Update on Congenital Cytomegalovirus: Antenatal and Postnatal Management

Cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, with an average prevalence of 0.6%.1 It remains one of the leading causes of nongenetic sensorineural hearing loss (SNHL) and neurological impairment in children.2 Despite significant challenges in prenatal and postnatal management, recent advancements and ongoing research are offering promising developments in this area, which require a concerted multidisciplinary approach to implement. PRENATAL MANAGEMENT Diagnosis of Maternal Infection Screening for CMV infection during pregnancy is not routinely performed in most high-income countries. Maternal cytomegalovirus infection can be a primary infection, in seronegative women, or a nonprimary infection (NPI), in previously infected women (seropositive). To identify women with maternal primary infection (MPI), maternal serology should include both IgM and IgG antibodies and be performed as early as possible in pregnancy. According to a recent meta-analysis, the highest risk of sequelae is associated with infection occurring within the first 14 weeks of gestation.3 Therefore, in seronegative women, serology should be repeated every 4 weeks until the gestational age of 14–16 weeks4 (Figure, Supplemental Digital Content 1, https://links.lww.com/INF/G270). Diagnosis of MPI is based on CMV IgM detection, together with a positive IgG with low or intermediate IgG avidity test.4 IgM assays show a sensitivity of >98% in detecting MPI within the previous month.5,6 The latest generation IgG avidity assays allow excluding a recent MPI (<3 months) and a semirecent MPI (3–6 months) with a sensitivity of 94%–100% and 80%-90%, respectively.6,7 CMV polymerase chain reaction (PCR) in blood and urine can remain positive for several months after a MPI, with significant interindividual variability.4 Therefore, its specificity for diagnosing recent MPI is low and should not be used to confirm or exclude a recent MPI.4 Serology is also recommended in pregnant women with symptoms of CMV infection (fever, elevated transaminases, mononucleosis syndrome) and whenever there are relevant fetal ultrasound findings; in such cases, negative maternal serology (IgM and IgG both negative) excludes fetal infection.4 Diagnosis of NPI during pregnancy is challenging and there is no laboratory test to identify those seropositive women at higher risk of fetal infection.4 Primary Prevention Exposure to young children (saliva and urine) is the main risk factor for MPI. A recent study conducted in a high-resource country identified a high-risk profile for MPI, characterized by young, educated, parous women who conceive within 2 years of their previous pregnancy.8 Hygiene measures should be recommended to all pregnant women irrespective of their serostatus. Although education plays an important role in reducing the risk of MPI during pregnancy, the influence it has on NPI is less clear.4,9 Secondary Prevention Pregnant women in their first trimester or periconceptional period with MPI are eligible for secondary prevention. Administration of oral valaciclovir (8g/d, preferably 2 g × 4/d) to the pregnant woman with MPI in the first trimester or the periconceptional period, starting as soon as possible and lasting until the amniocentesis, has been shown to result in a 66%–71% reduction in vertical CMV transmission, according to a randomized controlled trial (RCT) and a recent meta-analysis.10,11 In 2 RCTs, hyperimmune globulin (100 IU/kg) was not effective as secondary prevention.12,13 Some authors have proposed that higher doses of hyperimmune globulin, administered at shorter intervals and initiated early after infection, could play a role as secondary prevention in MPI. However, this hypothesis requires confirmation through randomized clinical trials.14 Diagnosis, Treatment and Prognosis of Fetal Infection CMV PCR on amniotic fluid (AF) is the gold standard for diagnosing fetal CMV infection.4 Amniocentesis can be performed after 17 weeks gestational age, but at least 8 weeks after MPI, for optimal sensitivity.15 After a negative result of CMV PCR in AF, valaciclovir can be discontinued since it has been shown that infected neonates born after a negative amniocentesis have a very low risk of long-term sequelae.16 A positive CMV PCR in AF confirms fetal infection: on those fetuses, serial fetal ultrasound assessment, followed by fetal magnetic resonance imaging (MRI) in the third trimester, is