Congenital Cytomegalovirus Infection: Clinical Guidelines

List of Abbreviations

IgG – class G immunoglobulins

IgM – class M immunoglobulins

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATC – Anatomical Therapeutic Chemical Classification System

GA – gestational age

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

EIA – enzyme immunoassay

CT – computed tomography

IU – international units

ICD-10 – International Classification of Diseases, 10th Revision

HC – healthcare organization

MRI – magnetic resonance imaging

NSG – neurosonography

ARVI – acute respiratory viral infection

PCR – polymerase chain reaction

RCTs – Randomized Controlled Trials

US – ultrasound examination

CLIA – chemiluminescence immunoassay

CMV — cytomegalovirus

CMVI – cytomegalovirus infection

CNS – central nervous system

Terms and Definitions

Congenital cytomegalovirus infection is an infectious disease resulting from antenatal transmission of the pathogen from mother to fetus during primary infection of a pregnant woman, reactivation of a previously acquired infection during pregnancy, or infection of a seropositive pregnant woman with a different strain of cytomegalovirus.

Cytomegalovirus infection (hereinafter referred to as CMV infection) is a common viral infection caused by cytomegalovirus (Human Cytomegalovirus) (CMV), characterized by diverse manifestations ranging from asymptomatic course to severe generalized forms with involvement of internal organs and the central nervous system (in immunocompromised individuals and in intrauterine fetal infection).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital cytomegalovirus infection is an infectious disease resulting from antenatal transmission of the pathogen from mother to fetus during primary infection of a pregnant woman, reactivation of a previously acquired infection during pregnancy, or infection of a seropositive pregnant woman with a different strain of cytomegalovirus [1–3]. Congenital CMV infection can cause fetal malformations, ante- or intranatal fetal death, severe generalized disease in the newborn up to fatal outcome, as well as irreversible disabling sequelae, such as sensorineural hearing loss, blindness, cerebral palsy, and neurodevelopmental delay.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The pathogen belongs to the species Cytomegalovirus hominis, subkingdom Deoxyvira, class Deoxicubika, order Haplovirales, family Herpesviridae (human herpesvirus type 5), subfamily Betaherpesviridae, genus Cytomegalovirus. Four CMV strains (AD169, Davis, Towne, Kerr) have been registered, all of which are pathogenic to humans.

CMV is characterized by significant antigenic diversity. When a seropositive person is infected with a different strain of the virus, the formation of specific immunity with the production of specific class M antibodies is similar to that observed upon primary contact.

CMV infection is considered primary if infection with cytomegalovirus and the development of the infectious process occur in a previously seronegative individual.

If a seronegative woman is infected with cytomegalovirus during pregnancy, regardless of the portal of entry of the infection, the active replication of the virus in affected cells results in the development of transient viremia, the duration of which depends on the rate of acquired immunity formation. The presence of CMV in the blood leads to placental infection, damage, and transmission of the virus to the fetus. The virus penetrating through the placenta actively replicates in the endothelial cells of fetal vessels and spreads via blood cells to target organs. As a result, the cells of the kidneys (viral replication in which leads to the virus entering the amniotic fluid), liver, myocardium, and brain are affected. Swallowing of infected amniotic fluid by the fetus can lead to damage to intestinal cells.

The degree of damage to the internal organs of the fetus largely depends on the gestational age at which the infection occurred [4]. The severity and magnitude of organ disorders resulting from intrauterine infection are higher the lower the gestational age of the fetus [3,5–7]. Also, the rate of transmission to the fetus during primary infection of a pregnant woman is influenced by the presence of cytomegalovirus DNA in the blood and amniotic fluid [8–10]. In cases where fetal infection occurs shortly before or during delivery, damage to internal organs and systems manifests in the neonatal period.

In the neonatal period, the disease can occur in clinical and subclinical forms. Severe CNS lesions caused by viral dissemination more frequently occur when infection takes place in early pregnancy [11].

The incidence of symptomatic congenital CMV infection and long-term sequelae, such as sensorineural hearing loss following intrauterine fetal infection, does not depend on whether the pregnant woman had a primary or secondary infection (reactivation of latent CMV infection or superinfection with a new CMV strain) [12–15].

1.3 Epidemiology of the Disease or Condition

CMV is ubiquitous. Specific IgG class antibodies confirming past infection are detected in approximately 60% of the adult population in developed countries, reaching up to 90–100% in developing countries, and vary significantly across different populations even within the same country depending on ethnic and socioeconomic factors [16–18]. In the Russian Federation, the seropositivity rate ranges from 50% to 80% [19–23]. Infection patterns vary widely across populations due to geographical, ethnic, and socioeconomic characteristics. CMV seropositivity rates depend on age, social status, level of material well-being, and sexual activity. Among pregnant women, the detection rate of CMV antibodies reaches 42.6–94.5% [24].

The source of infection for a pregnant woman is an individual infected with CMV. After primary infection, viral shedding from the body usually continues for several months. In children infected during the perinatal period, viral shedding can last up to 5 years [12,25]. In both adults and children, the state of latent infection can alternate with periodic reactivations, during which viral shedding resumes.

The incidence of primary CMV infection in women during pregnancy averages about 2%, and the rate of intrauterine fetal infection averages 32% [16,26]. The probability of vertical transmission to the fetus during maternal primary infection increases with advancing gestational age (from 30% in the 1st trimester to 72% in the 3rd trimester) [7]. At the same time, the most severe fetal damage occurs when infection happens in the 1st trimester of pregnancy [6,7,11]. Transplacental infection in the 1st trimester leads to malformations of the central nervous system, gastrointestinal tract, biliary tract (biliary atresia), congenital liver cirrhosis, chorioretinitis, and cardiac conduction block. Infection at later stages of pregnancy may cause progressive jaundice, hemorrhagic syndrome, hepatosplenomegaly, and pneumonia.

Upon reactivation of latent virus or CMV reinfection during pregnancy, the rate of transmission to the fetus is significantly lower: about 1.5–2% of cases during infection exacerbation and up to 20% during reinfection with CMV [16]. Differentiating reactivation of latent CMV infection from superinfection with a different viral strain is only possible using molecular analysis of isolated isolates. According to a number of studies, given that CMV reactivation or reinfection occurs significantly more frequently during pregnancy than primary infection, secondary infection accounts for 50–80% of all cases of intrauterine infection [15,27,28].

The prevalence of congenital CMV infection among live-born newborns ranges from 0.5% to 2.5%, averaging about 1%, and varies significantly across studied populations [16,29]. In Western European countries and North America, CMV infection is considered the most common congenital viral infection (up to 2.2% among all live births including asymptomatic carriage) [16,30].

The incidence of clinical forms of congenital CMV infection, according to cohort studies from various countries, ranges from 10% to 70%, with 20% to 60% of these children developing severe and moderately severe irreversible consequences, such as hearing impairment, epilepsy, mental, psychomotor and speech developmental delay, and optic atrophy [12,31–34]. Thirty to 90% of infected newborns have a subclinical form of congenital CMV infection, in which 10–20% of children subsequently develop long-term irreversible consequences [31,32,34].

