Congenital herpes simplex virus [herpes simplex] infection: clinical guidelines

List of Abbreviations

IgG – class G immunoglobulins

IgM – class M immunoglobulins

SEM disease – an acronym based on the initial letters of words denoting areas affected by the herpes simplex virus: Skin, Eye, Mouth (SEM)

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATC – Anatomical Therapeutic Chemical classification system

HSV – herpes simplex virus

HSV-1 – herpes simplex virus type 1

HSV-2 – herpes simplex virus type 2

HSV infection – infection caused by herpes simplex viruses

GA – gestational age

DIC syndrome – disseminated intravascular coagulation

DNA – deoxyribonucleic acid

EIA – enzyme immunoassay

CT – computed tomography

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

HC – healthcare organization

MRI – magnetic resonance imaging

NSG – neurosonography

PCR – polymerase chain reaction

RCTs – Randomized Controlled Trials

CSF – cerebrospinal fluid

US – ultrasound examination

CLIA – chemiluminescence immunoassay

CNS – central nervous system

EEG – electroencephalography

Terms and Definitions

Congenital infection caused by herpes simplex virus [herpes simplex] – an infectious disease of the fetus (rarely) and the newborn, developing as a result of antenatal (transplacental) or intranatal contact transmission of herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2).

SEM disease – an acronym based on the initial letters of words denoting areas affected by the herpes simplex virus: Skin, Eye, Mouth (SEM).

Infections caused by herpes simplex virus [herpes simplex] – infectious diseases caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) belonging to the family Herpesviridae, subfamily Alphaherpesviridae, with a predominantly latent course or lesions of the skin and mucous membranes. Diseases caused by HSV-1 and HSV-2 can occur at any age, including the neonatal period.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital infection caused by herpes simplex virus [herpes simplex] – an infectious disease of the fetus (rarely) and the newborn, developing as a result of antenatal (transplacental) or intranatal contact transmission of herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) [1–3]. May manifest within 6 weeks after birth [4–6]. Congenital HSV infection can be a cause of congenital malformations (ventriculomegaly, microcephaly, intracerebral calcifications, limb dysplasia [7], eye defects [8]), antenatal and intranatal fetal death [9,10], severe generalized neonatal disease with a high risk of mortality, as well as irreversible disabling damage to the central nervous system [2,3,11–14]. Involvement of the skin, mucous membranes, and eyes in congenital HSV infection is referred to in the literature by the collective term SEM disease, which is an acronym formed from the first letters of the words denoting the areas affected by the herpes simplex virus: Skin, Eye, Mouth (SEM).

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

Herpes simplex viruses (HSVs) are ubiquitous, host-adapted pathogens capable of causing a wide range of diseases. Humans are the sole natural reservoir of the virus, and no vectors other than humans are involved in transmission of the infection. The causative agent of the infection belongs to the virus family Herpesviridae. HSV belongs to the group of alphaherpesviruses. It is an enveloped virus with a diameter of about 160 nm, whose genome is represented by linear, double-stranded DNA [15].

There are two types of herpes simplex viruses (HSVs) – herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Both variants of the virus are closely related to each other, yet differ in epidemiological features [16]. HSV-1 has a tropism for the oral mucosal epithelium, whereas HSV-2 has a tropism for the genital epithelium; therefore, HSV-1 is traditionally associated with diseases of the facial skin and oral mucosa, while HSV-2 is traditionally combined with genital diseases. Nevertheless, the localization of disease manifestations does not always necessarily indicate the virus type, as in some unique subpopulations HSV-1 is more strongly associated with the development of genital infections compared to HSV-2.

