Congenital cytomegalovirus (cCMV) infection: Clinical features and diagnosis

INTRODUCTION — 

Congenital cytomegalovirus (cCMV) infection is common worldwide. It is the leading cause of nonheritable sensorineural hearing loss (SNHL) and can cause other long-term neurodevelopmental disabilities, including cerebral palsy, intellectual disability, vision impairment, and seizures.

The clinical features and diagnosis of cCMV will be reviewed here. Related topics include:

●(See "Congenital cytomegalovirus (cCMV) infection: Management and outcome".)

●(See "Overview of TORCH infections".)

●(See "Cytomegalovirus infection in pregnancy".)

●(See "Overview of cytomegalovirus (CMV) infections in children".)

TERMINOLOGY — 

Infants with cCMV are classified according to the presence or absence of apparent symptoms at the time of birth.

●We use the term "symptomatic" to refer to infants with one or more clinical sign attributable to cCMV at birth. This category is referred to as "cCMV disease" according to the United States Centers for Disease Control and Prevention (CDC) 2024 case definitions [1]. (See 'Symptomatic neonate' below.)

●We use the term "primary neurophenotype" to refer to patients with only central nervous system manifestations. This is a newly described category of symptomatic infants, and the use of this term in the published literature is inconsistent. (See 'Primary neurophenotype' below and 'Neuroimaging' below.)

●We use the term "asymptomatic" to refer to infants with laboratory evidence of cCMV infection with no apparent clinical signs of infection at birth, although some of these infants may develop hearing loss or subtle symptoms later in life. This category is referred to as "cCMV infection" according to the CDC 2024 case definitions [1]. (See 'Asymptomatic infection' below.)

●The term "cCMV with isolated hearing loss" refers to infants with isolated hearing loss at birth but no other signs of infection. In studies of cCMV after the advent of universal newborn hearing screening, categorization of these infants as "symptomatic" or "asymptomatic" is inconsistent. Historically, they were often classified as "asymptomatic" because the hearing loss may not have been detected at birth. However, with universal newborn hearing screening, many such infants come to medical attention in the newborn period. We consider these infants to represent a distinct category because they are not truly asymptomatic, but their disease is generally milder than that of symptomatic infants.

VIROLOGY — 

CMV is a member of the herpesvirus family, along with Epstein-Barr virus, herpes simplex viruses-1 and -2, varicella-zoster virus, and human herpesviruses (HHV)-6, -7, and -8. These viruses share structural properties, including a genome of double-stranded linear deoxyribonucleic acid (DNA), a virus capsid of icosahedral symmetry, and a viral envelope [2].

Like other herpesviruses, CMV has the biologic properties of latency and reactivation. With latent CMV infection, a low level of virus replication is detectable and the viral genome may be present in the peripheral blood mononuclear cells and bone marrow. Recurrent infections with CMV occur through reactivation of the host's endogenous strain of CMV or reinfection with a new exogenous strain. CMV strains may compartmentalize such that the strain in the urine, for example, may be different from that in the blood, eye, or central nervous system [2].

CMV replicates slowly, often taking as long as 24 hours to produce progeny in infected cells and several days to weeks to produce a visible cytopathic effect in laboratory cell lines. Clinical samples with high titer of virus, such as urine or saliva samples from congenitally infected newborns, have multiple foci of cytopathic effect visible within a few days of incubation, whereas clinical samples with low titer of virus may require one to three weeks of incubation to show classic focal cytopathic effect (picture 1).

EPIDEMIOLOGY — 

cCMV infection occurs worldwide, with a prevalence of 0.6 percent in developed countries [3-5]. Approximately 40,000 infants are born with cCMV annually in the United States [2].

The rate of cCMV infection, but not necessarily clinically apparent disease, is proportional to the seroprevalence of CMV in women of childbearing years. In areas of high CMV seroprevalence (80 to 100 percent), cCMV infection rates range from 1 to 5 percent, whereas in areas of relatively low CMV seroprevalence (40 to 70 percent), cCMV infection rates range from 0.4 to 2 percent [2,3,6-9].

Maternal CMV infection during pregnancy most often results from close contact with young children, particularly children attending daycare centers [10,11]. The risk of vertical transmission to the fetus is far higher with primary maternal infection than with recurrent infection (32 versus 1.4 percent) [3]. Other factors that are associated with transmission of CMV infection during pregnancy include maternal age and parity (increased risk in younger primigravid individuals) [3]. (See "Cytomegalovirus infection in pregnancy", section on 'Maternal infection'.)

Infants infected as a result of a primary maternal infection are more likely to have symptoms at birth and suffer long-term sequelae than those infected as a result of maternal recurrent CMV infection. The risk of hearing loss, however, appears to be similar in both groups. [4,12,13].

Sequelae appear to be more severe when infection is acquired earlier in pregnancy, particularly in the first trimester [14]. However, symptomatic cCMV may result from maternal infection at any time during pregnancy.

CLINICAL MANIFESTATIONS

In utero — The fetus may be silently infected or manifest CMV disease in utero. The diagnosis and management of congenital infection often begins while the fetus is still in utero. Findings on prenatal ultrasound that may suggest CMV disease in the fetus include periventricular calcifications (image 1), ventriculomegaly (image 2), migrational abnormalities of the brain (polymicrogyria, pachygyria, and lissencephaly), microcephaly, hyperechogenic fetal bowel (image 3), fetal growth restriction, ascites and/or pleural effusion (image 4A-B), and hepatosplenomegaly. These and other findings are reviewed in a separate topic review. (See "Cytomegalovirus infection in pregnancy", section on 'Ultrasound markers suggestive of congenital CMV infection'.)

