Recent advances in the prevention and management of Congenital Cytomegalovirus Infection

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ACHAIKI IATRIKI | 2026; 45(1):7–10

Editorial

Sofia Benou, Despoina Gkentzi

Department of Paediatrics, Patras Medical School, Rion, Greece

Received: 24 Jun 2025; Accepted: 15 Jul 2025

Corresponding author: Despoina Gkentzi, Department of Pediatrics, University General Hospital of Patras, Patras Medical School 26504, Greece. Τel.: +30 2613 603.543, Fax: +30 2610 994.683, e-mail: gkentzid@hotmail.com, gkentzid@upatras.gr

Keywords: Congenital CMV, treatment, prevention

 

Human cytomegalovirus (CMV) is an enveloped DNA virus that, like other members of the Herpesviridae family, establishes lifelong latency following primary infection. Reactivation or reinfection with a different CMV strain sometimes occurs and is referred to as recurrent infection [1]. CMV spreads through close contact with infected body fluids, including saliva and urine, particularly from infants and young children, sexual activity, blood transfusion or organ transplantation, as well as during pregnancy or lactation from mother to fetus or infant. Preschool-aged children are the primary source of infection for women of reproductive age and infection among pregnant women most frequently occurs through close contact with young children. CMV infection is typically asymptomatic or causes mild symptoms in immunocompetent individuals. However, it can lead to severe disease in immunocompromised populations, (including HIV-infected individuals and organ transplant recipients), and fetuses, where it may cause congenital CMV (cCMV) infection with potentially serious complications [1-3].

CMV is the most common cause of congenital infection worldwide, with a global prevalence of 0.64%, and the main non-genetic cause of congenital sensorineural hearing loss and neurodevelopmental abnormalities in developed countries [2-3]. About 10% of infants with cCMV infection present with symptomatic infection at birth [4]. Clinical manifestations include hepatosplenomegaly, jaundice, petechial/purpuric rash, auditory and visual impairment, as well as neurologic abnormalities such as microcephaly [5]. Approximately 40–60% of symptomatic newborns will develop a permanent disability, while 10-15% of newborns will develop long-term sequelae. Long-term effects of cCMV include sensorineural hearing loss (SNHL), cognitive impairment, and/or cerebral palsy [4-5].

cCMV can occur after both maternal primary infection and non-primary maternal infection. In seropositive mothers, reactivation of a latent virus or reinfection with a new CMV strain can also affect the fetus, causing cCMV disease with or without sequelae in the newborn and child [6]. Increasing evidence shows that the risk of symptomatic infection, especially when resulting in hearing loss, is similar after maternal primary or non-primary cytomegalovirus infection [2,7]. The risk of vertical transmission after maternal primary CMV infection increases with advancing pregnancy, but fetal sequelae are more likely when infection occurs in the first trimester [8].

Damage due to cCMV, infection may be prevented at various levels, including maternal awareness to prevent infection in pregnancy, prenatal diagnosis of congenital infection followed by antiviral treatment, and neonatal screening to identify the infected babies who could receive antiviral agents when indicated in order to prevent sequelae [2].

Expert consensus guidelines for cCMV infection diagnosis and management were published in 2017 [9] and revised in 2024 [10]. Of note, both prevention and management of cCMV infection remain the key principles in reducing the disease burden.

Primary prevention of cCMV infection remains the optimal and most effective way to reduce the disease burden. Exposure to young children is the main risk factor for maternal primary CMV infection, as infected children excrete the virus in their urine and saliva over a long period. Mothers of children attending daycare and childcare workers are considered high-risk populations [11]. Several studies have suggested that hygiene measures considerably reduce the risk of contracting a maternal primary infection during pregnancy while there is limited evidence about the role of hygiene measures in non-primary maternal infection [10]. However, in the absence of a licensed effective vaccine, the best primary prevention strategy for CMV infection in pregnancy is education on hygiene precautions [2]. The latter should be provided to all pregnant women regardless of their CMV serostatus [10]. Despite the impact of cCMV on newborn and children’s health, low awareness has been reported in the literature among both pregnant women and healthcare professionals regarding cCMV infection and their preventive measures [12].

Maternal CMV infection in pregnancy, both primary and non-primary, is commonly asymptomatic making the diagnosis challenging, particularly in the absence of routine antenatal screening. Serological testing can only diagnose maternal primary infection, while it is often unhelpful in non-primary infection. There is no screening test for non-primary infection during pregnancy that will predict the likelihood of congenital infection. The diagnosis and management of CMV infection during pregnancy have therefore focused on primary maternal infection.

CMV serology is essential to identify women at risk of maternal primary infection during pregnancy but also for diagnosing a maternal primary infection. Depending on local epidemiology, universal first-trimester CMV serology should be considered in women with unknown or negative CMV serostatus. CMV serology in the first trimester of pregnancy as early as possible is recommended, followed by a retest every 4 weeks until 14–16 weeks in seronegative women [10]. CMV serology is not recommended in pregnant women beyond 16 weeks except in cases with ultrasound CMV compatible symptoms [10].