HSV-1 and HSV-2 are characterized by unique biological features [15]: neurovirulence (the ability of the virus to penetrate and replicate in nervous system cells); latency (establishment and maintenance of a latent infection in nerve ganglia proximal to the site of infection development) and reactivation. Reactivation and replication of latent or "dormant" HSV always occurs in the area innervated by the ganglia where the virus resides in its latent state, and can be induced by various triggering factors (in particular, fever, trauma, emotional stress, excessive sun exposure, menstrual bleeding). This leads to clinically apparent or concealed recurrent infection and the release of HSV. The latent form of the infection maintains the endemicity of the virus in most human communities, along with periodic viral activation and asymptomatic shedding [17]. In the latent state, the virus is insensitive to antiviral drugs, as a result of which the infection (including after a course of antiviral treatment) persists in the host organism throughout life. Reactivation occurs more frequently and runs a more severe course in immunocompromised individuals [18].

Transmission of the virus from person to person occurs as a result of close personal contact, and the infection develops as a result of viral inoculation onto the surface of a mucosa capable of receiving HSV (in particular, the oropharynx, cervix, conjunctiva), or through minor skin cracks. The virus is rapidly inactivated at room temperature and upon drying. Accordingly, airborne droplet and contact-household transmission routes of herpes are rare. Infection of women with HSV via sexual contact is more typical for HSV-2 than for HSV-1 [19].

The majority of genital herpes infections are transmitted from individuals who are completely unaware that they are infected, or whose infection is asymptomatic at the time of transmission [20]. A prior history of HSV-1 infection triples the likelihood of an asymptomatic course of HSV-2 infection [22].

The risk of HSV transmission to the fetus varies significantly depending on the type of maternal infection – primary or secondary (recurrent). Primary infection is defined as the first registered occurrence of characteristic lesions in a pregnant woman who previously had no detectable antibodies to herpes simplex virus (HSV), while recurrent infection is an exacerbation of a previously experienced HSV infection. The highest risk of infection and vertical transmission is observed in the case of primary genital herpes infection in the third trimester of pregnancy. The risk of transmitting the herpes simplex virus to the newborn from a mother with no history of prior herpetic infection, but with active (fresh) infectious lesions at the time of delivery, ranges from 25% to 60% [5,23,24]. In recurrent herpetic infection, the risk of HSV transmission is significantly lower and does not exceed 2% [1].

Risk factors for HSV transmission include: female sex of the newborn, low socioeconomic status of the family, belonging to small ethnic groups, a history of other sexually transmitted infections, a high number of sexual partners [25], maternal age under 21 years [12–14]. Factors promoting vertical HSV transmission: vaginal delivery (compared to cesarean section); application of fetal scalp electrodes during labor or the use of other instrumental interventions leading to disruption of skin integrity in fetuses/neonates; presence in the mother of an infection (especially primary) caused by HSV-1 (compared to HSV-2); detection of HSV-1 or HSV-2 in cervical mucus (determination of herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in cervical canal discharge) or in the area of external genitalia at the time of delivery (determination of herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in vesicular fluid, scrapings from lesions by PCR, determination of herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in vaginal discharge by PCR); prolonged rupture of membranes [12,26,27]. Maternal fever is also a risk factor for the development of HSV infection in the newborn [28–33].

More than 75% of newborns with herpetogenic infection are born to mothers with no history of genital herpes infection, and limited maternal history data impacts the differential diagnosis during clinical assessment of the neonate [1, 28]. Therefore, empirical treatment should never be withheld in the presence of characteristic clinical symptoms of congenital HSV infection in a newborn solely based on the absence of a history of herpetic infection in the mother [34]. Unfortunately, up to 80% of mothers who transmit HSV to the fetus do not report a history of prior genital herpes [3]. It is important to note that transmission can occur not only with genital herpes, but also with other localizations of maternal HSV infection during pregnancy, such as gingivostomatitis [35, 36], which necessitates a more thorough history-taking with an emphasis on human diseases caused by HSV (Table 1).

Table 1. Diseases caused by herpes simplex virus [37].

^a – Including HSV-infected burn wounds, eczema herpeticum, etc.

^b – Skin lesions above the waist – 1 > 2; below the waist – 2 > 1; hand lesions – both virus types 1 and 2.