Symptomatic neonate — Approximately 10 percent of neonates with cCMV have signs of symptomatic infection at birth. Clinical findings in the symptomatic neonate can be similar to those in other congenital infections (table 1).

Clinical findings

Common findings — Clinical findings in the symptomatic neonate (picture 2) are similar to those in other congenital infections [8,9,15-18]:

●Petechiae (50 to 75 percent)

●Jaundice at birth (40 to 70 percent)

●Hepatosplenomegaly (40 to 60 percent)

●Small size for gestational age (SGA; 40 to 50 percent)

●Microcephaly (35 to 50 percent)

●Sensorineural hearing loss (SNHL; present at birth in approximately 35 percent, delayed SNHL can also occur)

●Lethargy and/or hypotonia (approximately 30 percent)

●Poor suck (approximately 20 percent)

●Chorioretinitis (10 to 15 percent)

●Seizures (5 to 10 percent)

●Hemolytic anemia (5 to 10 percent)

●Pneumonia (5 to 10 percent)

SNHL is a common sequela of cCMV and is detected in one-third to one-half of infants with symptomatic disease [2,4,17,19,20]. The hearing loss associated with symptomatic cCMV may be detectable at birth, but, in 18 to 30 percent of cases, it has delayed onset. In a systematic review, hearing loss was bilateral in 71 percent of children with symptomatic cCMV (compared with 43 percent of children with asymptomatic cCMV) [4]. The hearing loss associated with symptomatic cCMV is often progressive (18 to 63 percent of cases) [16,17,19,21,22] and eventually becomes severe to profound in the affected ear(s) of 78 percent of affected children [4].

Chorioretinitis is the most common ocular abnormality in symptomatic infants and correlates with poor long-term neurodevelopmental outcome. Other findings on eye examination may include retinal scars, optic atrophy, central vision loss, or strabismus [23,24]. Cataracts and microphthalmos are not typical in infants with cCMV and strongly suggest a disease other than CMV [25].

Cardiac involvement (eg, myocarditis, cardiomyopathy, ventricular trabeculations) and gastrointestinal involvement (eg, ascites, enterocolitis) are less common findings in symptomatic neonates.

Endocrinopathies (eg, Graves' disease, diabetes insipidus), and kidney involvement (eg, nephrotic syndrome), have been reported in newborns with symptomatic cCMV, but it is unclear whether these conditions are caused by CMV [26-28].

Life-threatening disease — Approximately 8 to 10 percent of newborns with symptomatic cCMV have severe, life-threatening disease. Life-threatening manifestations may include a sepsis-like illness, myocarditis, viral-induced hemophagocytic lymphohistiocytosis, and/or other severe end-organ involvement. Premature infants and infants with primary immune disorders of T cells or natural killer cells are at greatest risk for mortality from cCMV. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical features' and "CD3/T cell receptor complex disorders causing immunodeficiency" and "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Clinical features of NK disorders'.)

Many infants with fulminant disease at presentation die within days or weeks despite antiviral treatment and neonatal intensive care supportive measures. Mortality among such infants can be as high as 30 percent, whereas the overall mortality rate among infants with cCMV is approximately 4 to 8 percent within the first year of life [8,25,29]. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Outcome'.)

For infants with fulminant disease who do not survive, the most common causes of death are viral-associated hemophagocytic syndrome or severe end-organ disease of the liver, lungs, bone marrow, or central nervous system [8,9,30]. In survivors, jaundice and hepatosplenomegaly may subside, but neurologic sequelae (eg, microcephaly, intellectual disability, cerebral palsy, and hearing disorders) persist. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Long-term follow-up'.)

Preterm infants — Preterm infants born at <37 weeks gestation account for approximately 25 to 35 percent of infants with symptomatic cCMV [18,19]. Preterm neonates <32 weeks gestation with symptomatic cCMV are more likely to have pneumonitis, signs of viral sepsis, thrombocytopenia, and coinfections and less likely to have microcephaly or intracranial calcifications compared with term neonates [2,9,15,31].

Laboratory findings — Typical laboratory abnormalities associated with symptomatic cCMV include [2,8,9,16-19]:

●Elevated liver transaminases (50 to 83 percent)

●Thrombocytopenia (48 to 77 percent)

●Elevated direct and indirect serum bilirubin (36 to 69 percent)

Other less common findings include hemolytic anemia, neutropenia, lymphopenia, lymphocytosis, thrombocytosis, or leukemoid reaction. In newborns who undergo lumbar puncture, cerebrospinal fluid protein may be elevated (46 percent in one case series) [18].

