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6 Congenital Infections andHearing Loss: AnOverview

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80. Nielsen-Saines K, Brasil P, Kerin T, etal. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat Med. 2019;25:1213–7.

81. Mitsikas D, Gabrani C, Giannakou K, Lamnisos D.Intrauterine exposure to Zika virus and hearing loss within the rst few years of life: a systematic literature review. Int J Pediatr Otorhinolaryngol. 2021;147:110801.

82. Barton LL, Mets MB. Congenital lymphocytic choriomeningitis virus infection: decade of rediscovery. Clin Infect Dis. 2001;33:370–4.

83. Pencole L, Sibidue J, Weingartner AS, Mandelbrot L, Vauloup-Fellous C, Picone O.Congenital lymphocytic choriomeningitis virus: a review. Prenat Diagn. 2022;42:1059–69.

84. Anderson JL, Levy PT, Leonard KB, Smyser CD, Tychsen L, Cole FS.Congenital lymphocytic choriomeningitis virus: when to consider the diagnosis. J Child Neurol. 2014;29:837–42.

85. Enninga EAL, Theiler RN.Lymphocytic choriomeningitis virus infection demonstrates higher replicative capacity and decreased antiviral response in the rst-trimester placenta. J Immunol Res. 2019;2019:7375217.

86. Bonthius DJ.Lymphocytic choriomeningitis virus: an underrecognized cause of neurologic disease in the fetus, child, and adult. Semin Pediatr Neurol. 2012;19:89–95.

87. Bale JF.Congenital infections. Neurol Clin. 2002;20:1039–60.

88. Mahant S, Hall M, Schondelmeyer AC, Berry JG, Kimberlin DW, Shah SS.Neonatal herpes simplex virus infection among Medicaid-enrolled children: 2009-2015. Pediatrics. 2019;143:e20183233.

89. Looker KJ, Magaret AS, May MT, etal. First estimates of the global and regional incidence of neonatal herpes infection. Lancet Glob Health. 2017;5:e300–9.

90. Flagg EW, Weinstock H.Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics. 2011;127:e1–8.

91. Westerberg BD, Atashband S, Kozak FK. A systematic review of the incidence of sensorineural hearing loss in neonates exposed to herpes simplex virus (HSV). Int J Pediatr Otorhinolarynghol. 2008;72:931–7.

92. Whitley RJ.Congenital cytomegalovirus and neonatal herpes simplex virus infections: to treat or not to treat? Pediatr Infect Dis J. 2019;38(Suppl 1):S60–3.

93. Kaga K, Kaga M, Tamai F, Shindo M.Auditory agnosia in children after herpes encephalitis. Acta Otolaryngol. 2003;123:232–5.

94. Neumann K, Mathmann P, Chadha S, Euler HA, White KR.Newborn hearing screening benets children, but global disparities persist. J Clin Med. 2022;11:271.

Congenital Cytomegalovirus Infection

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andHearing Loss

MeltemPolat, AyşeEnginArısoy, andGailJ.Demmler-Harrison

7.1 Introduction

Cytomegalovirus (CMV) is the most frequent congenital infection and the leading cause of nongenetic sensorineural hearing loss (SNHL) in children worldwide. Congenital CMV (cCMV) infection (cCMVI) may be asymptomatic or symptomatic at birth. Although the minority of infants with cCMVI have symptoms at birth, these symptomatic infants are at signicant risk for long-term sequelae. Sensorineural hearing loss (HL) is the most common sequela of cCMVI and can occur in asymptomatic and symptomatic cases [1, 2]. The association between cCMVI and HL was rst described by Medearis in 1964 [3] and has been further described in numerous longitudinal studies since that time [4].

This chapter summarizes the current knowledge about the epidemiology, diagnosis, treatment, and prevention of cCMVI and focuses on the association of cCMVI with HL.

M. Polat (*) Division of Pediatric Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, Türkiye e-mail: meltempolat@gazi.edu.tr

A. E. Arısoy Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Kocaeli University, Kocaeli, Türkiye e-mail: arisoyengin@yahoo.com

G. J. Demmler-Harrison Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

Infectious Disease Service, Texas Children’s Hospital, Houston, TX, USA e-mail: gdemmler@bcm.edu

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. E. Arısoy et al. (eds.), Hearing Loss in Congenital, Neonatal and Childhood Infections, Comprehensive ENT, https://doi.org/10.1007/978-3-031-38495-0_7

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M. Polat et al.