^c – Often a fatal disease.

^d – HSV-2 in newborns.

HSV can be transmitted to the fetus via various routes: intrauterine transmission of HSV resulting from transplacental or transcervical (via the amniotic-chorial membrane) transfer (5%) with a frequency ranging from 1 in 100,000 to 1 in 300,000 births [1], or during delivery through infected birth canals via direct contact with maternal vaginal secretions (85%) [38]. Intrauterine (prenatal) transmission of HSV can lead to miscarriages, damage to the central nervous system (CNS) of the fetus (ventriculomegaly, microcephaly, hydranencephaly, agenesis of the corpus callosum, intracranial calcifications), premature birth, intrauterine growth restriction, intrauterine fetal demise [43–52], and non-immune fetal hydrops [53].

The aforementioned outcomes of congenital HSV infection of the fetus occur predominantly in cases of primary maternal HSV infection during pregnancy, but may also be observed during a recurrence of HSV infection during this period [54]. Intrauterine infection must be considered in cases of HSV infection developing in the neonatal period, despite delivery by caesarean section prior to the onset of labor and with intact fetal membranes [25,55,56], including even in the absence of maternal evidence of acute HSV infection during labor [57].

If a seronegative woman is infected with HSV during pregnancy, then regardless of the entry portal of the infection, the consequence of active viral replication in the affected cells is the development of transient viremia, the duration of which depends on the rate of acquired immunity development. The presence of HSV viremia leads to infection of the placenta, its damage, and transmission of the virus to the fetus. The presence of HSV-2 in the placenta of women is possible even in the absence of characteristic symptoms of HSV infection [71]. The mechanisms responsible for fetal HSV infection have not been fully elucidated, although it has been established that resistance to HSV is provided by the syncytiotrophoblast. Contamination of the syncytiotrophoblast with HSV is accompanied by the expression of viral "entry mediators", resulting in inflammation that leads to the destruction of the syncytiotrophoblast. This allows HSV to penetrate the fetal bloodstream [7,72]. HSV can be detected in dorsal root ganglia after primary infection [73]. Transneural migration of HSV to the endometrium can lead to transmission of the virus via the uterus during pregnancy [73]. Infection of endothelial cells in maternal microvessels can also cause HSV infection [7,72]. The penetration of HSV into the placenta leads to herpetic placentitis (villitis, intervillositis, necrosis combined with the presence of viral inclusion bodies and the potential appearance of plasma cells) [53], followed by the formation of placental calcifications [51]. The development of herpetic placentitis leads to hematogenous transplacental HSV infection of the fetus. An indirect indicator of placental HSV infection in pregnant women with asymptomatic HSV infection can be considered the detection of a higher titer of IgG class antibodies to HSV-2 in the umbilical cord blood serum compared to the titer of IgG class antibodies in the maternal blood [74].

1.3 Epidemiology of the Disease or Condition

The global prevalence of herpetic infections caused by HSV-1 and HSV-2 has increased over the past few decades, making herpetic infection a significant public health problem [16]. According to WHO estimates, 3.7 billion people under the age of 50 (67%) worldwide are infected with herpes simplex virus type 1 (HSV-1), and 491 million people aged 15–49 (13%) are infected with herpes simplex virus type 2 (HSV-2) [75].

Among individuals aged 14 to 49 in the USA, the prevalence of HSV-1 is 47.8%, and HSV-2 is 11.9% [76,77]; both prevalences increase with age and are higher in women than in men [78].

In the Russian Federation, the incidence of anogenital herpetic viral infection in 2021 was 8.7 cases per 100,000 population [79].