Neuroimaging — Imaging of the brain with ultrasonography, unenhanced computed tomography (CT) (image 5A-B), or magnetic resonance imaging (MRI) (image 6) demonstrates abnormalities in 70 percent of infants with symptomatic cCMV [32-36]. Findings on neuroimaging include:

●Intracranial calcifications, usually periventricular (34 to 70 percent)

●Lenticulostriate vasculopathy (27 to 68 percent)

●White matter disease (22 to 57 percent)

●Ventriculomegaly (10 to 53 percent)

●Migrational abnormalities, including focal polymicrogyria, pachygyria, and lissencephaly (10 to 38 percent)

●Periventricular leukomalacia and cystic abnormalities, especially germinolytic cysts or anterior temporal lobe cysts (11 percent)

Additional findings that have been reported include ventricular septations and adhesions, cerebral atrophy, corpus callosum dysgenesis, and cerebellar hypoplasia [32,35,36].

Abnormalities on cranial imaging, particularly microcephaly, intracranial calcifications, and migrational abnormalities, correlate with poor long-term neurodevelopmental outcome [32,33,37]. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Outcome'.)

Primary neurophenotype — Some infants present with primarily neurologic findings (what we refer to as the "primary neurophenotype"). These infants lack the typical somatic manifestations, such as jaundice, petechiae, or hepatosplenomegaly. They may appear completely healthy at birth or may have mild microcephaly. They usually are not diagnosed with cCMV at birth unless they are cared for at a center where all newborns are screened for CMV. (See 'Newborn screening for congenital cytomegalovirus' below.)

In the absence of newborn screening, a high index of suspicion is necessary to identify cCMV as the etiology of the neurologic abnormalities in these infants. As they grow, infants with cCMV who have a primary neurophenotype usually develop more significant microcephaly and neurologic manifestations (eg, global developmental delay, abnormal tone, hemiparesis, seizures). A presentation similar to a genetic leukodystrophy has also been described [38]. If neuroimaging is performed, it typically shows polymicrogyria or other cortical dysplasia. (See 'Neuroimaging' above.)

Asymptomatic infection — Approximately 90 percent of newborns who are congenitally infected have no signs of CMV infection at birth. Subtle differences, such as lower birth weight and slightly earlier gestational age, have been observed in newborns with asymptomatic cCMV [12].

Ten to 15 percent of apparently asymptomatic newborns experience SNHL [4,13,39]. (See 'Isolated hearing loss' below.)

Ocular abnormalities, including retinal lesions and strabismus, occur in 1 to 2 percent of infants with apparently asymptomatic cCMV, but these are rarely sight-threatening [23,24,40].

Abnormal brain imaging findings of periventricular leukomalacia, ventriculomegaly, and punctate calcifications have been observed in 5 to 20 percent of otherwise asymptomatic congenitally infected newborns (image 7).

Isolated hearing loss — Approximately 10 to 15 percent of apparently asymptomatic newborns with cCMV develop SNHL in infancy and early childhood; by age 18 years, up to 25 percent develop SNHL [4,13,20,39,41]. Some affected newborns have congenital hearing loss and may fail newborn hearing screening in one or both ears. In a systematic review of 37 observational studies, children with asymptomatic cCMV were less likely to have delayed-onset SNHL compared with symptomatic patients (9 versus 18 percent) and less frequently had bilateral severe to profound hearing loss (43 versus 65 percent) [4]. The two groups had similar rates of progressive hearing loss (approximately 20 percent) and fluctuating hearing loss (approximately 20 to 25 percent). In a study of 92 infants with asymptomatic cCMV, 20 children (22 percent) developed SNHL over a median follow-up of 17 years, including nine with congenital/early-onset SNHL and 11 with delayed-onset (at a median age of five years) [42]. Frequency-specific hearing thresholds were worse in ears with congenital/early-onset compared with delayed-onset SNHL. The severity of SNHL worsened over time in both groups. Approximately 2 percent of children with otherwise asymptomatic cCMV eventually develop SNHL severe enough to qualify for cochlear implantation [41]. (See "Hearing loss in children: Treatment", section on 'Cochlear implants'.)

Universal newborn hearing screening programs may identify some of these otherwise asymptomatic infants. In a study of 572 newborns who failed newborn hearing screening, 6 percent were found to have cCMV; 75 percent of infants with cCMV were identified solely on the basis of the abnormal newborn hearing screen [43].

Studies in older infants and children suggest that CMV-related hearing loss accounts for approximately 10 to 20 percent of all SNHL in children [4]. It is the leading cause of nonheritable SNHL in children. (See "Hearing loss in children: Etiology", section on 'Infection'.)

Because cCMV commonly presents as isolated congenital hearing loss, many birthing hospitals in the United States, Canada, and Europe have adopted targeted newborn screening protocols wherein testing for CMV is routinely performed in all newborns who do not pass the newborn hearing screen, as discussed below. (See 'Targeted newborn screening' below.)

Late complications — Approximately 70 to 80 percent of infants who are symptomatic at birth develop late complications which may include [2,25,44]:

●SNHL

●Intellectual disability

●Microcephaly

●Strabismus

●Dental disease

●Seizures

●Cortical visual impairment

●Chorioretinitis

●Cerebral palsy

●Autism spectrum disorder

Long-term outcomes and follow-up for children with cCMV are discussed in greater detail separately. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Outcome' and "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Long-term follow-up'.)

DIAGNOSTIC APPROACH — 

A high index of suspicion is important for timely diagnosis. The manifestations of cCMV are variable and nonspecific, and infants may present with most, some, or just one clinical sign or symptom.