7.2 Etiology

Human CMV, also known as human herpesvirus 5, is a member of the Herpesviridae family and the beta-herpesvirus subfamily. It is the largest member of Herpesviridae and shares many properties with other herpes viruses, including genome structure and the ability to cause latent and persistent infections. The complete virion consists of a linear, double-stranded deoxyribonucleic acid (DNA) genome within an icosahedral capsid of 162 capsomeres, which yields a nal diameter of 200–300nm [1, 2].

7.3 Epidemiology

Cytomegalovirus is the agent of the most frequent congenital viral infection, occurring in approximately 1–2% of live births worldwide [1, 5]. The birth prevalence of cCMVI is proportional to the seroprevalence of CMV among women of reproductive age in the population, which varies widely according to geographic regions and sociodemographic factors, such as age, race, and ethnicity [1]. Seroprevalence is higher among non-whites and individuals in low- and middle-income countries and groups with lower socioeconomic status in high-income countries [2, 5]. A recent review estimated a global CMV seroprevalence of 86% in women of reproductive age, with the highest (89–92%) seroprevalences in low- and middle-income countries in the Eastern Mediterranean, Western Pacic, African, and Southeast Asian regions and the lowest (70–79%) in the European region and the Americas [6]. However, even within the same geographic region, variable rates of CMV seroprevalence could be seen in women of different ethnic, racial, and socioeconomic backgrounds, reecting the distinct epidemiological patterns of cCMVI [7].

Transmission of CMV can occur through contact with infected bodily uids, such as saliva, urine, blood, or genital secretions. Children aged 1–3years who excrete the virus in saliva and urine for extended periods are the most important CMV infection (CMVI) sources for young women [1, 2]. Maternal CMV acquisition usually occurs through frequent and prolonged contact with young children, especially children in the home and attending daycare or group care centers, as well as breast milk feedings and close contact situations.

Intrauterine transmission of CMV from mother to fetus can occur by primary (new) or nonprimary maternal infection during pregnancy. Nonprimary maternal infection, also called recurrent or secondary infection, may result from re-infection with a new strain or reactivation of latent CMV [1]. The rates of cCMVI due to nonprimary maternal infection are hard to determine and possibly underestimated due to difculties in its diagnosis. It is highly difcult to identify by serologic and virologic markers which pregnant woman may experience a re-infection with a new strain or reactivation of the latent virus and to determine the timing of transmission due to nonprimary infection during pregnancy [7]. However, it contributes substantially to the burden of cCMVI because most women of reproductive age worldwide are CMV-seropositive [8].

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Although it is estimated that 75% of cCMVIs in the United States of America (USA) result from nonprimary maternal infection [9], reliable estimates of prevalence from low- and middle-income countries are not available [7]. A previous meta-analysis estimated that the majority of cCMVIs in most populations result from nonprimary maternal infections [10]. Earlier studies suggested that symptomatic CMV disease and permanent sequelae are much more likely in infants infected due to a primary maternal infection than those infected due to nonprimary maternal infection [11, 12]. However, increasing evidence indicates that neither symptomatic CMVI nor the development of long-term sequelae, including SNHL, is correlated to the maternal infection type, and symptomatic disease and sequelae can be observed following nonprimary maternal infections [8]. The likelihood of maternal–fetal transmission is much greater during primary versus nonprimary maternal CMVI (32 versus 1.4%) [5].

At the time of primary maternal infection, gestational age is considered a signicant factor affecting the intrauterine CMV transmission rate and the development of symptomatic disease and long-term sequelae [1, 2]. The vertical transmission rate appears to increase with advancing gestational age. A meta-analysis pooled data from ten studies (2942 fetuses) reported that vertical transmission rates increased, from 21% for infection at the periconceptional period to 36% in the rst, 40% in the second, and 66% in the third trimesters [13]. Although symptomatic cCMVI may result from maternal infection at any time during pregnancy, severe sequelae and symptomatic diseases are more common when infection occurs earlier in pregnancy, particularly in the rst trimester [1, 14].

7.4 In Utero Findings

The fetus with in-utero CMVI might show ultrasonographic abnormalities, including fetal growth restriction, microcephaly, ventriculomegaly, periventricular calcications, neuronal migration abnormalities (polymicrogyria, pachygyria, and lissencephaly), cerebellar hypoplasia, large cisterna magna, enlarged liver or spleen, hepatic calcications, echogenic bowel patterns, pleural effusion, and ascites. Although not pathognomonic or diagnostic, these ndings could suggest fetal CMVI in the presence of maternal infection [1, 15].