recommended to acquire additional information regarding prognosis.4 Treatment with valaciclovir of infected fetuses seems to reduce the proportion of symptomatic neonates at birth.17 Expert teams should carry out the management of infected fetuses. Some experts recommend continuing valaciclovir treatment until delivery in cases of positive amniocentesis.4 In general, the risk of long-term sequelae, in terms of severe SNHL and neurodevelopmental impairment, in fetuses infected after an MPI has been reported to be 23% for first, 0.1% for second and 0% for third-trimester infections.3 POSTNATAL MANAGEMENT The algorithm summarizing the postnatal management, diagnosis and treatment, is shown in Figure 1, further details are provided in the text.FIGURE 1.: Diagnostic and treatment algorithm for congenital cytomegalovirus (cCMV) infection.Diagnosis of Congenital Cytomegalovirus in the Newborn Whom to Test Testing is recommended in the case of:4 Suspected MPI or NPI in pregnancy or if virologic evidence suggests CMV activity. Prenatal imaging findings indicative of congenital infection. Clinical and laboratory signs consistent with congenital cytomegalovirus (cCMV). While a definitive scoring system to quantify specific manifestations is not yet available, most signs are nonspecific. The signs and symptoms that can be present in cCMV infection are: microcephaly (head circumference <-2 Z score) , petechiae/purpura, blueberry muffin rash, jaundice, hepatomegaly, splenomegaly, hypotonia, lethargy, seizures and poor sucking reflexes. Suggestive laboratory signs include anemia, leukopenia, isolated neutropenia, thrombocytopenia (platelets <100,000/mmc), increased liver enzymes (alanine aminotransferase > 80 U/L) and hyperbilirubinemia (direct bilirubin level > 2 mg/dL).18 SNHL should always prompt testing for cCMV.19,20 Symmetric intrauterine growth restriction (ie, weight and head circumference both affected) of unknown etiology.4 In preterm infants (<32 weeks) and/or those with very low birth weight (<1500 g), testing is advised to distinguish congenital from postnatal infection. Postnatal infection in this population can be severe in some cases.4 Virologic Diagnosis Molecular diagnostic methods (PCR) have replaced culture techniques as the gold standard for cCMV diagnosis. Serology in the newborn is not recommended as a screening or diagnostic tool. To differentiate congenital from postnatal infection, testing in saliva, urine and/or blood must be performed within the first 14–21 days of life. Saliva is a convenient specimen with high sensitivity (93%–100%) and high negative predictive value (98%–99%). It is an excellent screening tool, but a positive result requires confirmation with a urine sample, which remains the gold standard, with near-perfect sensitivity (100%) and specificity (99%).4 False-positive results in saliva have been described due to contamination (breast milk, other fluids). A negative PCR result in saliva effectively rules out cCMV infection. After 21 days of life, retrospective diagnosis can be attempted using PCR on dried blood spots or dried cord blood samples.21 In a meta-analysis, the overall sensitivity of dried blood spots was 84% (95% confidence interval: 81%–87%), but sensitivity ranged from 28% to 100%.22 Around 7% of children with cCMV have an undetectable viral load in their blood after birth, so a negative blood PCR at birth does not exclude cCMV.23 It is recommended to have at least 2 positive samples for microbiological confirmation (urine and blood for example or 2 urine samples). Extensive Diagnostic Workup Once the infection is confirmed, the neonate should undergo an extensive diagnostic workup as soon as possible. A complete anthropometric evaluation and physical examination: looking for signs and symptoms consistent with cCMV. Blood tests with full blood count, liver enzymes and bilirubin (both direct and indirect). Neuroimaging: cranial ultrasounds (cUS) should be performed in all children with cCMV at birth. cUS and cerebral MRI have been proven to be complementary in detecting central nervous system (CNS) involvement and have a significant prognostic role in predicting sequelae.24–26 MRI is recommended in children with clinical manifestations of cCMV at birth, SNHL, chorioretinitis or abnormalities detected on cUS. There is no consensus about performing routine MRI in children born after MPI in the first trimester of pregnancy or where the timing of transmission is unknown.4 Conversely, computed