Clinical suspicion — cCMV should be suspected in the following clinical scenarios [45]:

●Newborns with signs and symptoms consistent with cCMV – Findings that may warrant testing for CMV, especially if not explained by other causes, include (see 'Symptomatic neonate' above):

•Microcephaly

•Small size for gestational age (SGA)

•Unexplained thrombocytopenia

•Hepatosplenomegaly

•Clinically significant jaundice at birth – Jaundice that fits other patterns (eg, ABO incompatibility) does not necessarily warrant testing for CMV. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Causes of significant unconjugated neonatal hyperbilirubinemia'.)

The yield of CMV testing is greatest when there are multiple suggestive clinical findings. In most studies, the diagnostic yield of CMV testing in the setting of an isolated finding (eg, SGA) was relatively low [45-49]. The author of this topic review still favors testing for CMV in the setting of isolated SGA; however, other experts do not routinely perform CMV testing in this setting. (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns", section on 'Further evaluation' and "Overview of TORCH infections", section on 'Specific evaluation'.)

●Newborns with abnormal neuroimaging consistent with CMV, if the findings are not explained by other causes. Suggestive neuroimaging findings include periventricular calcifications, lenticulostriate vasculopathy, white matter disease, ventriculomegaly, migrational abnormalities (eg, polymicrogyria), germinolytic cysts, anterior temporal lobe cysts, or periventricular leukomalacia. (See 'Neuroimaging' above.)

●Newborns who have documented sensorineural hearing loss (SNHL), regardless of whether they have other symptoms of cCMV [45].

For infants who do not pass the newborn hearing screen but have not yet had a formal audiologic evaluation, the optimal approach to testing for CMV is uncertain, and practice varies. In our practice, newborns who do not pass the initial hearing screen in one or both ears have a repeat screen performed before discharge from the nursery. Newborns who fail the repeat screen are referred for audiologic assessment and tested for CMV before discharge or at least within the first three weeks of life. Other centers do not routinely screen for CMV in this setting. This issue is discussed in greater detail below. (See 'Targeted newborn screening' below.)

●Newborns born to a parent with known or suspected CMV infection during pregnancy, including birthing parents with:

•Seroconversion during pregnancy

•Presumptive primary CMV infection with positive CMV immunoglobulin G (IgG) and CMV immunoglobulin M (IgM) antibody

•Mononucleosis-like illness during pregnancy

•Abnormal fetal imaging suggestive of in utero CMV infection (see 'In utero' above)

●Newborns born to birthing parents living with HIV – Neonates born to birthing parents with human immunodeficiency virus (HIV) are more likely to have cCMV infection, especially if the neonate is infected with HIV. Since cCMV is best diagnosed within the first three weeks after birth, when the HIV status of the neonate is not yet known, we test all HIV-exposed infants for cCMV. (See "Pediatric HIV infection: Management of infants born to mothers with HIV in resource-abundant settings", section on 'Congenital CMV testing'.)

●Immune-compromised newborns, particularly infants with an abnormal T cell receptor excision circles (TRECs) result on newborn screening, which is indicative of severe combined immunodeficiency disorder (SCID), because cCMV infection can have devastating consequences in these severely immune-compromised hosts. (See "Newborn screening for inborn errors of immunity" and "Severe combined immunodeficiency (SCID): An overview".)

Approach to testing — Laboratory diagnosis of cCMV is accomplished by molecular detection of CMV from urine or saliva samples collected within the first three weeks after birth.

We prefer urine samples over saliva samples for CMV testing. Saliva samples may be used if no urine is available. Although saliva is easier to collect, false-positives are more common with saliva samples compared with urine [50]. False-negatives may occur at a higher rate because saliva samples are more susceptible to sampling errors (ie, inadequate amount). False-positives may occur rarely due to contamination of the saliva sample with retained breast milk in the mouth of the newborn [51,52]. When this occurs, the quantitative CMV DNA level is usually lower than in neonates with true infection.

The available tests to detect CMV include polymerase chain reaction (PCR), viral culture, and modified culture (also called rapid culture or shell vial assay) (table 2). PCR is the preferred first-line test, though viral culture methods are acceptable alternatives. PCR is preferred because it is more sensitive compared with rapid culture and may be more accurate, especially if the sample must be transported to a reference lab over a long distance. In addition, PCR provides quantitative results [53]. Most newborns with cCMV have high levels of CMV DNA in their urine and saliva. If a low level is detected on CMV PCR, the results should be confirmed by repeat PCR testing or culture.

PCR testing of blood or plasma samples for CMV is not recommended as a first-line test because false-negative results may occur, especially in asymptomatic or minimally symptomatic newborns. This is because such patients may not be viremic at the time of testing. However, if blood or plasma PCR is performed and is positive, this is diagnostic of cCMV.

Serologic tests for CMV (ie, IgG and IgM antibodies) are not recommended for the diagnosis of cCMV. CMV IgM is far less sensitive compared with urine PCR and thus false-negative results are common (table 2). CMV IgM is positive in only 50 to 80 percent of newborns with confirmed cCMV based on urine PCR [54,55]. Detection of CMV IgG antibody in neonates and young infants has no value in diagnosing cCMV because it reflects passive transfer of maternal IgG (ie, it indicates prior CMV infection in the birthing parent, not necessarily during the pregnancy). However, the absence of detectable CMV IgG makes cCMV infection very unlikely.

Prenatal — Diagnosis of in utero CMV infection can be made by detection of CMV DNA in amniotic fluid by PCR. Fetal diagnosis is discussed in detail separately. (See "Cytomegalovirus infection in pregnancy", section on 'Diagnosis of fetal infection'.)