According to Rosstat data, for the period 2010–2018, 22,240 cases of CMV infection were officially registered in the Russian Federation, including 2,023 cases in 2018. The actual number of patients with CMV infection, both children and adults, significantly exceeds the number of registered cases. Annual incidence rates of congenital CMV infection in the Russian Federation for the period 2008–2018 show a downward trend from 0.15 in 2008 to 0.09 per 100,000 population in 2018 [35]. However, statistical data do not reflect the real picture. According to federal statistical observation forms No. 2 for the period from 2009 to 2018, only 63 cases of congenital CMV infection were registered in Moscow [36]. Today, the number of registered cases of the disease is negligible compared to the estimated number of congenital CMV infection cases in infants. Given that the number of births in 2019 in the Russian Federation was 1,648,954, and in Moscow 137,355, and the incidence of congenital CMV infection averages 0.5–1% among live newborns, the number of infants antenatally infected with CMV in the reporting year should range from 8,000 to 16,000 nationwide and from 700 to 1,400 in Moscow, of which 800–1,600 and 70–140 should have a clinically manifested form of the disease [37,38].

1.4 Features of Coding the Disease or Condition

P35.1 – Congenital cytomegaloviral disease

1.5 Classification of the disease or condition

Congenital CMV infection [39]:

1. Clinical forms:

- moderate and severe,

- mild,

- isolated hearing loss;

2. subclinical form

3. Complications

1.6 Clinical presentation of the disease or condition

Clinical forms of congenital CMV infection are the result of transplacental fetal infection, typically before 20 weeks of gestation. The most severe form is generalized clinically manifest CMV infection, characterized by involvement of the bone marrow, liver, gastrointestinal tract, and nervous system. The main clinical manifestations and symptoms are presented in Table 1. Neurosonography (NSG) and computed tomography (CT) of the brain may reveal the following changes: calcifications (most commonly periventricular, as well as cortical), cysts (subependymal, periventricular, porencephalic), ventriculomegaly, lenticulostriate vasculopathy, and rarely, intracranial hemorrhage. Magnetic resonance imaging (MRI) is not sensitive enough to detect calcifications, but it is the best method for diagnosing neuronal migration disorders, cortical malformations (atypical gyral patterns such as lissencephaly or polymicrogyria), cortical atrophy, and delayed myelination [40–45]. Mortality among newborns with severe congenital CMV infection reaches 5–7% [46, 47].

Table 1. Potential clinical manifestations and symptoms in infants with congenital CMV infection [48, 49].

In 2015, experts in the management of congenital cytomegalovirus infection in children reached a consensus on the need to classify clinical forms of congenital CMV infection by disease severity [39, 48].

Moderate to severe forms include clinical and instrumental manifestations of CNS involvement, a life-threatening disease course, or multiple manifestations characteristic of congenital CMV infection [39]:

– multiple manifestations (thrombocytopenia, petechiae, hepato- and splenomegaly, small for gestational age, hepatitis [elevated transaminases and/or bilirubin]);

– clinical signs of meningoencephalitis, including seizures;

– ophthalmological signs of chorioretinitis;

– microcephaly;

– characteristic brain structural abnormalities detected by NSG, CT, or MRI (calcifications, periventricular cysts, ventriculomegaly, subependymal pseudocysts, white matter abnormalities, cortical atrophy, gray and white matter migration disorders, cerebellar hypoplasia, cerebral hypoplasia, hippocampal dysplasia, lenticulostriate vasculopathy).

Mild forms include isolated manifestations (1 or 2), clinically insignificant or transient, such as mild hepatomegaly, a single low platelet count, or a single elevated alanine aminotransferase level.

Congenital CMV infection with isolated hearing loss. This form presents with no clinical or laboratory signs of disease, except for isolated hearing loss (equal to or greater than 20 dB) [49]. At the same time, in infants who have not undergone newborn hearing screening using otoacoustic emissions, a differential diagnosis must be made between congenital CMV infection and other causes of hearing loss.

Congenital CMV infection, subclinical form is diagnosed when cytomegalovirus is detected in biological fluids (blood, urine, saliva) in the absence of clinically significant disease signs, blood count abnormalities, biochemical blood test changes, or instrumental examination findings. Despite this, in a significant proportion of such children—up to 10–20% of cases of congenital CMV infection that are asymptomatic in the neonatal period—delayed psychomotor development, sensorineural hearing loss, and chorioretinitis begin to gradually develop within the first 3–6 months of life ("late" manifestations of congenital CMV infection). Children with the subclinical form require outpatient follow-up monitoring.

Hearing loss (ranging up to deafness) may progress over several years. In children with congenital CMV infection (including the subclinical form), hearing function monitoring should continue until school age, as about 40% of hearing impairments develop after the neonatal period in children with normal neonatal hearing test results [40, 41, 50, 51].

Complications.

The risk of long-term adverse outcomes is highest in clinically manifest cytomegalovirus infection [51–54]. Psychomotor and intellectual developmental delays (50% of cases), sensorineural deafness (50%) or bilateral hearing loss (37%), speech perception impairment with preserved hearing (27%), visual impairments (22–58%), and one or more of the following signs (microcephaly, seizures, paresis/paralysis, chorioretinitis) with a frequency of about 50% may develop [14, 30, 54–57]. Congenital CMV infection is associated with sensorineural disability [58]. In the presence of microcephaly, the disability rate exceeds 50% [52, 59]. In 25–40% of cases, children experience intellectual deficits manifesting at an older age: cognitive impairment, poor academic performance, reading disability, hyperactivity combined with inattention, and behavioral problems [52].

Chronic hepatitis, liver cirrhosis, renal pathology (cystic dysplasias, nephrotic syndrome), pulmonary sclerosis, and intraventricular hemorrhages may develop.

Not only clinically manifest, but also subclinical CMV infection can lead to complications such as significant hearing deterioration (5–23% of cases), vision loss, seizure disorders, physical and intellectual developmental delays (4–5%), sensorineural disorders, and learning difficulties [14, 31, 51, 52, 55, 57, 60]. CNS damage associated with CMV in a child increases the rate of pediatric disability and reduces indicators of intellectual, mental, and physical development. Hearing loss in congenital CMV infection is accompanied by vestibular system impairment (up to 92.3%), which frequently progresses (up to 50%) [53, 61]. There is significant underestimation of isolated balance disorders with preserved hearing. In latent congenital CMV infection, vestibular function disorders of varying severity are diagnosed in nearly half (up to 45%) of children by early school age [62].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis of congenital cytomegalovirus infection, indicating the specific form of the disease, is established based on:

1. Maternal history data (see Table 2);

2. Presence of clinical manifestations on physical examination (see Tables 1 and 2);

3. Laboratory testing methods (see Table 1). Proof of antenatal CMV infection is the detection of CMV DNA in any biological specimen (oropharyngeal swab/saliva, blood, urine, and/or cerebrospinal fluid) within the first 3 weeks of life [48, 63, 64]. According to studies, the sensitivity of detecting CMV DNA by polymerase chain reaction (PCR) in urine from infants with congenital CMV infection is 98.8–100% with a specificity of 99.1%; the sensitivity of detecting CMV DNA in oral swabs is 93–100% with a negative predictive value of 98–99%, a specificity of 91–99.7%, and a low positive predictive value of 49–73% [49, 65–70]. Evidence regarding the prognostic value of positive DNA in cerebrospinal fluid is contradictory [44, 71–73]. Positive CMV DNA in cerebrospinal fluid confirms CNS involvement in the infectious process, though a negative result does not rule out neuroinfection [73]. The sensitivity of the method is 81%, and the specificity is 47.8% [74].