7.5 Clinical Characteristics

The clinical presentation of cCMVI is highly variable and ranges from asymptomatic infection to severe multi-organ involvement. Infants with cCMVI are generally classied as “asymptomatic” or “symptomatic” based on the presence of clinical symptoms and signs at birth [1, 2].

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M. Polat et al.

7.5.1 Asymptomatic Congenital Cytomegalovirus Infection

Most newborns (~90%) with cCMVI have no apparent symptoms at birth and are thus termed asymptomatic. However, some of these infants may have detectable SHNL at birth and are classied as “asymptomatic with congenital SNHL” or “asymptomatic with isolated HL,” or they may develop delayed-onset SNHL and are classied as “asymptomatic with normal hearing at birth, with later-onset SNHL” [1]. Approximately 7–11% of asymptomatic infants with cCMVI experience SNHL up to 5years and 25% by age 18 [16, 17]. Lanzieri etal. [16] demonstrated that 2% of children with asymptomatic cCMVI developed SNHL severe enough to require cochlear implantation. Ocular abnormalities, such as small retinal lesions, were also reported in asymptomatic newborns; however, the visual impairment risk appears negligible [18, 19].

7.5.2 Symptomatic Congenital Cytomegalovirus Infection

Approximately 10% of newborns with cCMVI are symptomatic at birth [5, 20]. The clinical spectrum of symptomatic cCMV disease ranges from mild to moderatesevere manifestations [21]. At present, there is no standard denition for symptomatic cCMV disease. The informal International Congenital Cytomegalovirus Recommendations Group has categorized the symptomatic cCMV disease as “mildly symptomatic” or “moderately to severely symptomatic” [21].

The mildly symptomatic disease has been dened as the presence of isolated (one or two at most), mild, and transient manifestations of cCMVI (e.g., mild hepatomegaly or thrombocytopenia). In contrast, moderately to severely symptomatic disease includes central nervous system (CNS) involvement (e.g., microcephaly, neuroimaging ndings consistent with cCMV disease, SNHL, and chorioretinitis) or multiple manifestations of cCMVI, such as petechiae, thrombocytopenia, hepatosplenomegaly, and hepatitis [21]. The characteristics of symptomatic cCMV disease are summarized in Table7.1 [1, 2, 22, 23]. Figure7.1 shows the neuroimaging ndings associated with symptomatic cCMV disease.

Since cCMVI has a broad spectrum of clinical manifestations and can present with subtle or atypical signs and symptoms, a high suspicion index is necessary to identify cases. Some infants present with only CNS manifestations, such as microcephaly, seizures, and abnormal neuroimaging ndings, including polymicrogyria or cortical dysplasia, and are classied as “primary neurophenotype.” These infants may appear completely healthy at birth or have mild microcephaly without the classic somatic manifestations of cCMVI [1].

Approximately 10% of infants with symptomatic cCMVI have severe diseases, and among these severely affected infants, mortality rates might be as high as 10–30%. However, the overall mortality rate due to cCMVI is generally low (0.3–1.0%) [20].

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Table 7.1 Clinical, laboratory, and neuroimaging ndings in children with symptomatic congeni- tal cytomegalovirus infection

Clinical ndings

Prematurity Small for gestational age (birth weight <10 percentile) Microcephaly Poor suck Hypotonia, lethargy

Seizures Jaundice at birth

Hepatosplenomegaly Sensorineural hearing loss Strabismus, chorioretinitis, cortical visual impairment, optic atrophy Petechiae Anemia

Laboratory ndings

Anemia, hemolytic anemia Thrombocytopenia Neutropenia Lymphopenia Lymphocytosis Leukemoid reaction Elevated liver transaminases Elevated direct and indirect serum bilirubin Increased cerebrospinal uid protein

Neuroimaging ndings

Intracranial calcications (typically periventricular) Periventricular leukomalacia Periventricular cystic abnormalities Ventriculomegaly Cerebral atrophy White matter disease Corpus callosum dysgenesis Cerebellar hypoplasia Migrational abnormalities (polymicrogyria, pachygyria, lissencephaly) Lenticulostriate vasculopathy Fetal brain sequence disruption or arrest syndrome

Adapted and modied from Ref. [1, 2, 22, 23]

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M. Polat et al.