Birth to three weeks — The diagnosis of cCMV infection can be established within the first three weeks after birth by detection of CMV in the urine or saliva by PCR (table 2). Testing should be carried out as soon as the diagnosis is suspected so that evaluations for end-organ disease can be performed and, if indicated, antiviral therapy can be started promptly. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Antiviral treatment'.)

Three weeks to one year — After three weeks, the detection of CMV in urine or saliva may indicate either congenital or postnatal CMV infection. In term infants, postnatal CMV infection usually is clinically benign or self-limited. However, preterm very low birth weight infants can have severe postnatally acquired CMV infection. (See "Overview of cytomegalovirus (CMV) infections in children", section on 'Early postnatal infection'.)

A retrospective diagnosis of cCMV can be made by performing PCR testing on the dried blood spot sample that is obtained for routine newborn screening [56-61]. Detection of CMV DNA in the newborn dried blood spot sample indicates that CMV viremia was present and confirms cCMV infection. However, a negative result does not exclude cCMV infection. False-negative results may occur, particularly in newborns with no or mild symptoms since these newborns may not be viremic at the time the blood spot sample is obtained.

In the United States, with written parental permission, newborn dried blood spot cards may be retrieved from state newborn screening laboratories and tested for CMV DNA by selected research or public health laboratories experienced in this specialized testing. The use of newborn dried blood spot cards for diagnosis of cCMV is gaining popularity, and some reference laboratories now offer CMV testing on these samples. This approach is particularly useful for testing infants who have delayed-onset hearing loss [62].

In addition, some states in the United States and several provinces in Canada are evaluating the utility of newborn dried blood spot testing for universal screening for cCMV, as discussed below. (See 'Universal newborn screening' below.)

If testing of the dried blood spot sample is negative or not feasible, alternative methods of testing infants ≥3 weeks old include:

●Testing the urine or saliva for CMV (via viral culture, shell vial assay, or PCR)

●Measurement of CMV IgG antibody in the blood

Detection of CMV by any of these methods in a symptomatic infant at age three weeks to one year suggests cCMV infection, though they cannot definitively diagnose cCMV because of the possibility of postnatal infection.

Older than one year — Establishing a diagnosis of cCMV infection beyond the first year of life is generally not feasible. Retrospective diagnosis of cCMV via PCR analysis of dried blood spots as described above may be possible in some regions; however, this may not be possible in the United States and other regions because many state health laboratories that perform newborn screening discard the dried blood spot samples after one year.

In addition, many young children, particularly those attending daycare, become infected with CMV during the first few years of life. Thus, detection of CMV in the urine or saliva or CMV antibodies in the blood of a child older than one year is far more likely to represent postnatal infection than congenital infection. However, a negative CMV IgG antibody and a negative CMV culture of urine or saliva provides evidence against a cCMV infection.

A small number of studies have reported late diagnosis of cCMV infection using PCR methods on preserved umbilical cords [63-65]. In Japan, for example, it is common for families to preserve their newborn's umbilical cord as a symbol of the mother-infant bond, and CMV testing of the umbilical cord has been performed for the retrospective diagnosis of cCMV infection [66]. However, this method is generally not recommended, because it has not been adequately studied and the reliability of results of umbilical cord testing is unclear. Contamination of the sample with maternal blood or other sources may cause false-positive results.

Interpretation — The presence or absence of cCMV infection can be determined based on the timing and results of diagnostic tests, as follows:

●Virologically proven cCMV infection can be diagnosed on the basis of any of the following:

•Detection of CMV via PCR in urine, saliva, or blood samples obtained within the first three weeks after birth, confirmed on repeat testing

•Detection of CMV via viral culture or shell vial assay in urine or saliva samples obtained within the first three weeks after birth (positive shell vial assay results generally warrant repeat or confirmatory testing)

•Detection of CMV via PCR of the newborn screening dried blood spot

●Possible cCMV infection – It may not be possible to confirm the diagnosis of cCMV infection if testing is performed after the first three weeks of life (because of the possibility of postnatal acquisition). Newborn dried blood spot testing can be helpful if available, but negative results do not exclude cCMV infection. A diagnosis of "possible" cCMV infection may be made if all of the following criteria are met:

•One or more signs or symptoms of cCMV

•Other conditions that cause these abnormalities have been excluded (see 'Differential diagnosis' below)

•CMV is detected in urine or saliva samples (via viral culture, shell vial assay, or PCR) or CMV IgG antibody is detected in the blood after the first three weeks of life, up to one year of age

●Not infected – Infants in whom CMV is not detected in urine or saliva (via viral culture, shell vial assay, or PCR) during the newborn period do not have cCMV. Because of the high specificity of these tests (table 2), a negative result excludes the diagnosis of cCMV infection. In our practice, we usually perform at least two tests (urine or saliva or both) to exclude the diagnosis with confidence. CCMV infection can also be excluded beyond the newborn period if CMV IgG antibody testing is negative (provided the infant has a normal immune system), indicating that CMV infection never occurred in the child.

POST-DIAGNOSIS EVALUATION — 

Infants with virologically confirmed cCMV infection should be evaluated for evidence of organ involvement. Comprehensive evaluation should be performed even in infants who appear asymptomatic to detect subtle or subclinical subtle findings. The evaluation includes:

●Thorough physical, neurologic, and neurodevelopmental examination, including measurements of weight, length, and head circumference (to detect microcephaly).