The diagnosis of maternal primary infection is based on CMV IgM detection. CMV IgM is present in 50–80% of sera for up to 6 months after maternal primary infection and cross-reactivity as well as non-specific reactivity may occur, resulting in low specificity for diagnosing a recent infection [10]. As a result, IgG avidity testing is used to exclude or confirm a recent (less than 90 days) maternal primary infection in cases with positive IgM and positive IgG. Low avidity indicates recent maternal primary infection. High IgG avidity in the first trimester allows with a high probability to exclude a recent maternal primary infection during the first trimester and the preconceptional (two–eight weeks before conception) period [10]. In any case of primary maternal infection, all efforts must be made to ascertain the timing of infection, since it influences the risk of vertical transmission and the risk of long-term sequelae.

CMV DNA detected by PCR in a sample of amniotic fluid is the gold standard for the diagnosis of fetal infection. An amniocentesis for CMV should be performed when maternal primary infection is revealed by maternal symptoms or following prenatal serology screening or when prenatal ultrasound is suggestive of fetal infection [2]. Amniocentesis can be scheduled after 17 weeks of gestation and at least six–eight weeks after the suspected maternal infection [13]. Perinatal outcome following confirmed fetal cytomegalovirus infection ranges from healthy asymptomatic livebirth to stillbirth or postnatal survival with severe disability [2]. Oral valacyclovir at a dose of 8g/day is recommended following maternal primary infection in early pregnancy, as soon as possible after infection and until the result of the CMV PCR in amniocentesis [10]. In confirmed fetal infection, women should undergo serial targeted fetal ultrasounds in combination with third-trimester magnetic resonance imaging (MRI), to collect complementary prognostic information.

Diagnosis of cCMV infection is based on positive CMV DNA PCR in infant’s urine within three weeks of life [2]. Saliva PCR testing may serve as an alternative diagnostic method but requires confirmation with urine testing. Retrospective testing via PCR of dried blood spots, routinely collected in the first week after birth, enables diagnosis in children older than 3 weeks of age [10].

In the neonatal age, cCMV infection might be symptomatic or asymptomatic. Indications for testing for cCMV include evidence of maternal primary infection during pregnancy, presence of indicative features on prenatal ultrasonography or MRI or neonatal clinical manifestations consistent with cCMV [10]. The strongest evidence exists for SNHL either bilateral or unilateral. However, a major challenge for physicians caring for newborns remains early detection of long-term cCMV-complications -particularly SNHL, among infants asymptomatic at birth [4,14]. Indeed, early identification of SNHL allows timely interventions that will optimize speech outcomes [5]. As a result, despite the implementation of targeted cCMV screening for newborns who fail universal neonatal hearing screening, concerns remain about inadequacy of this approach in properly identifying all infected infants who are at risk of complications [15]. Cost-effectiveness of universal versus targeted cCMV screening remains a major topic of debate among literature [16].

Investigations following virological diagnosis of cCMV infection should access organ involvement to predict outcome and guide treatment decisions. All infected newborns should be evaluated with a clinical examination that includes anthropometrics, full blood count, liver enzymes, bilirubin (total and conjugated), ophthalmologic and audiologic assessment. Regarding the evaluation of the central nervous system, while cranial ultrasound (cUS) is the first-line imaging modality, MRI can reveal significant abnormalities, such as white matter changes and cortical malformations, frequently missed by cUS. Overall, blood viral load tends to be higher in symptomatic infants, though, there is no consensus for a threshold for risk stratification [10,17].

Infants with significant symptoms/signs of cCMV should be treated with antivirals (intravenous ganciclovir at a dose of 6mg/kg/dose, twice daily, or its oral pro-drug valganciclovir at a dose of 16 mg/kg/dose, twice daily) [2]. Antiviral treatment for 6 months is recommended in significant CMV-related symptoms at birth or isolated hearing loss [10,18]. For infants with isolated persistent thrombocytopenia or hepatitis and no other manifestation, antiviral treatment for six weeks is recommended. Oral valganciclovir is the treatment of choice, but intravenous ganciclovir may be used for infants unable to take enteral medication, switching to oral route as soon as possible. Antiviral treatment should be started as early as possible and before the first month of age [10].

During antiviral treatment, full blood count and liver function tests should be checked regularly. Hearing screening follow-up, ophthalmological and neurodevelopmental assessments, and vestibular testing should be performed based on the severity of disease and estimated timing of infection. Hearing follow-up is recommended up to five years of age for infants with normal hearing at birth and unknown timing or first-trimester infection. Asymptomatic children with normal imaging and documented maternal primary infection in the second or third trimester may follow standard pediatric care [10]. In conclusion, cCMV infection constitutes a significant burden on patients, family and society. A multidisciplinary team including psychological support may be very helpful for families in the early stages of the journey.

Conflict of interest

None to declare.

Declaration of funding sources

None to declare.

Author contributions

DG: Conceptualization, SB: Literature research-writing- original draft preparation, DG: critical correct manuscript- review-editing- supervision. All authors have read and agreed to the published version of the manuscript.

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