   Determination of IgM class antibodies to CMV can be used to establish the diagnosis of congenital CMV infection if PCR is unavailable, or in doubtful cases as an additional test, but potential false-negative and false-positive results must be taken into account. The sensitivity of the method ranges from 40.7% to 84.4%, and specificity is 100% [75–77].

4. Instrumental diagnostic methods (see tables 1 and 2).

The diagnosis of "Congenital CMV infection" cannot be established solely on the basis of detecting IgG class antibodies to CMV in a newborn [78]. There is no compelling evidence in the literature regarding the diagnostic significance of IgG avidity for diagnosing congenital CMV infection in newborns. Diagnostic results may be confounded by transplacental maternal antibodies [79–81].

The diagnosis of "Congenital cytomegalovirus infection" indicating the severity of the clinical form is established in a newborn upon confirmation of antenatal CMV transmission and the presence of characteristic disease features (Table 1), with the etiology confirmed by detecting cytomegalovirus DNA in biological samples via PCR [39,48].

The severity of the clinical form is determined in accordance with the criteria listed in subsection 1.6.

The diagnosis of "Congenital cytomegalovirus infection, subclinical form" is established in a newborn upon confirmation of antenatal cytomegalovirus transmission by detecting CMV DNA in any biological specimen (saliva, urine, blood) in the absence of characteristic disease features (Table 1) [39,48].

Table 2. Indications for screening for congenital CMV infection in newborns [48,49].

2.1 Complaints and Anamnesis

• If the maternal history includes suspected or confirmed data indicating a CMV infection (primary, latent, or reinfection with another strain) during pregnancy, it is recommended to order a CMV screening for the newborn for timely diagnosis of congenital CMV infection [13,28,48,82,83].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: suspicion of a potentially recent CMV infection during pregnancy may be prompted by an acute respiratory viral infection (ARVI)-like illness or fever during pregnancy when the etiology of these clinical manifestations remains unconfirmed [84]. If quantitative testing is unavailable, qualitative testing may be used.

• In the presence of intrauterine infection signs detected antenatally via fetal ultrasound and MRI, it is recommended to order a CMV screening for the newborn for timely diagnosis and treatment of congenital CMV infection [48,82,85–89,98].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: specific ultrasound features of CMV infection include cerebral calcifications (most commonly periventricular), ventriculomegaly, microcephaly, and hepatosplenomegaly. Less specific ultrasound features that may still occur in CMV infection include periventricular cysts, subependymal cysts, white matter anomalies, cortical atrophy, gray and white matter migration disorders, cerebellar hypoplasia, lenticulostriate vasculopathy, intrauterine growth restriction, ascites, and hydrothorax [48,85]. According to several studies, antenatal ultrasound signs of intrauterine infection have a sensitivity of 50%–90.6%, specificity of 66.4%–97.5%, positive predictive value of 61.1%–84.4%, and negative predictive value of 83.8%–96.1% as predictors of congenital CMV infection [85,86,89]. If quantitative testing is unavailable, qualitative testing may be used.

• All preterm newborns with a gestational age of 32 weeks or less or a birth weight of 1500 g or less are recommended to undergo CMV screening for further differential diagnosis in the event of developing postnatal cytomegalovirus infection [48,49,90–93].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: if quantitative testing is unavailable, qualitative testing may be used.

• If histological signs of placental damage characteristic of CMV infection or CMV antigens are detected during pathomorphological examination of the placenta, it is recommended to prescribe an examination for CMV infection in the newborn for the timely diagnosis and treatment of congenital CMV infection [94].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: if quantitative testing is unavailable, qualitative testing may be used.

• If the newborn has laboratory and/or instrumental signs characteristic of CMV infection, it is recommended to prescribe an examination for CMV infection for the timely diagnosis and treatment of congenital CMV infection [13,48,54,56,95–98].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: the range of possible laboratory and instrumental changes is presented in Tables 1 and 2. If quantitative testing is unavailable, qualitative testing may be used.

2.2 Physical Examination

• It is recommended to perform a clinical physical examination [39,48,52,54] in a newborn with suspected congenital CMV infection.

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: the main clinical signs characteristic of congenital CMV infection are presented in Table 1.

Microcephaly is most frequently observed in newborns with congenital CMV infection and serves as a prognostic sign of unfavorable long-term neurological outcomes; therefore, most experts agree on screening newborns who are small for gestational age in combination with microcephaly, rather than routinely screening newborns who are only small for gestational age [48]. According to a meta-analysis, microcephaly significantly correlates with adverse neurological outcomes [98].

• If clinical signs of a congenital infection are present, it is recommended to prescribe an examination for CMV infection in the newborn for the timely diagnosis and treatment of congenital CMV infection [48,52,54,96].

Level of Evidence AGrade of Evidence 3Level of Recommendations A (Grade of Evidence – 3)

Comments: the main clinical signs characteristic of congenital CMV infection are presented in Table 1.

2.3 Laboratory Diagnostics

• As the primary diagnostic method in newborn infants with suspected congenital CMV infection, it is recommended to use the detection of Cytomegalovirus DNA by PCR in peripheral and umbilical cord blood, detection of Cytomegalovirus DNA by PCR in saliva, detection of Cytomegalovirus DNA in oropharyngeal swabs by PCR, detection of Cytomegalovirus DNA in urine by PCR, with quantitative testing performed in the first 3 weeks of life for etiological verification of the viral infection [48,65,66,68]. If quantitative testing is unavailable, qualitative testing may be used.

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: diagnostics must be performed as early as possible. If the virus is isolated after 3 weeks of life, intrapartum or early postnatal infection can no longer be excluded. The most informative method for detecting CMV is testing saliva/oropharyngeal swab and urine, and to a lesser extent, blood. Saliva/oropharyngeal swab and/or urine contain a higher concentration of the virus than blood, making these tests highly sensitive as well as non-invasive [65,66,69,99]. When testing saliva in breastfed newborns, a false-positive result may be obtained due to the presence of breast milk in the sample; therefore, it is advisable to collect the saliva sample 90 minutes after feeding, and in the case of a positive result, a confirmatory quantitative PCR assay for Cytomegalovirus DNA in urine must be performed [27,48,49,66,99].