Fig. 7.1 Magnetic resonance images of the brain of a 1-month-old infant with symptomatic congenital cytomegalovirus infection. Sagittal T2-weighted images demonstrate scattered periventricular punctate foci of parenchymal calcications (black arrows), neuronal migration abnormality leading to diffuse polymicrogyria in the bilateral frontoparietal region (white arrows), periventricular cysts (arrowheads), ventriculomegaly (curved arrows), and posterior fossa arachnoid cyst in the posterior fossa (star). (Courtesy Meltem Polat, MD)

7.6 Late Complications andSequelae

Long-term sequelae can develop in asymptomatic and symptomatic infants with cCMVI, with the more frequent and severe sequelae occurring in symptomatic infants [20]. Approximately 40–60% of symptomatic infants had CMVI-related disabilities, with SNHL being the most common. Other reported late sequelae in children with symptomatic CMVI include motor and cognitive decits, cerebral palsy, seizures, intellectual disability, chorioretinitis, strabismus, optic atrophy, cortical visual impairment, and dental abnormalities [20, 24].

Long-term sequelae in infants with asymptomatic cCMVI are less apparent because most have not been diagnosed [17]. It has been estimated that 13.5% of the asymptomatic infants with cCMVI will develop long-term sequelae, most commonly manifest as SNHL [20]. Although some earlier studies suggested that neurodevelopmental impairments might occur in children with asymptomatic cCMVI, recent studies concluded that these children do not have an increased risk of neurodevelopmental sequelae compared with healthy controls [17]. Additionally, Lopez etal. [25] found that infants with asymptomatic cCMVI who had normal hearing by age 2years had no difference in intelligence, language development, or academic achievement during childhood compared with uninfected children. Conversely, intelligence and receptive vocabulary scores were lower than normal controls in children with asymptomatic cCMVI who developed SNHL by age 2years [25]. Recent studies demonstrated that vestibular disorders can also occur in children with cCMVI, with or without associated SNHL [26].

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7.7 Congenital Cytomegalovirus Infection andHearing Loss

Congenital CMVI is the leading nonhereditary cause of SNHL in children worldwide, accounting for approximately 21% and 25% of cases of HL at birth and 4years of age, respectively [4]. Congenital CMVI-related HL can occur following primary and nonprimary maternal infections [4, 8]. Sensorineural HL is the most common sequela of cCMVI and occurs in up to 50% of symptomatic and 15% of asymptomatic cases [4]. However, since there are many asymptomatic infants, most patients with SNHL due to cCMVI occur in this group [27]. Therefore, dening the actual contribution of cCMVI to permanent HL in childhood has been challenging.

The HL associated with asymptomatic or symptomatic cCMVI may be present at birth or later in life (late-onset). Late-onset HL occurs in up to 50% of children with cCMVI [4], mostly in the rst 5–6years [27–29]. There are considerable interstudy variabilities regarding the age at which children with cCMVI develop lateonset HL.Dahle etal. [30] reported the median age of late-onset HL to be 33months in symptomatic and 44 months in asymptomatic children with cCMVI. Another study by Goderis etal. [31] reported the mean age of late-onset HL to be 18months and found that 75% of the HL presented before 24months of age, and none occurred after 61 months. In children with asymptomatic cCMVI, the risk of late-onset SNHL was reported to return to a level comparable to uninfected controls by age 5years [16]. However, recent reviews have shown that late-onset HL can appear as late as the mid-teens [28, 32]. Riga etal. [32] found that late-onset HL was reported until 15.2 years in asymptomatic and 16.4 years in symptomatic children with cCMVI.

Recent systematic reviews have demonstrated that the nature of cCMVI-related HL (e.g., onset, severity, and course) is quite variable and unpredictable, as presented in Table7.2 [17, 27–29, 32]. Regardless of symptomatic and asymptomatic statuses at birth, cCMVI-related SNHL may be unilateral or bilateral and has various patterns, including stable, uctuating, progressive, and improving [27–29, 32]. These multiple patterns and changes can be seen in children with congenital, early onset, or late-onset SNHL and children treated or untreated with antiviral therapy [29]. The severity of HL can vary widely and range from unilateral high-frequency to bilateral severe to profound loss [4, 27]. Compared with asymptomatic children, symptomatic children with cCMVI tend to have more severe and often bilateral HL and are less likely to improve [27, 29, 32].

