with other symptoms at birth, we compared baseline and clinical characteristics of newborns with and without hearing loss. Table 2 shows the results of the univariate analyses. A total of 13 significant factors were found (timing of seroconversion, birth weight, birth length, head circumference, hepatomegaly, splenomegaly, petechiae, periventricular cysts on MRI, gyration disorders on MRI, calcifications on MRI, vermis hypoplasia on MRI, hyperintensity white matter on MRI, and ventriculomegaly on MRI). Certain pathological findings on clinical examination and MRI were associated with congenital hearing loss, whereas abnormalities on cranial ultrasonography, aberrant laboratory findings, and ophthalmological anomalies were not. Prematurity was not associated with hearing loss in contrast to biometric features. A significantly higher prevalence of congenital hearing loss was found after seroconversion in the first trimester (34 of 122 [27.9%]) compared with the second (6 of 71 [8.5%]) or third trimester (2 of 24 [8.3%]).
Several factors might be interrelated in their associations with congenital hearing loss; therefore, a regression analysis was performed. As there was no statistical difference in congenital hearing loss between a seroconversion in the second trimester and third trimester (second trimester, 6 of 71 newborns [8.5%]; third trimester, 2 of 24 newborns [8.3%]; P = .68), these 2 groups were combined in further analyses. We found 3 independent risk factors for congenital hearing loss. First, if a child presented with petechiae at birth, the risk of cCMV-related hearing loss was higher compared with the absence of petechiae (aOR, 6.7; 95% CI, 1.9-23.9). Second, the risk of congenital hearing loss was higher for periventricular cysts on MRI compared with no cysts on MRI (aOR, 4.6; 95% CI, 1.5-14.1). Third, newborns with a seroconversion in the first trimester had a higher risk of congenital hearing loss compared with seroconversion in the second or third trimester (aOR, 3.1; 95% CI, 1.1-9.3).
Of the newborns with petechiae, 46.2% (12 of 26) had SNHL at birth. This figure was 42.4% (14 of 33) for newborns with periventricular cysts on MRI and 27.9% (34 of 122) for newborns with a seroconversion in the first trimester. The clinical prediction risk model found that an increasing risk of congenital hearing loss was largely associated with the presence of more than 1 independent risk factor (petechiae at birth, periventricular cysts on MRI, and seroconversion in the first trimester). For example, newborns with a total score of 3 had a higher risk of congenital hearing loss (OR, 13.42; 95% CI, 3.80-47.43) (Table 4).
Table 4. Clinical Prediction Risk Model for Congenital Hearing Loss in Group With Other Symptoms.
| Total pointsa | Patients, No. (%) | Odds ratio (95% CI) | |
|---|---|---|---|
| Total (n = 453) | With congenital hearing loss (n = 58) | ||
| 0 | 235 | 8 (3.4) | 0.12 (0.06-0.26) |
| 1 | 188 | 34 (18.1) | 2.22 (1.27-3.89) |
| 2 | 18 | 9 (50.0) | 7.88 (2.99-20.79) |
| 3 | 11 | 7 (63.6) | 13.42 (3.80-47.43) |
| 4 | 1 | 0 | NA |
Abbreviation: NA, not applicable.
Points were assigned based on the relative values for the adjusted odds ratio as follows: 2 points for petechiae at birth, 1 point for periventricular cysts on magnetic resonance imaging, and 1 point for seroconversion in the first trimester. Total points were calculated as the sum of points for each condition present.
Risk Factors for Congenital Hearing Loss in the Group Without Other Symptoms
Because newborns without other symptoms did not have clinical, neurological, or laboratory abnormalities at birth, only 6 factors were assessed as potential risk factors for congenital hearing loss. Two factors were found to be associated with congenital hearing loss: timing of seroconversion (Cramer V, 0.28; 95% CI, 0.20-0.36) and head circumference (Hedges g, 0.38; 95% CI, 0.03-0.72). The rate of hearing loss for newborns with a seroconversion in the first trimester was 16.8% (26 of 155), second trimester was 2.1% (3 of 140), and third trimester was 1.0% (1 of 97). We retained only 1 independent risk factor: the risk of congenital hearing loss was higher after a seroconversion in the first trimester compared with the second or third trimester (OR, 29.8; 95% CI, 3.9-225.5). Of the newborns without other symptoms and with a known seroconversion during the first trimester, 16.8% (26 of 155) had congenital SNHL.
Viral Load and Risk Factors for Hearing Loss Severity
We found similar viral loads in 115 newborns without other symptoms (median [IQR] viral load, 513.0 [141.0-2447.5] copies/mL) and 91 newborns with other symptoms (median [IQR] viral load, 445.0 [32.5-2293.0] copies/mL) regardless of their hearing loss (Table 1). The median (IQR) viral load was lower in 196 newborns without congenital hearing loss (447.0 [39.3-2345.8] copies/mL) compared with 10 newborns with congenital hearing loss (1349.5 [234.3-14 393.0] copies/mL) for a median difference of −397.0 (95% CI, −5058.0 to 174.0) copies/mL. We found no association between baseline, clinical, neurological, or laboratory abnormalities and the severity of hearing loss.
Discussion
This cross-sectional study based on the data from the Flemish CMV registry identified several risk factors for congenital hearing loss on univariate analyses but only 3 independent factors on logistic regression analyses: petechiae at birth, periventricular cysts on MRI, and timing of seroconversion. Petechiae at birth was associated with the highest risk of congenital hearing loss followed by periventricular cysts on MRI. Seroconversion in the first trimester was associated with a higher risk of congenital hearing loss compared with seroconversion during the second or third trimester. The more of these independent risk factors that are present at birth, the higher the risk of congenital hearing loss.