According to studies, viral load in the blood correlates with the severity of CMV infection and CNS involvement. To date, the clinical significance of various CMV DNA concentrations in a child's biological materials has not been precisely characterized. Further studies are required [100,101].

• If the PCR method is unavailable, as well as in questionable cases for examining newborn infants with suspected congenital CMV infection, it is recommended to use the detection of IgM antibodies to Cytomegalovirus in the blood for etiological verification of the viral infection [75–77].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: the test is performed using ELISA (or CLIA) with indication of sensitivity thresholds for the given test system (for IgG in IU/ml, for IgM in arbitrary units, as a positivity coefficient or optical density values of the test sample and positive control serum). Specific IgM in the first days of life indicate a primary infection, but possible false-negative and false-positive results must be taken into account. The first blood test for serological diagnostics in a newborn must be performed prior to the administration of immunoglobulins.

• Newborns with suspected congenital CMV infection are recommended to undergo a complete (clinical) blood count with a differential leukocyte count (leukocyte formula) to identify laboratory signs of CMV infection (anemia, thrombocytopenia, leukopenia, neutropenia) [46,96,102,103].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• When treating newborns with congenital CMV infection with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide groups, excluding reverse transcriptase inhibitors (ATX code J05AB), it is recommended to perform a complete blood count (CBC) with a differentiated leukocyte count (leukocyte formula) to monitor treatment efficacy and safety, including therapy with colony-stimulating factors (ATX code L03AA) [39,48,104–107].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: monitoring of the complete blood count (CBC) with a differentiated leukocyte count (leukocyte formula) is performed weekly for the first 6 weeks, then at week 8, and subsequently monthly throughout the course of antiviral therapy [39]. If necessary, blood tests may be monitored more frequently at the physician's discretion. During therapy with colony-stimulating factors (ATX code L03AA), the complete blood count (CBC) with a differentiated leukocyte count (leukocyte formula) is monitored daily during therapy until an absolute neutrophil count above 1000 cells/µL is achieved.

• In newborns with suspected congenital CMV infection, as well as when organ involvement due to congenital CMV infection is suspected (hepatitis, acute kidney injury), it is recommended to perform a general clinical blood biochemistry test (determination of alanine aminotransferase activity in the blood, determination of aspartate aminotransferase activity in the blood, measurement of free and conjugated bilirubin levels in the blood, measurement of creatinine levels in the blood, measurement of blood urea levels) to detect laboratory signs of CMV infection and the severity of organ damage [39,46,96,102,103,108].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: laboratory changes characteristic of CMV infection are presented in Tables 1 and 2. Relevant biochemical blood parameters are used to detect organ damage.

• When treating newborns with congenital CMV infection with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide groups, excluding reverse transcriptase inhibitors (ATX code J05AB), it is recommended to perform a general clinical blood biochemistry test (determination of alanine aminotransferase activity in the blood, determination of aspartate aminotransferase activity in the blood, measurement of free and conjugated bilirubin levels in the blood, measurement of creatinine levels in the blood, measurement of blood urea levels, measurement of blood sodium levels, measurement of blood potassium levels) to monitor treatment efficacy and safety for timely dose adjustment of the antiviral drug [39,48,104,105].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: parameters are monitored monthly during the course of therapy [39]. If necessary, blood tests may be monitored more frequently at the physician's discretion.

• In newborns with suspected congenital CMV infection, routine determination of cytomegalovirus (Cytomegalovirus) DNA in cerebrospinal fluid by PCR (quantitative assay to determine CNS involvement) is not recommended [48,52,74].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: several studies have demonstrated the absence of CMV DNA in the cerebrospinal fluid in cases of CNS involvement confirmed by neuroimaging, as well as in children who had no clinical or neuroimaging abnormalities and subsequently developed severe neurological disorders caused by congenital CMV infection [52,74].

• When treating newborns with congenital CMV infection with direct-acting antivirals (ATX code J05A), it is recommended to determine cytomegalovirus (Cytomegalovirus) DNA by PCR in peripheral and umbilical cord blood (quantitative assay) to monitor treatment efficacy [48,104,105].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: monitoring of viral load by quantitative PCR in the blood must be performed at the start of treatment and dynamically every 2–4 weeks throughout treatment [48,104,105]. The lack of a positive viral load trend during treatment may be a consequence of virus strain resistance to the therapy or the presence of primary or secondary immunodeficiency in the child.

• In a child with congenital CMV infection, it is recommended to perform a urinalysis to diagnose renal dysfunction [109–111].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: studies have demonstrated that children with congenital CMV infection exhibit proteinuria with tubulointerstitial renal damage [109].

2.4 Instrumental Diagnostics

• In a newborn with suspected or confirmed congenital CMV infection, as well as with antenatally detected ultrasound or MRI brain changes, it is recommended to perform neurosonography to detect CNS lesions [13,45,48,98].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In a newborn with suspected or confirmed congenital CMV infection, as well as with antenatally detected ultrasound or MRI brain changes, it is recommended to perform hearing screening using otoacoustic emissions to detect sensorineural hearing loss [45,48,51,58,60,112,113,161,162,163].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: in extremely premature infants, hearing screening using otoacoustic emissions is performed after they reach a postmenstrual age of 34 weeks.

• In a newborn with confirmed congenital CMV infection in the presence of neurological disorders and ultrasound brain abnormalities, it is recommended to perform brain magnetic resonance imaging to clarify the extent and nature of structural CNS lesions [45,48,114–117].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: this procedure is performed provided the specific medical organization has the capability to carry it out. Magnetic resonance imaging is a more sensitive method than computed tomography.

• In a newborn with confirmed congenital CMV infection, when organ involvement is suspected, it is recommended to perform a comprehensive abdominal ultrasound, ultrasound of the kidneys and adrenal glands, echocardiography, chest X-ray, and abdominal overview radiography, depending on which internal organs are involved in the infectious process [108,118–125].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3) for ultrasound of the kidneys and adrenal glands

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4) for abdominal ultrasound, echocardiography, chest X-ray, and plain abdominal radiography

• In a child with any form of congenital CMV infection, regardless of audiologic screening results, it is recommended to perform auditory brainstem response testing by 3 months of age to diagnose delayed hearing loss [126,127].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.5 Other Procedures

• In a newborn with confirmed congenital CMV infection, it is recommended to have an initial/follow-up ophthalmologist appointment (examination, consultation) to detect visual organ damage [48,56].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: to detect visual organ damage in extremely premature infants undergoing inpatient nursing care, follow-up ophthalmologist appointments (examinations, consultations) should be performed at least once every 2 weeks.

• In a newborn with confirmed congenital CMV infection, it is recommended to have an initial/follow-up neurologist appointment (examination, consultation) to detect neurological disorders [13,104,105].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: to detect neurological disorders in extremely premature infants undergoing inpatient nursing care, follow-up neurologist appointments (examinations, consultations) should be performed at least once every 2 weeks.