●Laboratory testing, including:

•Complete blood count with differential and platelet count.

•Liver function tests.

•Kidney function tests.

•Coagulation studies in selected cases with liver disease or viral sepsis.

•In addition, we suggest measuring CMV viral load with quantitative polymerase chain reaction (PCR) of whole blood or plasma for any infant who will be treated with antiviral therapy. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Pretreatment evaluation'.)

●Hearing evaluation by auditory brainstem response.

●Ophthalmology evaluation.

●Neuroimaging – Cranial ultrasonography should be performed in all infants with confirmed cCMV. Ultrasonography is better able to detect lenticulostriate vasculopathy than advanced imaging and will detect most major, obvious brain abnormalities.

MRI should be obtained in infants with any of the following:

•Abnormal cranial ultrasound findings

•Abnormal neurologic examination (eg, focal abnormalities, globally increased or decreased tone, abnormal reflexes)

•Seizures

•Abnormal head circumference (microcephaly or macrocephaly).

•Hearing loss

Some experts advocate for performing brain MRI in all newborns with confirmed cCMV [67].

CT is another option for neuroimaging. The choice between MRI versus CT should be individualized based on the relative advantages and disadvantages. The advantages of CT are that it can be performed quickly and is useful in detecting ventriculomegaly or calcifications. The main downside is that CT exposes the newborn to radiation. MRI requires a longer procedure time, often requires sedation, but does not entail initial radiation exposure and is far more sensitive than CT for identifying structural abnormalities, though it is less sensitive for identifying calcification. Newer MRI imaging techniques, such as susceptibility-weighted imaging, may visualize calcium better and can be performed in infants and newborns.

DIFFERENTIAL DIAGNOSIS

●Other congenital and neonatal infections – The classic findings of symptomatic cCMV infection include petechiae, jaundice, hepatosplenomegaly, small size for gestational age (SGA), and microcephaly. These nonspecific findings may also occur in:

•Other TORCH infections (including Zika virus infection, congenital herpes simplex virus infection, congenital rubella syndrome, and congenital toxoplasmosis) (see "Overview of TORCH infections" and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate")

•Other less common pathogens such as lymphocytic choriomeningitis virus (see "Viral meningitis in children: Epidemiology, pathogenesis, and etiology", section on 'Lymphocytic choriomeningitis virus')

•Neonatal bacterial or viral sepsis (see "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at or after 35 weeks gestation")

Although other congenital infections may have characteristic clinical findings (table 1), appropriate virologic, microbiologic, and serologic studies generally are necessary to make a specific diagnosis. (See "Overview of TORCH infections", section on 'Initial evaluation'.)

●Other causes of abnormal neurologic findings – A variety of genetic and metabolic disorders, as well as in utero exposure to drugs and toxins (eg, alcohol, cocaine, isotretinoin), may mimic the neurologic findings of cCMV infection. The presence and pattern of calcifications on computed tomography (CT) imaging of the brain can be helpful in distinguishing between CMV infection and other causes of neurologic disease. Intracranial calcifications, particularly in periventricular distribution, are a common finding in CMV-infected neonates. Additional testing such as chromosomal analysis, metabolic studies, and drug screening may be used to exclude other causes of neurologic disease in newborns, including [2]:

•Tuberous sclerosis complex (see "Tuberous sclerosis complex: Clinical features")

•Sturge-Weber syndrome (see "Sturge-Weber syndrome")

•Aicardi syndrome

•Galactosemia (see "Galactosemia: Clinical features and diagnosis")

•Urea cycle deficiencies (see "Urea cycle disorders: Clinical features and diagnosis")

•Organic acidemias (see "Organic acidemias: An overview and specific defects")

•Lysosomal diseases (see "Inborn errors of metabolism: Classification", section on 'Lysosomal storage disorders')

•Peroxisomal disorders (eg, Zellweger syndrome, infantile Refsum disease, adrenoleukodystrophy) (see "Peroxisomal disorders" and "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy")

•Other inherited leukodystrophies (see "Metachromatic leukodystrophy" and "Alexander disease")

•In utero exposure to drugs and toxins (eg, alcohol, cocaine, isotretinoin) (see "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Cocaine')

●Other causes of hepatosplenomegaly, hepatitis, and hyperbilirubinemia – The differential diagnosis for the hepatic findings associated with cCMV infection includes:

•Other causes of viral hepatitis (hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, herpes simplex virus, enterovirus, adenovirus) (see "Hepatitis viruses and the newborn: Clinical manifestations and treatment")

•Ischemic injury

•Thrombosis

•Hemolytic disease (see "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Causes of significant unconjugated neonatal hyperbilirubinemia')

•Biliary atresia (if conjugated hyperbilirubinemia is present and persistent) (see "Biliary atresia")

•Metabolic and genetic disorders that involve the liver (eg, Gaucher disease) (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Hepatosplenomegaly' and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis")

The clinical course and appropriate virologic tests distinguish CMV from these other causes. Infants with cCMV and persistent liver dysfunction or persistent conjugated hyperbilirubinemia should be evaluated for biliary atresia or alpha-1 antitrypsin deficiency since CMV may coexist with other disorders of liver function, presenting a diagnostic challenge. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis" and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening".)