The frequency of neonatal HSV infection varies and, according to WHO data, is rare globally, with an estimated global incidence of 10 newborns per 100,000 births [75], while according to various authors it ranges from 3 to 30 per 100,000 live births [14,80–85]. These significant differences are apparently related to variations in the prevalence of genital herpes in different regions of the world. In the United States of America (USA), the annual incidence of neonatal herpetic infection, according to Flagg E.W. et al. (2011) and Donda K. et al. (2019), is approximately 8 to 10 cases per 100,000 live births [14,84]. In economically developed countries, the incidence of neonatal HSV infection varies from 1.6 to 33 observations per 100,000 live births [12–14,80,86]. Globally, the number of cases of neonatal herpetic infection is estimated at 14,000 cases per year [64].

The highest risk of developing congenital HSV infection has been established in newborns born to mothers with primary genital herpetic infection (i.e., HSV-seronegative): 54 per 100,000 live births compared to 26 per 100,000 live births in HSV-1 seropositive mothers, and 22 per 100,000 live births if the mother was HSV-2 seropositive [87].

The prevalence of congenital HSV infection in newborns has increased since the early 2000s [84]. One of the reasons for this growth is that the prevalence of genital herpetic infection in the general population has increased. In particular, the frequency of genital HSV-1 infection has increased somewhat among adolescents and young adults, and thus the prevalence of neonatal herpetic infection caused by HSV-1 may have increased [64]. As a result, a larger relative proportion of neonatal herpetic infections is currently caused by HSV-1, and to a lesser extent by HSV-2 [64,89]. Despite the seemingly low prevalence, neonatal herpetic infection accounts for 0.2% of total hospital admissions and 0.6% of in-hospital mortality cases in the USA [23,93–95].

The estimated incidence of neonatal herpes in Russia for 2009 ranged from 1 in 3,000 to 1 in 30,000 births [96].

1.4 Features of Coding the Disease or Condition

P35.2 – Congenital viral disease caused by herpes simplex virus [Herpes simplex]

1.5 Classification of the disease or condition

Congenital HSV infection [1,4,97]:

1. Route of transmission:

– antenatal;

– intranatal.

2. Clinical forms:

– localized congenital HSV infection (indicating leading manifestations);

– isolated CNS involvement (cerebral form);

– disseminated form of the disease.

3. Complications

1.6 Clinical presentation of the disease or condition

Extreme vigilance is required regarding HSV infection in a newborn. The clinical picture of neonatal herpes is diverse and does not always present with specific manifestations (e.g., fever, poor appetite, lethargy, irritability, and tachypnea), which can mimic other neonatal conditions and complicate diagnosis [90,98,99]. Asymptomatic courses of congenital HSV infection are extremely rare.

In cases of antenatal (transplacental) infection, various clinical manifestations and symptoms may be identified in infants at birth, as presented in Table 2.

Table 2. Potential clinical manifestations and symptoms in infants with congenital HSV infection acquired antenatally [3,51,52].

The average age of HSV manifestation in intranatally acquired infection ranges from 1.5 to 3 weeks [4]. The highest incidence of neonatal HSV infection is observed in the second week of life and significantly decreases in the second month of life [90]. The following clinical forms of congenital HSV infection are distinguished [4,13,90,100,101]:

– localized congenital HSV infection (SEM disease): isolated involvement of the skin, eyes, and/or oral mucosa (approximately 45% of all neonatal herpes cases);

– isolated CNS involvement or cerebral form of HSV infection (herpetic meningoencephalitis), accounting for approximately 30% of all neonatal HSV cases;

– disseminated form of the disease, manifesting with multiple herpetic rashes of various localization and signs of systemic inflammatory response characteristic of sepsis (25%).