tomography scan is no longer recommended due to high radiation exposure. Detectable abnormalities on ultrasound in cCMV include calcifications, ventriculomegaly and caudothalamic or subependymal cysts. Additionally, there are nonspecific findings, such as lenticulostriated vasculopathy, whose prognostic significance is not yet fully understood.18,27 White matter abnormalities, periventricular cysts, ventricular adhesions, cerebellar hypoplasia, lissencephaly, polymicrogyria and other migration abnormalities are best assessed by MRI. Audiological assessment: all infants with cCMV should undergo audiologic assessment. Visual assessment: ophthalmologic evaluation, including a fundus oculi exam, should be performed to identify potential eye involvement, mainly chorioretinitis. Of note, a routine lumbar puncture to detect CMV DNA and abnormal cerebral fluid indices is no longer recommended for diagnosis or prognostic reasons.4 The Definition of a Symptomatic Patient The definition of a “symptomatic” infant varies among authors and guidelines. Newborns with apparent infection and abnormalities on physical examination are generally classified as “symptomatic” in guidelines.18,28 However, according to most authors, the definition of symptomatic based only on physical examination falls short in terms of treatment eligibility. Therefore, abnormal laboratory findings, chorioretinitis, SNHL and abnormalities detected on neuroimaging are widely included in the “symptomatic” categorization. Although SNHL is one of the most common sequelae of cCMV and is included as a criterion for symptomatic cases,4,18 some authors classify infants with isolated SNHL separately, referring to them as “asymptomatic children with isolated SNHL.” 28 The “Symptomatic versus asymptomatic” definition is very relevant because there is no evidence of the effectiveness of antiviral treatment in asymptomatic children. To move beyond the binary classification of “symptomatic” and “asymptomatic” infants, some researchers advocate for a management approach based on prognosis. This involves using severity scores that incorporate both radiological24 and clinical assessments to guide treatment decisions. Sequelae and Long-term Follow-up The cCMV infection can result in audiologic, vestibular, ophthalmological and neurodevelopmental sequelae. Long-term sequelae are present in 50%– 70% of symptomatic cases and 8%–15% of asymptomatic cases; therefore, a large proportion of children with cCMV require long-term multidisciplinary follow-up.2,19,29,30 Children born after confirmed MPI in the second or third trimester (>14 weeks of gestation) showed a low risk of sequelae. Therefore, asymptomatic children with normal neuroimaging at birth and documented MPI after the first trimester can follow standard pediatric care.4 There is no difference in severity among infants infected after an MPI and a NPI.31 Audiology SNHL is the most frequent sequela in cCMV-infected patients; it can be present at birth or appear later in childhood [late-onset SNHL (LO-SNHL)].19,32 Overall rate of SNHL is 12.6% (32.8% in symptomatic and 9.9% in asymptomatic children).19 Risk of LO-SNHL ranges from 2.5% to 14%.4,33,34 SNHL is associated with maternal infection in the first trimester, presence of other symptoms and/or neuroimaging abnormalities at birth, but can also occur in infants with no apparent disease at birth.30,32 The risk of developing LO-SNHL after the age of 5 in those infants born asymptomatic and without hearing loss, is similar to uninfected controls.34 Infants with first-trimester infection or unknown time of maternal infection require audiology follow-up for the first 5 years of life.4 Children with unilateral SNHL at birth have a high risk (>50%) of developing SNHL in the contralateral ear.34 Vestibular The reported prevalence of vestibular impairment in children with cCMV ranges from 14% to 90.4% and can affect both asymptomatic and symptomatic infants and those with and without SNHL.35 Abnormal vestibular tests can be associated with impaired balance and/or impaired gross motor performance.36,37 Vestibular physiotherapy has been shown to improve gross motor outcomes in infants with vestibular dysfunction and can be taught to parents using simple videos.38,39 Vestibular screening tests should therefore be performed within the first year of life in high-risk children with cCMV (first trimester/unknown timing of infection, hearing loss, developmental delay, CNS involvement).4 Neurodevelopment