NEWBORN SCREENING FOR CONGENITAL CYTOMEGALOVIRUS — 

There is growing interest in newborn screening for cCMV. Given the substantial public health impact of cCMV, most CMV experts support targeted and/or universal newborn screening for cCMV infection [68-70]. However, the optimal approach remains uncertain.

The goals of newborn screening include [71-76]:

●Early identification of infected infants with subtle symptoms who may benefit from antiviral therapy. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Antiviral treatment'.)

●Identification of asymptomatic infants who are at risk for delayed hearing loss and warrant more frequent audiologic evaluation. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Long-term follow-up'.)

Targeted newborn screening — Targeted newborn screening involves testing for CMV in all newborns who fail their newborn hearing screen in one or both ears. Many birthing hospitals in the United States, Canada, and Europe have adopted targeted CMV screening programs that aim to identify infected infants in the newborn period, so that appropriate evaluations for end-organ involvement can be performed and antiviral treatment, if indicated, may be provided [68].

As discussed above, our practice is to perform CMV testing in all newborns who fail both the initial and repeat follow-up hearing screen in one or both ears (see 'Clinical suspicion' above). In such neonates, we perform testing for cCMV before discharge, if feasible, or otherwise within the first three weeks after birth. The initial screening test consists of a urine CMV PCR test. Neonates with positive CMV screening results should have confirmatory testing performed and, if cCMV is confirmed, they should undergo additional evaluation to determine the extent of end-organ involvement. (See 'Post-diagnosis evaluation' above.)

As of 2025, 11 states in the United States have passed legislation requiring that targeted CMV testing be performed or offered to all newborns who do not pass the newborn hearing screen (in addition to Minnesota, which began a universal cCMV screening programs in 2023) [70].

However, practice varies and some centers do not routinely screen for CMV in newborns who fail the hearing screen.

Targeted screening for CMV in the setting of a failed newborn hearing screen is discussed in greater detail separately. (See "Screening the newborn for hearing loss", section on 'Screening for cytomegalovirus (CMV)'.)

Universal newborn screening — Universal newborn screening for cCMV has been proposed by many CMV experts, audiologists, otolaryngologists, and public health officials [73,77,78].

●Potential benefits of universal screening – The main goal of this approach is to identify asymptomatic infected infants in order to provide careful monitoring for delayed-onset hearing loss. As discussed above, asymptomatic newborns with cCMV infection have a risk of delayed-onset hearing loss that is not detected by newborn hearing screen protocols (see 'Isolated hearing loss' above). If delayed-onset hearing loss is identified, educational accommodations, speech/language therapies, and other appropriate interventions can be initiated at an early stage in order to optimize the child's language development and learning. (See "Hearing loss in children: Treatment".)

Another potential benefit of universal newborn screening for CMV is that it may eliminate the diagnostic odyssey experienced by many newborns with cCMV. In the absence of universal screening, the diagnosis of cCMV is often delayed because many infected newborns do not exhibit classic signs and symptoms. Among newborns who fail newborn hearing screening, testing for CMV may not be performed until completion of confirmatory auditory testing and evaluation by otolaryngology specialists, which often is around two to three months of age.

In addition, universal screening may facilitate timely initiation of antiviral therapy in infants who are found to have evidence of end organ involvement. Antiviral treatment is generally not recommended for infants with asymptomatic infection (ie, those who pass the newborn hearing screen, have normal brain imaging and retinal examination, and have no other signs of infection). Indications for antiviral therapy are discussed separately. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Who to treat'.).

●Supporting evidence – Modeling studies suggest that universal newborn screening for cCMV may be cost effective [79]. However, the most reliable and cost-effective method for universal newborn screening for cCMV is not established. Methods that have been investigated for the purpose of universal cCMV screening include [60,69,77,80-85]:

•Testing of dried blood spots collected for routine newborn screening panels [60,84,85]. Improvements in PCR testing methodologies has led to improved sensitivity of blood spot testing [60]. (See "Overview of newborn screening", section on 'Blood spot panel'.)

•Detection of CMV in saliva or urine samples collected at birth and tested by central laboratory high-throughput technology. In two reports from centers in Europe and Israel, performing testing on pooled saliva samples was an efficient and cost-sparing approach [82,83].

•Simple point-of-care detection methods that are under development.

Two large studies have reported on the experience of performing universal cCMV screening with dried blood spots [84,85]. One study is from Ontario, Canada, which began a universal newborn cCMV screening program in 2019 [85]. The other is from the state of Minnesota, which implemented universal newborn cCMV screening in 2023 [84]. Combined, the studies included >600,000 newborns who underwent screening and a total of 863 infants who screened positive (0.13 percent in the Ontario study and 0.29 percent in the Minnesota study). Of the 863 positive screening results, 89 percent were confirmed on follow-up testing, 4 percent were false positives, and the remainder either didn't have confirmatory testing performed or the results were indeterminate. Among confirmed cases, most were asymptomatic (84 percent in the Ontario study; 88 percent in the Minnesota study), whereas 12 to 16 percent had either isolated hearing loss or findings consistent with symptomatic cCMV disease. Among the 113 cases of confirmed symptomatic cCMV disease in the two studies, 73 percent came to light because of the positive screening result whereas 27 percent were detected through routine neonatal care. During the study periods, there were a total of 22 infants who had negative screening results but were subsequently diagnosed with cCMV by clinician-ordered testing, yielding a false-negative rate of 3.4 per 100,000 screened infants. However, this likely underestimates the true false-negative rate since there was no systematic protocol for capturing false negatives; identifying these cases relied on voluntary reporting. Furthermore, the prevalence rates of cCMV in these reports (0.1 and 0.3 percent) are considerably lower than in other population-based reports (approximately 0.6 percent). (See 'Epidemiology' above.)