Localized congenital HSV infection (SEM disease) involving the skin, eyes, and oral mucosa manifests several days after birth (typically on days 5–11 of life) [4]. In newborns with the localized form, cutaneous herpetic lesions alone occur in 80% of cases, while involvement of the eyes and/or oral mucosa is observed in 20% of newborns [101,102]. Classic cutaneous manifestations of herpes infection typically begin as areas of erythema that rapidly progress to isolated or multiple confluent, predominantly small vesicles filled with yellowish fluid, located on a hyperemic base. The vesicles become pustular within 24–48 hours and crust over or ulcerate (forming small pustules, crusts, or erosions) [2]. Skin lesions can be located virtually anywhere on the body. However, the distribution of vesicles also depends on fetal presentation and is more frequent on skin areas that were closest to and had the longest contact with the cervical region through which the infection was transmitted. Scalp, facial, and corneal involvement occur more frequently in cephalic presentation, while genital involvement is more common in breech presentation [103]. Skin lesions are also more frequent near areas of structural disruption, sometimes resembling disseminated lesions of herpes zoster. Cutaneous herpetic involvement can be considered a specific sign for all clinical variants of neonatal herpes infection. Nevertheless, it should be borne in mind that characteristic herpetic skin manifestations may be absent at the onset of the disease [99,101,104–106].

The localized form of congenital HSV infection of the skin, eyes, or oral mucosa (SEM disease) is characterized by the most favorable morbidity and mortality outcomes [100,101].

Involvement of the oral and laryngeal mucosa may be accompanied by gingivostomatitis and supraglottitis [107], is extremely rare, and manifests as vesicular lesions and small ulcerations (erosions) on the tongue, lips, lip mucosa, gums, soft and hard palate, and larynx [107]. Feeding difficulties may arise due to pain during sucking and swallowing.

In neonatal ocular herpes simplex virus infection, keratoconjunctivitis [108], unilateral keratitis [34], bilateral chorioretinitis [109], panuveitis [110], and vasculitis with peripheral exudative retinopathy [109] may develop. Keratoconjunctivitis can be unilateral [34]; follicular conjunctivitis may develop with concurrent localized enlargement of regional lymph nodes, vesicular eyelid rashes, marked eye irritation, pain, photophobia, edema, and corneal opacity [108]. Bilateral acute retinal necrosis has been described in two neonates with ocular HSV-2 infection [111], as well as in a 17-day-old infant with CNS HSV-1 infection [68].

The cerebral form of congenital HSV infection (herpetic meningoencephalitis) manifests relatively late (between day 10 and weeks 4–6 of life), typically presenting between days 8 and 17 of life [112], most often on days 16–19 [4]. It may occur in isolation or as part of a disseminated infection [91]. It manifests with both non-specific CNS symptoms such as decreased or inadequate enteral feeding, hyperexcitability or lethargy, and thermal instability, which can mimic a bacterial infection in the newborn [99,101], and symptoms quite typical of HSV-induced meningoencephalitis: fever, bulging anterior fontanelle, apnea [28,109,113], seizures [4,77,90,100,101], and subsequently lethargy, stupor, or coma. Hyperthermia is more characteristic of full-term infants, whereas premature infants more often have normal temperature or develop hypothermia. Seizures occur in 60–80% of newborns and are most frequently generalized. In severe cases (with delayed or ineffective treatment), signs of decortication or decerebration are recorded as early as day 10 of the illness.

Only 30% of congenital HSV infections in newborns are characterized by CNS involvement combined with cutaneous manifestations or as an isolated finding [100,101,114], and in approximately 60% of herpetic meningoencephalitis cases, clinical manifestations of HSV infection on the skin, eyes, and mucous membranes are absent [115]. Typical cerebrospinal fluid (CSF) changes include mononuclear pleocytosis [28,109,116–118], elevated protein levels, and a moderately decreased glucose concentration [28,114]. Peripheral blood may show leukocytosis with a left shift.

Neurosonography (NSG) findings in the first days of disease onset are non-specific and may include increased echogenicity of the gray and white matter, basal ganglia, and thalamus, as well as thickening of the choroid plexuses of the lateral ventricles and sulci. As the disease progresses, foci of decreased density (necrosis) are identified and dynamically increase—most commonly in the cortical or subcortical areas of the frontal, temporal, and less frequently parietal and occipital lobes—along with cystic changes in the white matter of both cerebral hemispheres and encephalomalacia, detected also by brain magnetic resonance imaging (MRI) and computed tomography (CT) [109].