• In a child with congenital CMV infection receiving treatment with direct-acting antivirals (ATX code J05A), it is recommended to consult a clinical pharmacologist in the event of adverse reactions to determine further therapeutic strategy [128].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• In a child with congenital CMV infection receiving treatment with direct-acting antivirals (ATX code J05A) who develops severe neutropenia, it is recommended to have an initial/follow-up hematologist appointment (examination, consultation) to determine further management of neutropenia [129].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Etiotropic therapy

Treatment of congenital CMV infection is carried out with direct-acting antiviral drugs (ATX code J05A), which to date belong to the off-label group: #ganciclovir**, #valganciclovir**. The drugs have serious side effects and, furthermore, experimental studies have revealed their carcinogenic effect and toxic impact on the gonads [63,64,105]. Due to their high toxicity, these drugs are used for vital indications in severe or moderate-to-severe CMV infection after obtaining informed consent from the parents.

#Ganciclovir** inhibits CMV DNA polymerase and thereby its replication. #Ganciclovir** is used in the absence of enteral nutrition in the patient or in a life-threatening course of the disease. The drug can cause a myelotoxic effect with the development of severe neutropenia, thrombocytopenia, and possesses teratogenic, mutagenic, and carcinogenic activity. #Valganciclovir** (a prodrug of #ganciclovir**) is less toxic compared to #ganciclovir**. In Russia, the tablet form of #valganciclovir** is registered; the suspension form of the drug is not registered in Russia.

Treatment with direct-acting antivirals (ATX code J05A) leads to a decrease in viral load, but by the end of a six-week course of therapy, the virus may be detected in more than 50% of patients [64,130,131]. It should be borne in mind that after discontinuation of the antiviral drug, viral excretion and viremia may return to baseline levels [42,43]. Detection of an increase in the number of CMV copies during treatment with a direct-acting antiviral drug (ATX code J05A) will most likely indicate resistance of the virus to this drug [131], which is extremely rare.

Achieving negative PCR results in blood, saliva, and urine is not the direct goal of therapy in the acute period of the clinical form.

The decision to discontinue etiotropic therapy or prolong it is made based on the results of clinical, laboratory, and instrumental assessment of disease dynamics (by decision of a medical board). If a relapse of the disease is observed after discontinuation of etiotropic therapy, it is resumed.

There are publications where the authors present clinical cases and cohorts describing the combined use of an antiviral drug and human anti-cytomegalovirus immunoglobulin (ATX code J06BB09) in children with congenital CMV infection [132–141]. Experiments have shown a positive effect of human anti-cytomegalovirus immunoglobulin (ATX code J06BB09) in brain damage in newborn animals [142].

Human anti-cytomegalovirus immunoglobulin (ATX code J06BB09), 1 ml of which contains at least 100 IU of antibodies against cytomegalovirus, is prescribed simultaneously with direct-acting antivirals (ATX code J05A) by continuous intravenous administration at a dose of 1 ml/kg of body weight every 48 hours until clinical and laboratory improvement is achieved. Intravenous administration of human anti-cytomegalovirus immunoglobulin (ATX code J06BB09) is performed in strict accordance with the drug's instructions.

The possibility of using normal human immunoglobulins (ATX code J06BA) in the complex therapy of congenital CMV infection in newborns is due to the presence of antibodies to CMV in it (15-20 IU/ml), as well as antibodies of various classes to a number of other microorganisms, but their efficacy in active CMV infection is significantly lower than that of human anti-cytomegalovirus immunoglobulin (ATX code J06BB09).

• A patient with a severe and moderate form of congenital CMV infection is recommended therapy with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide group, excluding reverse transcriptase inhibitors (ATX code J05AB) (#valganciclovir**) at a single dose of 16 mg/kg 2 times a day orally for 6 months for the main etiotropic treatment and reduction of adverse long-term neurological outcomes, including sensorineural hearing loss. #Ganciclovir** (ATX code J05AB) is used in the absence of enteral nutrition or in a life-threatening course of the disease at a single dose of 6 mg/kg 2 times a day intravenously [39,49,104,105].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: antiviral therapy is initiated as soon as possible after diagnosis.

#Valganciclovir** is the drug of choice as a less toxic drug and, in the absence of intolerance to enteral nutrition, treatment is started with #valganciclovir**. The total duration of #ganciclovir** administration should not exceed 6 weeks if possible due to the high toxicity of the drug [143].

If severe neutropenia develops during treatment (less than 500 cells per 1 µl), the direct-acting antiviral drug (ATX code J05A) of the nucleoside and nucleotide group, excluding reverse transcriptase inhibitors (ATX code J05AB), is temporarily discontinued for several days, or the dose can be reduced by half, and if the neutrophil count does not normalize, the drug should be temporarily discontinued [105] or, if #ganciclovir** therapy is administered, switched to a less myelotoxic drug #valganciclovir**. #Ganciclovir** can also cause the development of thrombocytopenia. If thrombocytopenia persists during treatment with #ganciclovir** to a platelet level of less than 25.0·10⁹/L, the drug is temporarily discontinued [43,63,104,106].

• A newborn with a mild form of congenital CMV infection is routinely not recommended treatment with direct-acting antivirals (ATX code J05A) [39].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: treatment may be prescribed on an individual basis by decision of a medical board and with the consent of the parents. Drug dosages are presented in the thesis recommendation above.

• A newborn with congenital CMV infection with isolated hearing loss is recommended therapy with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide group, excluding reverse transcriptase inhibitors (ATX code J05AB) (#valganciclovir**) at a single dose of 16 mg/kg 2 times a day orally for 6 weeks to improve hearing function. Treatment should be started as early as possible [144,145].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: the published non-randomized comparative study "The Leiden CONCERT Study 2.0" (NCT02005822) demonstrated hearing improvement when antiviral therapy was initiated in the first 3 months. The duration of therapy was 6 weeks [144]. Published results of a double-blind, placebo-controlled, randomized study of therapy for isolated hearing loss lasting 6 weeks with late initiation of therapy from 1 month to 4 years (NCT01649869) (median time of therapy initiation was 18.7 months) showed no hearing improvement with late initiation of therapy [145]. The double-blind, placebo-controlled, randomized clinical trial of therapy for isolated hearing loss with #valganciclovir** lasting 6 months ValEAR (NCT03107871) was prematurely terminated due to difficulties in participant recruitment caused by the predominance of parental decisions to treat their children [146]. A retrospective study of therapy for isolated hearing loss demonstrates hearing improvement after 1 year of therapy with direct-acting antivirals (ATX code J05A) [147].