●Uncertainties and challenges – While the Ontario and Minnesota experiences suggest that universal screening is feasible, important uncertainties and challenges remain [86]:

•Consensus is lacking regarding the optimal method of screening (blood spot sample versus urine or saliva sample).

•The optimal follow-up and management of newborns with positive screening results is uncertain.

•Ensuring timely follow-up and linkage to care after a positive screen is a particular challenge. Most experts agree that if antiviral therapy is to be given for cCMV, it should be started within the first three months after birth, ideally within the first 30 days. An effective screening program must ensure that screening tests are quickly processed, analyzed, and reported to the clinician; that confirmatory testing on positive screens is completed within 21 days after birth; and that confirmed cases undergo complete diagnostic evaluation (ie, neuroimaging, audiology, eye examination) ideally within 30 days after birth, and no later than three months of age. Given the high prevalence of cCMV, this could put substantial strain on health systems. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Timing'.)

•Standardized criteria for initiating antiviral treatment in infants with cCMV identified through newborn screening are not established. There is generally no role for antiviral therapy in asymptomatic infants with normal hearing. However, for infants with isolated hearing loss, limited data are available as to whether antiviral therapy improves hearing outcomes, and expert opinion varies regarding use of antiviral therapy in this setting. This is discussed separately. (See "Congenital cytomegalovirus (cCMV) infection: Management and outcome", section on 'Who to treat'.)

•The cost-effectiveness of universal screening remains uncertain.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: TORCH infections".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Congenital cytomegalovirus (cCMV) infection affects approximately 30,000 to 40,000 infants annually in the United States and is associated with long-term neurodevelopmental disabilities, including sensorineural hearing loss (SNHL), cerebral palsy, seizures, intellectual disability, and vision loss. It is the leading cause of nonheritable SNHL in children. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical manifestations

•Clinical findings in symptomatic newborns – Approximately 10 percent of newborns with cCMV have signs of symptomatic infection at birth, while 90 percent are asymptomatic. Clinical findings in symptomatic neonates are nonspecific and may include petechiae, jaundice, hepatosplenomegaly, small size for gestational age (SGA), and microcephaly. (See 'Symptomatic neonate' above.)

•Hearing loss – SNHL is the most common sequela of cCMV infection, occurring in 30 to 50 percent of symptomatic infants and approximately 25 percent of asymptomatic infants. The newborn hearing screen is a valuable tool for detecting otherwise asymptomatic infants with cCMV. (See 'Clinical findings' above and 'Isolated hearing loss' above and "Screening the newborn for hearing loss".)

•Laboratory and imaging findings – Common laboratory findings in symptomatic neonates include thrombocytopenia, elevated transaminases, and elevated direct and indirect serum bilirubin. Imaging of the brain often shows periventricular intracranial calcifications, migrational abnormalities, cysts, or other abnormalities (image 5A-B and image 6). (See 'Laboratory findings' above and 'Neuroimaging' above.)

●Clinical suspicion – cCMV should be suspected in infants with (see 'Clinical suspicion' above):

•One or more of the typical signs of symptomatic disease (eg, microcephaly, SGA, thrombocytopenia, petechiae or purpura, hepatosplenomegaly, or jaundice at birth).

•Abnormal neuroimaging with otherwise unexplained periventricular calcifications, lenticulostriate vasculopathy, white matter disease, ventriculomegaly, migrational abnormalities (eg, polymicrogyria), germinolytic cysts, anterior temporal lobe cysts, or periventricular leukomalacia.

•Documented SNHL in one or both ears.

•Birthing parent who had known or suspected CMV infection during pregnancy or abnormal fetal imaging suggestive of in utero CMV infection, or birthing parent living with HIV.

●Diagnosis – The diagnosis of cCMV infection is confirmed by molecular detection of CMV from urine or saliva samples collected within the first three weeks after birth (table 2). Polymerase chain reaction (PCR) tests have high sensitivity and specificity for detection of CMV in infected neonates. Viral culture is an acceptable alternative method for confirming the diagnosis. Serology does not play a role in the diagnosis of cCMV in neonates. (See 'Diagnostic approach' above.)

●Screening – Given the substantial public health impact of cCMV, there is growing interest in newborn screening for cCMV using either a targeted or universal screening approach. However, important uncertainties and challenges remain, and the optimal approach is uncertain. (See 'Newborn screening for congenital cytomegalovirus' above.)

●Differential diagnosis – The differential diagnosis of cCMV includes other congenital infections (table 1), viral or bacterial sepsis, genetic and metabolic disorders, and in utero exposure to drugs and toxins. Appropriate virologic and microbiologic studies, metabolic and genetic studies, drug screening, and presence and pattern of calcifications on computed tomography (CT) imaging of the brain will aid in differentiating among these possibilities. (See 'Differential diagnosis' above.)