Progression of HL occurs at any time during childhood, even after years, in up to 50% of symptomatic and asymptomatic patients with cCMVI [32, 33]. A recent review found that SNHL has been reported to progress until 15.5years in asymptomatic and 17.4years in symptomatic children [32]. The reported age at which progression is rst documented has varied from study to study. Fowler etal. [34] reported that the median age for asymptomatic children’s rst progression was 18months. In another study by Dahle etal. [30], the median age for the rst progression was 26months in symptomatic and 51months in asymptomatic children with cCMVI.Fluctuating HL is common and may occur in one or both ears [4]. Improvement of HL may also be seen among children with cCMVI and occurs

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Vos etal. (2021) [29]

Number of studies: 65

Riga etal. (2018) [32]

Number of studies: 11

M. Polat et al.

Table 7.2 Summary of literature reviews on the nature of congenital cytomegalovirus infection-related hearing loss according to symptomatic and asymptom-

atic status

Fletcher etal. (2018) [28]

Number of studies: 36

Bartlett etal. (2017) [17]

Number of studies: 29

Goderis etal. (2014) [27]

Number of studies: 37

Symptomatic Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatic

32.8 9.9 34–41 7–11 40.7–100 7–27 44.2 8.9 33.7–71.4 0–14.9

cCMVI

Proportion of HL

(% or range)

Characteristics of

HL (% or range)

Late-onset HL 18 9 – – 9–29 11–18 – – 0–27.1 0–24.2

Unilateral HL 28.8 56.9 – – – – 32.2 55.9 – –

76.8 77.7 – – – – – – – –

Bilateral HL 71.2 43.1 – – – – 67.8 44.1 – –

Severe to profound

65.1 42.6 – – – – – – – –

Bilateral severe to

profound HL

Progressive HL 17.7 20.3 – 1.6–54 27–54 50–62.5 – – – –

Fluctuating HL 21.5 24 – 16–54 – – – – – –

cCMVI congenital cytomegalovirus infection, HL hearing loss

Ref. [17, 27–29, 32]

7 Congenital Cytomegalovirus Infection andHearing Loss

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predominantly in asymptomatic cases compared with symptomatic patients (40 versus 20%) [32].

It has been found that the presence of petechiae, intrauterine growth retardation (IUGR), microcephaly, and abnormal neuroimaging ndings are predictive of the risk of SNHL in children with symptomatic cCMVI.Among asymptomatic cases of cCMVI, low birth weight and prematurity were associated with SNHL [1, 33]. An association between CMV viral load and HL has also been described [33]. However, despite these ndings, there are no reliable virological and clinical markers to predict which children with cCMVI will have SNHL; it is also difcult to predict which children will develop late-onset or progressive SNHL [4, 33]. Studies have also suggested that inammatory genes or genetic mutations might contribute to the development of cCMVI-related SNHL [1].

7.8 Differential Diagnosis

The differential diagnosis of cCMVI includes other intrauterine infections (e.g., toxoplasmosis, rubella, syphilis, herpes simplex virus, lymphocytic choriomeningitis virus [LCMV], and Zika virus infections). The differential diagnosis should also include bacterial sepsis or noninfectious disorders, such as genetic and metabolic disorders, and in-utero exposure to toxins or drugs [1].

7.9 Diagnostic Evaluation andLaboratory Diagnosis

For a timely diagnosis of cCMVI, a high clinical suspicion index is essential. In addition to the clinical, laboratory, and neuroimaging ndings (Table 7.1) not explained by other causes and suggestive of cCMVI, laboratory testing for CMV should be considered in newborns born to mothers with suspected or known CMVI during pregnancy.

Laboratory diagnosis of cCMVI requires detecting the virus within the rst 3weeks of life since testing after this period cannot conclusively distinguish congenital from postnatal infection [1]. Viral culture is the traditional diagnostic test for cCMVI; however, it has been replaced by polymerase chain reaction (PCR) based tests in most clinical laboratories due to the requirement of tissue culture facilities and longer turnaround time. Saliva and urine are the preferred specimens for testing as most newborns with cCMVI have high viral loads in these uids. Although saliva is the easiest to obtain, false-positive results may rarely occur due to breastfeeding. Therefore, it is recommended that samples be taken at least 60min after breastfeeding to avoid contamination of the saliva with CMV from breast milk. A positive result should be conrmed with a repeat PCR test (preferably urine) [1, 21, 35]. For infants who have not undergone neonatal PCR testing within the rst 3weeks, CMV PCR testing on the archived dried blood spot (DBS) specimens obtained for routine newborn screening panels allows for diagnosing cCMVI retrospectively. However, a negative DBS PCR result cannot denitively exclude cCMVI because of this

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