• A newborn with a subclinical form of congenital CMV infection is routinely not recommended treatment with direct-acting antivirals (ATX code J05A) [39].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: currently, there is no evidence-based data on the treatment of the subclinical form of congenital CMV infection. A non-randomized study on the prevention of sensorineural hearing loss in children with congenital subclinical CMV infection with #valganciclovir** therapy lasting 4 months (NCT03301415) was prematurely terminated due to a small number of recruited patients (7 people) [148]. The timing and possibility of resuming the study are unknown.

• A newborn with clinical forms of congenital CMV infection requiring treatment with direct-acting antivirals (ATX code J05A) is recommended the administration of human anti-cytomegalovirus immunoglobulin (ATX code J06BB09) in combination with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide group, excluding reverse transcriptase inhibitors (ATX code J05AB) (#ganciclovir**, #valganciclovir**) to develop a CMV-specific immune response and increase treatment efficacy [134,135,137–141,149,150].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: human anti-cytomegalovirus immunoglobulin (ATX code J06BB09) is prescribed at a dose of 1 ml/kg every 48 hours until clinical symptoms disappear. Literature cases describe courses of up to 6 administrations [138,140,150]. Doses and duration of treatment with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide group, excluding reverse transcriptase inhibitors (ATX code J05AB) (#ganciclovir**, #valganciclovir**), are indicated in the thesis recommendation for the treatment of severe and moderate forms.

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

Pathogenetic therapy

The scope and nature of pathogenetic therapy are determined by the leading syndromes.

Symptomatic therapy

Symptomatic therapy includes the administration of medications depending on the clinical manifestations of the infectious process (anti-hemorrhagic, hemostatic, anticonvulsant, sedative, cardiotonic, vasopressor, infusion therapy).

• For an infant with congenital CMV infection receiving direct-acting antiviral therapy (ATC code J05A) who develops severe neutropenia (less than 500 cells/µL) that is not resolved by temporary discontinuation of direct-acting antiviral drugs (ATC code J05A), it is recommended to prescribe colony-stimulating factors (ATC code L03AA) – filgrastim** to treat neutropenia at a dose of 5 µg/kg/day subcutaneously or intravenously. If ineffective, the dose may be increased to 10 µg/kg/day [48,104,106,107].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the therapy is prescribed after an appointment (examination, consultation) with a hematologist. During therapy with colony-stimulating factors (ATC code L03AA), daily monitoring of the absolute neutrophil count is performed (complete blood count with differential and leukocyte count). The target absolute neutrophil count is 1000 cells/µL or more. The most frequent applied regimen is 1-3 days. Neutrophil recovery is observed in most cases within 24-48 hours [151].

• For an infant with congenital CMV infection who develops thrombocytopenia, either before treatment or during therapy with direct-acting antiviral drugs (ATC code J05A), of less than 25,000 cells/µL in newborns and less than 20,000 cells/µL in children older than 1 month of life in the absence of bleeding, it is recommended to transfuse leukoreduced donor platelet concentrate (blood transfusion) in a volume of 10-15 ml/kg to prevent thrombocytopenic bleeding [152–155].

GCR ALeE 2Level of Evidence Compass A (Level of Evidence – 2) – for newborns

GCR CLeE 5Level of Evidence Compass C (Level of Evidence – 5) – for children older than 1 month and for the transfusion volume

Medical Nutrition Therapy

• For newborns with any form of congenital CMV infection, it is recommended not to discontinue breastfeeding in order to provide the body with essential nutrients (proteins, fats, carbohydrates, vitamins, and micronutrients) [156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Pain Management

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is carried out depending on organ damage under the direction of specialized experts (neurologist, otorhinolaryngologist-audiologist, ophthalmologist).

5. Prevention and Dispensary Observation

Prevention

Preventive measures to reduce the incidence in pregnant women and transplacental transmission of the virus are presented in the approved Clinical Guidelines «Cytomegalovirus infection (CMVI) in adults».

Dispensary follow-up (Active surveillance)

• For newborns with any form of congenital CMV infection, it is recommended to have a dispensary appointment (examination, consultation) with an otorhinolaryngologist-audiologist to monitor hearing function [39,48,60,95,113,157,158].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: a dispensary appointment (examination, consultation) with an otorhinolaryngologist-audiologist is carried out every 3 months during the first year of life, every 6 months up to three years of age, and annually up to 18 years [39,48,95,127,157,158].

• For newborns with any form of congenital CMV infection, it is recommended to have a dispensary appointment (examination, consultation) with an infectious disease specialist to monitor therapy, side effects of therapy, delayed organ damage, and complications [48,158].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: a dispensary appointment (examination, consultation) with an infectious disease specialist is carried out at least once every 2-3 months in the first year of life, then as clinically indicated [158].

• For newborns with any form of congenital CMV infection, it is recommended to have a dispensary appointment (examination, consultation) with an ophthalmologist to assess visual function and diagnose long-term consequences of congenital CMV infection [39,48,56,158,159].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: a dispensary appointment (examination, consultation) with an ophthalmologist is carried out:

– premature infants at risk for or with retinopathy of prematurity — at least once every 2 weeks until 6 months of life;

– full-term infants and late preterm infants without risk of retinopathy of prematurity – once a month until 6 months of life;

– after 6 months of life — once every 3 months up to 1 year, twice a year up to 3 years of life, then annually up to 18 years, or more frequently at the discretion of the ophthalmologist [39,48,56,158,159].

Long-term consequences of both clinical and subclinical forms of congenital CMV infection, such as strabismus, nystagmus, optic atrophy, cortical visual impairment, and chorioretinitis reactivation, can develop throughout childhood. A large cohort study showed that optic atrophy in children with congenital CMV infection was detected on average at 5.4 years of age, cortical visual impairment at 5.1 years, strabismus at 4.5 years in the clinical form of congenital CMV infection and 10.9 years in the subclinical form, nystagmus at 7.9 years, and chorioretinitis reactivation in the 1st–2nd year of life. Various visual impairments in the subclinical form were diagnosed up to 17.1 years of age [159].

• For newborns with any form of congenital CMV infection, it is recommended to have a dispensary appointment (examination, consultation) with a neurologist to assess neurological disorders and manage long-term consequences of congenital CMV infection [39,48,51,158,160].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: a dispensary appointment (examination, consultation) with a neurologist is carried out annually up to 7 years, or more frequently at the discretion of the neurologist [34,51,160]. Children with subclinical and mild forms of congenital CMV infection are subject to follow-up by a neurologist at 1, 3, 6, 9, and 12 months of age; children with moderate and severe forms of congenital CMV infection with symptoms of CNS damage are monitored by a neurologist every month up to 3 months of age, then once every 3 months up to 1.5 years, and then once every 6 months up to 7 years of age [158].

6. Organization of Medical Care

A newborn with suspected clinical congenital CMV infection should be transferred from the obstetric hospital to a specialized department (department of pathology of newborns and premature infants, neonatal intensive care unit of a children's hospital, perinatal center, etc.). Examination of the infant can be performed both in the obstetric setting and in specialized departments (depending on the capabilities of specific medical organizations). Newborns from mothers with primary CMV infection during pregnancy and/or antenatal signs of congenital CMV infection, but without characteristic clinical and laboratory manifestations of congenital CMV infection after birth, should, if possible, be referred to the second stage of nursing care for examination and exclusion of congenital CMV infection.