Risk factors for cCMV-related congenital hearing loss were previously assessed, albeit less extensively and on a smaller scale than the current study. Madden et al30 reported better initial hearing in newborns presenting with hepatosplenomegaly. Similar to the findings reported by Madden et al,30 we found that microcephaly or ophthalmological abnormalities were not associated with an increased risk of congenital SNHL. Airlangga and Bashiruddin40 found no association between a low birth weight or head circumference and a higher risk of congenital hearing loss. Madden et al30 and Airlangga and Bashiruddin40 also did not find an association between prematurity and cCMV-related hearing loss at birth. In this study, white blood cell and platelet counts were not helpful in estimating congenital hearing loss.
Several studies found that significantly more newborns with initial hearing loss had intracranial anomalies on cranial ultrasonography, MRI, or computed tomography.27,37,41 In this study, we analyzed the different abnormalities found on imaging in particular. No abnormalities found by neonatal ultrasonography were associated with hearing loss. In contrast, periventricular cysts, gyration disorders, calcifications, vermis hypoplasia, ventriculomegaly, and hyperintensity white matter found by MRI were all associated with congenital hearing loss. These discrepancies might be attributed to the different sensitivities of both imaging modalities.37
Congenital CMV is known to cause widespread clinical symptoms and abnormalities on central imaging. These symptoms may be interrelated, which makes it challenging to investigate risk factors for congenital hearing loss in patients with cCMV.41,42 In contrast to the previously mentioned studies, we had access to a large, multicentric database, allowing us to perform regression analyses and correct for confounding factors and multicollinearity. It is not fully understood whether a cytopathic effect, an autoimmune inflammatory reaction, or a combination of both is associated with cCMV-related brain16,43,44 and inner ear damage.45,46 We hypothesize that petechiae and periventricular cysts are signs of a severe inflammatory reaction. Hearing loss might also be the result of a severe inflammatory response in the inner ear, and the extent of immune response might be related to the level of blood viral load. Further evidence is needed to confirm or refute these hypotheses.
The risk of neurodevelopmental consequences and hearing impairment is higher in cases of maternal seroconversion in the first trimester,14,28,47 which is not surprising as the inner ear is formed in the early fetal period.48 However, controversy remains about the audiological consequences of a seroconversion later in pregnancy. Some authors have argued that sequelae in primary infections are limited to infections acquired in the first trimester of pregnancy.48 In the present study, congenital hearing loss was also diagnosed in patients with a seroconversion in the second or third trimester. These findings reveal that hearing impairment may still be seen from infections acquired later in gestation, which has been confirmed by other studies29,47,49,50 as well.
Several researchers expressed the need to further establish the predictive role of viral load.33,34,51 Results of the present study revealed that viral load is not associated with clinical, neurological, or laboratory findings at birth. In contrast, significantly higher mean or median values of blood viral load in newborns with symptomatic cCMV infection compared with those with asymptomatic infection have been described.31,33,34 In addition, some studies have reported that newborns with congenital hearing loss had an equal34,52 or higher24,51 initial viral load compared with newborns with normal hearing at birth. The contradictory results of these different studies might be explained by the low sample size, different definitions, inclusion criteria, or outcome measurements. We found lower viral loads in newborns with normal hearing compared with newborns with congenital hearing loss. A total of 206 cases were included, which is, to our knowledge, the largest series in literature. Nevertheless, a significant difference was not found; this outcome might be attributable to a lack of power due to the low number of cases with initial hearing loss. To date, the importance of blood viral load as a risk factor for congenital hearing loss remains unclear.
The observed risk factors may be used by clinicians to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. Moreover, findings of this study support the use of MRI in addition to cranial ultrasonography during the neonatal period as previously suggested, especially in the setting of a seroconversion in the first trimester.53 Finding associations between clinical features and hearing loss may provide new insights into the pathogenesis of cCMV-related hearing loss.31,33
Limitations
This study has limitations. Information about whether the infection was primary or nonprimary was not collected in the registry. Due to the lack of universal screening in Belgium, the majority of asymptomatic cCMV infections go unnoticed. Consequently, the proportion of asymptomatic cCMV is underestimated. As a standardized test to detect blood viral load across laboratories is lacking, results were limited to 1 center to prevent analytical bias.33,34,54 The focus was laid on risk factors for hearing loss at birth; risk factors for progressive and late-onset hearing loss remain to be assessed.
Conclusions
This cross-sectional study based on data from the Flemish CMV registry found that newborns infected with cCMV with petechiae at birth, periventricular cysts on MRI, or a seroconversion in the first trimester are at higher risk of congenital hearing loss. These risk factors may be used by clinicians to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. The importance of viral load as a risk factor for congenital hearing loss remains unclear.
eTable 1. Baseline Characteristics and Clinical Outcome After a First (0-13 Weeks), Second (14-27 Weeks), and Third (>27 Weeks) Trimester Infection
eTable 2. Characteristics of Baseline Hearing Loss
eFigure. Distribution of Ears With Congenital Hearing Loss by Severity in Newborns With and Without Clinical, Neurological, or Laboratory Abnormalities
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Baseline Characteristics and Clinical Outcome After a First (0-13 Weeks), Second (14-27 Weeks), and Third (>27 Weeks) Trimester Infection
eTable 2. Characteristics of Baseline Hearing Loss
eFigure. Distribution of Ears With Congenital Hearing Loss by Severity in Newborns With and Without Clinical, Neurological, or Laboratory Abnormalities
Data Sharing Statement