Neuroimaging is the best predictor of neurologic outcome in infants with cCMV as normal neuroimaging predicts near normal neurodevelopment, whereas major abnormalities are associated with poor prognosis.4 The incidence of gross motor delay in children with symptomatic cCMV ranges between 30% and 43%.40 In case–control studies, asymptomatic infants often perform similarly to healthy controls in developmental assessments.40 Speech-language delay is common in children with cCMV, especially in those with hearing loss. Some recent studies have suggested children with cCMV may have an increased risk of autistic spectrum disorder and attention deficit hyperactivity disorder.41 Formal neurodevelopmental assessment is therefore recommended at 24–36 months for children at higher risk of long-term sequelae (first-trimester infection/infection of unknown timing, symptomatic, SNHL, neuroimaging abnormalities) and children should be followed up until school age.4 Visual Impairment Ocular abnormalities are found at birth in around 10%–13% of symptomatic patients and 0%–2.1% of children without symptoms and include chorioretinitis, retinopathy, optic atrophy and strabismus.42,43 Ocular abnormalities often correlate with the presence of CNS involvement.44 Ophthalmologic follow-up is only recommended for infants with ocular abnormalities at birth.4,42,44 Treatment The treatment of children with cCMV should be multidisciplinary. Hearing aids/cochlear implants, hearing and language rehabilitation and physiotherapy are the cornerstones of this treatment. RCTs showed modest benefits in hearing preservation using intravenous ganciclovir for 6 weeks in symptomatic infants.45 When compared to 6 weeks of valganciclovir versus 6 months of treatment, 6 months showed discrete benefits in hearing and neurodevelopment.46 In a non-randomized trial, 6 weeks of oral valganciclovir started before 13 weeks of age has been found to prevent hearing deterioration in infants with hearing loss without other symptoms of cCMV.47 However, another RCT in children (1 month–4 years of age) with SNHL treated with 6 weeks of oral valganciclovir did not show any hearing benefits.48 Valganciclovir oral solution is the recommended treatment of choice and ganciclovir should be limited to severe cases or in those children unable to take oral medications and should be switched to the oral route as soon as possible.4,45,46 Treatment indications vary based on how they are classified at birth (symptomatic/asymptomatic) and on the type of manifestations presented. The treatment indication references are shown in Figure 1 and are based on the ECCI consensus of 2024.4 It should be noted that in children with isolated SNHL with no other symptoms, there is no consensus on treatment duration (6 weeks vs. 6 months).4,18,49 There is no clear evidence of the benefit of the antiviral treatment in children small for gestational age at birth but no other symptoms and normal neuroimaging.4 Antiviral treatment should be started as soon as possible after birth and before 4 weeks of life. Treatment started 1–3 months may have some benefits.47 After 3 months of age, there is no evidence of efficacy and cases should be discussed with an expert.4,47 Valganciclovir 16 mg/kg per dose, twice daily, and ganciclovir 6 mg/kg per dose, twice daily, are the dosing of choice.45,46 Bone marrow suppression (neutropenia mostly, rarely anemia or thrombocytopenia) can be developed in around 19% (valganciclovir) and up to 63% (ganciclovir) of patients.45,46 Full blood count and liver function tests should be performed at 2 and 4 weeks after treatment start and then every 3 weeks until treatment completion.4 If neutrophil counts drop <500 cs/mm3, treatment should be stopped and retested in 1 week. CONCLUSION Significant advances have been made in the management of CMV infection during pregnancy and in infected newborns. In recent years, new data have emerged regarding the efficacy of valaciclovir for the secondary prevention of fetal infection. The timing of maternal infection has become a key factor in assessing the risk for infected fetuses, while oral valganciclovir is now the treatment of choice for symptomatic infants with moderate to severe disease. Additionally, new evidence has surfaced on the use of antivirals in specific scenarios, such as isolated SNHL. In the coming years, we are expected to move toward more individualized treatment approaches and tailored follow-up plans based on child’s risk profile.