If the infant for any reason was not hospitalized from the maternity hospital to the second stage of nursing care, or if the newborn showed a negative hearing screening result using otoacoustic emissions, the discharge recommendations must indicate the need for infant examination and dynamic outpatient monitoring to rule out/confirm the subclinical form (including isolated hearing loss) of congenital CMV infection. In this case, verification (exclusion) of congenital CMV infection is carried out on an outpatient basis by pediatric polyclinic specialists (pediatrician, infectious disease specialist). If a clinical form of congenital CMV infection is detected on an outpatient basis, or if it is impossible to perform CMV DNA determination by PCR or due to insufficient informative value of dynamic serological studies, the newborn must be referred in accordance with regional routing to the specialized medical organization where comprehensive examination and treatment of a newborn with congenital infectious pathology will be provided.

Treatment of newborns with the clinical form of congenital CMV infection should be initiated in an inpatient setting (using both intravenous and oral formulations of direct-acting antiviral drugs (ATC code J05A)). Given the long course of antiviral therapy, after discharge from the hospital, outpatient treatment is continued with oral direct-acting antiviral drugs (ATC code J05A), provided the infant's condition is stable. Monitoring of treatment efficacy and safety is carried out both in the inpatient setting and during outpatient follow-up.

Indications for discharging a patient from a medical organization:

1) Stable, satisfactory condition of the infant;

2) Stabilization of laboratory parameters;

3) Absence of contraindications to discharge.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ekaterina N. Balashova - PhD in Medicine, Associate Professor, Leading Research Fellow at the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics; Associate Professor at the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

2. Natalia P. Vainshtein - PhD in Medicine, Head of Infectious Diseases Department No. 1 for Newborns, City Children's Hospital No. 9 named after G.N. Speransky; Associate Professor at the Department of Hospital Pediatrics, N.I. Pirogov Russian National Research Medical University.

3. Valery V. Vasilyev - Doctor of Medical Sciences, Professor at the Department of Infectious Diseases, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health; Head of the Department of Congenital Infectious Diseases, Leading Research Fellow at the Federal Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency; Professor.

4. Nikolay N. Volodin - Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, President of the Russian Association of Perinatal Medicine Specialists (RAPSM); Head of the Department of Pediatrics, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Health of Russia.

5. Dmitry N. Degtyarev - Doctor of Medical Sciences, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Head of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

6. Marina V. Degtyareva - Doctor of Medical Sciences, Professor, Head of the Department of Neonatology, Faculty of Continuous Postgraduate Education, N.I. Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

7. Viktor V. Zubkov - Doctor of Medical Sciences, Director of the Institute of Neonatology and Pediatrics, Head of the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

8. Anna A. Ivanova - Clinical Pharmacologist, St. Petersburg City Children's Hospital No. 17 of St. Nicholas the Wonderworker.

9. Irina V. Ignatko - Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Professor at the Department of Obstetrics, Gynecology and Perinatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

10. Oleg V. Ionov - Doctor of Medical Sciences, Associate Professor, Head of the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University); President of the Russian Society of Neonatologists.

11. Anna L. Karpova - PhD in Medicine, Anesthesiologist-Resuscitologist, Neonatologist, Moscow Doctor; Head of the Neonatal Inpatient Unit, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow City Health Department; Associate Professor at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia; Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Institute of Professional Development, Yaroslavl State Medical University of the Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

12. Elena S. Keshishyan - Doctor of Medical Sciences, Professor at the Department of Innovative Pediatrics and Pediatric Surgery, Head of the Early Childhood Development Correction Center; Head of the Research Department of Neonatology and Pathology of Early Age Children, Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

13. Anna R. Kirtbaya - Doctor of Medical Sciences, Associate Professor, Head of Clinical Work at the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University); Member of the Council of the Russian Society of Neonatologists.

14. Yuri V. Lobzin - Doctor of Medical Sciences, Professor, Director of the Research Institute of Children's Infections of the Federal Medical-Biological Agency, Academician of the Russian Academy of Sciences.

15. Lyudmila V. Malyutina - PhD in Medicine, Chief Freelance Neonatologist of the Ministry of Health of the Moscow Region, Deputy Chief Physician for Pediatrics, Shchelkovo Perinatal Center; Associate Professor at the Department of Neonatology, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky; Member of the Council of the Russian Society of Neonatologists.

16. Dmitry Y. Ovsyannikov - Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, Patrice Lumumba Peoples' Friendship University of Russia.

17. Lyudmila L. Pankratyeva - Doctor of Medical Sciences, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Health of Russia, Head of Department.

18. Marina S. Savenkova - Doctor of Medical Sciences, Professor at the Department of Clinical and Functional Diagnostics, Pirogov Russian National Research Medical University.

19. Olga A. Senkevich - Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics, Neonatology and Perinatology with a Course of Emergency Medicine, Institute of Continuing Professional Education and Accreditation, Far Eastern State Medical University of the Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists.

20. Nikolay P. Shabalov - Doctor of Medical Sciences, Professor, Head of the Department of Children's Diseases, S.M. Kirov Military Medical Academy.

21. Vasily I. Shakhgildyan - PhD in Medicine, Senior Research Fellow, Central Research Institute of Epidemiology of Rospotrebnadzor; Infectious Disease Physician at MD-GROUP Hospital (Perinatal Center) and Lapino Clinical Hospital, Mother and Child Group of Companies.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, e-library, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and The European Society for Neonatology. The search depth was 34 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Scales for assessing levels of evidence (LE) (Tables 1, 2) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GR) (Table 3) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions).

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not evaluated.

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

Recent changes to these guidelines are presented for discussion in a preliminary version. An updated version for wide discussion has been posted on the website of ·            Association of Specialists in Perinatal Medicine, Healthcare for Pregnant Women, Fetuses, Newborns and Children under 3 Years of Age (ASPM+) http://www.aspm.pro/ , Russian Society of Neonatologists (RSN) www.neonatology.pro, public discussion portal of the Russian Ministry of Health https://portalcr.minzdrav.gov.ru/ so that all interested parties can take part in the discussion and improvement of the guidelines.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. neonatologists:

2. anesthesiologists-intensivists;

3. pediatricians;

4. infectious disease specialists;

5. obstetricians-gynecologists;

6. neurologists;

7. ophthalmologists;

8. pediatric otorhinolaryngologists-audiologists;

9. general practitioners (family medicine);

10. medical school students;

11. residents and interns.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision—at least once every three years or upon the emergence of new information on patient management tactics for a given disease, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The proposals formed must take into account the results of a comprehensive evaluation of drugs and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

2. Order of the Russian Ministry of Health dated April 14, 2025, No. 203n "On approval of criteria for assessing the quality of medical care."

3. Order of the Ministry of Health of Russia No. 222n dated April 17, 2025, "On Approval of the Procedure for Providing Medical Care in the Profile 'Neonatology'."

4. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization), 2019 version.

5. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

6. Decree of the Government of the Russian Federation No. 3867-r dated December 18, 2025 "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicines for Medical Use and the Minimum Assortment of Medicines Required for Medical Care".

7. Methodological Letter of the Ministry of Health of Russia dated March 4, 2020, No. 15-4/I/2-2570 "Resuscitation and Stabilization of Newborn Infants in the Delivery Room." Edited by E.N. Baibarina. Moscow: Ministry of Health of the Russian Federation; 2020.

8. State Register of Medicines: https://grls.rosminzdrav.ru

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Cytomegalovirus infection: What pregnant women need to know.

Cytomegalovirus infection during pregnancy, the consequences of which can be irreversible, is a serious disease caused by cytomegalovirus (CMV). Medical data show that 65–70% of people harbor this virus in their bodies. Women are more susceptible to this disease. For this reason, cytomegalovirus infection during pregnancy is a fairly common occurrence.

The virus is transmitted through close contact with an infected person, sexual intercourse, or disregard for personal hygiene (sharing towels, toothbrushes, utensils, etc.). An infected child poses a high risk of transmission. Children infected with CMV can shed the virus for up to 5 years. Therefore, if even one family member becomes ill, all family members are likely to become infected.

The virus multiplies in all body tissues and can be found in all biological fluids of an infected person: saliva, urine, semen, breast milk, blood, etc. Therefore, the risk of infection is very high during sexual contact, blood transfusion, organ and tissue transplantation, childbirth, or breastfeeding.

The causative agent is cytomegalovirus, which belongs to the herpesvirus group. In addition, this group includes herpes simplex virus, shingles or chickenpox virus, and Epstein-Barr virus. This virus can penetrate the tissues of the nervous system, posing a risk of nerve cell damage upon infection.

Symptoms of cytomegalovirus infection may be absent, but 10% of people experience the following symptoms: nausea, fever, headache, fatigue, muscle pain, mild cough, sore throat, swollen lymph nodes, and skin rashes.

During pregnancy, immunity decreases, and a woman may be susceptible to infection or reactivation of an existing cytomegalovirus infection. The disease can be either asymptomatic or present with ARVI-like symptoms: mild catarrhal signs, fever, lymphadenopathy, and a dry cough. The greatest danger of cytomegalovirus infection during pregnancy is the infection of the fetus or newborn.

Approximately 45–50% of children are infected vertically during primary maternal infection. A child may be born without any signs of the disease, with minimal manifestations (such as changes in the complete blood count), or with severe symptoms of congenital CMV infection, such as hepatosplenomegaly, jaundice, hemorrhagic skin rash, bleeding of various localizations, seizures, and respiratory failure. Blood tests may show changes characteristic of hepatic or renal failure, along with thrombocytopenia and leukopenia. Cytomegalovirus can affect various organs (lungs, liver, kidneys, intestines, eyes, brain), causing pneumonia, hepatitis, nephritis, enteritis, chorioretinitis, and meningoencephalitis, respectively. One of the severe consequences of congenital cytomegalovirus infection is sensorineural hearing loss resulting from the virus's impact on the central nervous system, which requires long-term treatment and follow-up by an audiologist-otorhinolaryngologist.

To reduce the risk of infection during pregnancy, personal hygiene measures should be followed. Avoid any contact with biological secretions (urine, saliva, etc.), as the virus in biological fluids can remain active outside the human body for several hours. If primary infection occurs in the first trimester of pregnancy, the risk of fetal infection is very high; at this time, miscarriage may occur, or the child may develop various disorders. In this case, a perinatal council is held, which may recommend termination of pregnancy. In the second trimester, if maternal infection has occurred, additional examinations are necessary, including a fetal ultrasound and amniotic fluid testing. If the child is infected, there is no probability of them being born healthy. Primary infection in the third trimester does not cause severe fetal damage, but closer monitoring should be performed and efforts made to boost the immune system. The pregnancy may proceed without any complaints.

Treatment of CMV infection during pregnancy is difficult because all direct-acting antiviral drugs (ATC code J05A) have contraindications. The pregnant woman should be managed by an obstetrician-gynecologist, allergist-immunologist, infectious disease specialist, and general practitioner.

To prevent CMV transmission to the fetus, the physician may prescribe immunoglobulin preparations.

In the event of primary infection during pregnancy or reactivation of cytomegalovirus infection, treatment must be approached with utmost responsibility. Therapy should be administered in accordance with the gestational age. After 20 weeks of gestation, the obstetrician-gynecologist, in cooperation with an infectious disease specialist and a general practitioner, may decide to prescribe a direct-acting antiviral drug (ATC code J05A).

Treatment initiated in a timely manner and conducted under the supervision of the attending physician yields favorable results: the probability of the child being infected is minimized. If the child has indeed contracted CMV, the next pregnancy should be planned only after three years.

Preventive measures to prevent congenital CMV infection are quite challenging, given that the virus can lurk everywhere. The only advice that can be given to women planning a pregnancy is to avoid promiscuous sexual contact and observe personal hygiene; then the probability of infection will be minimal.

There is another method that can protect a pregnant woman: a vaccine, which is currently still in the clinical trial phase.

There are risk groups of pregnant women who need to undergo primary screening for CMV infection. These include:

- pregnant women under the age of 25;

- pregnant women who have suffered (especially in the first half of pregnancy) an ARVI-like illness with minor catarrhal manifestations, combined with lymphadenopathy, hepatosplenomegaly, and the presence of atypical lymphocytes in the blood;

- pregnant women working in organized childcare groups (nurseries, kindergartens, schools, etc.), as well as pregnant women whose children attend such groups;

- pregnant women whose fetal ultrasound reveals signs of fetal CMV infection, polyhydramnios, or placental enlargement.

Here are a few tips for women who are in regular contact with children:

1. Wash hands thoroughly with soap and warm water after the following activities:

    changing diapers,

    feeding or bathing young children,

    caring for a toddler with a runny nose or wiping saliva,

    handling children's toys,

   since children are considered active carriers of CMV, and the probability of infection from them is very high.

2. Avoid contact with the saliva of a child under 5 years old when kissing them.

3. Ensure you and the children have separate tableware and cutlery.

4. Do not consume food and drinks intended for children. Do not finish children's leftovers or use their utensils!

5. Do not lick a child's pacifier.

6. Do not use a toothbrush previously used for a child's oral care.

7. Thoroughly clean toys, tabletops, and other objects that may be contaminated with a child's saliva or urine.

8. Female workers in childcare facilities, nurseries, and kindergartens are advised to take leave during pregnancy or limit contact with children.

9. Harden your body, visit the swimming pool, and spend enough time in the fresh air (try to strengthen your immune system, especially before pregnancy).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.