Changes detected by brain MRI and CT in the first days of symptom onset are likewise non-specific. Initial brain CT and MRI may demonstrate diffuse cerebral edema, diffusely abnormally low density of the white matter and basal ganglia, and ischemic changes. As the disease progresses, CT and MRI typically show a sharp increase in the density of cerebral gray matter [119], severe bilateral cystic and megacystic encephalomalacia with necrosis, gliosis, and cortical atrophy, dural venous sinus thrombosis, punctate to extensive calcifications [43,109,114,120], and hemorrhagic brain lesions of various localization (subdural and parenchymal hemorrhages) [109,113,121]. Neonatal encephalitis may be multifocal or restricted solely to the frontal or temporal lobes, brainstem, or cerebellum [122]. Atrophic changes appear rapidly, becoming evident by the 3rd week [120].

Disseminated neonatal herpes typically manifests on the 10th–12th day of life [13], but may also develop in the third or fourth week of life. The clinical presentation may resemble bacterial sepsis with the development of multiorgan failure: shock [56], fever or hypothermia, body temperature instability [90], jaundice, hepatosplenomegaly, ecchymoses and petechiae [121], disseminated intravascular coagulation (DIC), cardiovascular failure (due to myocarditis) and respiratory failure (pneumonia), acute CNS involvement (meningoencephalitis), adrenal [123] and hepatic involvement (hepatitis, acute liver failure) [31,56,106,123–126]. Herpes simplex virus (HSV)-induced neonatal hepatitis accounts for only 1% of all cases of acute liver failure in newborns, yet it has an extremely aggressive and fulminant clinical course with a mortality rate of 85% [127]. Liver involvement is characterized by elevated blood alanine aminotransferase (ALT) activity (> 1.5 times the upper limit of normal [128]), elevated direct bilirubin levels, and ascites [4]. In approximately 2/3 of cases of disseminated (generalized) herpetic infection in newborns, the CNS is involved in the infectious process [100]. In 40% of cases, characteristic signs of herpetic skin lesions are absent at disease onset [13]. The disease may be accompanied by a significant increase in blood C-reactive protein levels, hypercytokinemia, hypofibrinogenemia (< 150 mg/dL), and elevated serum ferritin levels (> 500 mcg/L) [66,129].

Complications.

CNS involvement by herpes simplex virus in newborns is a rare but important cause of neurological disability [130], and the risk of adverse outcomes is highest in the cerebral and disseminated forms of neonatal herpes. However, even in localized congenital HSV infection (lesions of the skin, eyes, oral mucosa, and larynx), dissemination (generalization) of the infectious process with CNS involvement (meningoencephalitis) [107,114] and the development of long-term neurological complications [130,131] are possible, especially in cases of inadequate disease management [112,123]. Recurrences of skin manifestations are possible [64,132].

Complications of ocular herpetic infection include corneal ulcer, optic atrophy, retinal detachment, and blindness [111]. With adequate antiviral therapy, long-term consequences in the form of neurological symptoms and/or ocular clinical manifestations account for less than 2%. In the absence of etiotropic therapy in newborns, herpetic eye infection can lead to generalization of the process or herpetic CNS involvement [123].

In untreated herpetic CNS involvement, approximately 50% of newborns die, and severe neurological sequelae are observed among survivors [31,109]. However, even with adequate HSV infection therapy, mortality in CNS involvement and disease dissemination can reach up to 23% [91]. At the same time, the use of high-dose acyclovir** (60 mg/kg/day) leads to a significant improvement in the survival of patients with congenital HSV infection [30,133], and mortality can decrease from 20.9% to 5.6% [64]. When treating the cerebral form of congenital HSV infection with high-dose acyclovir**, the probability of normal development at 12 months of age is 6.6 times higher compared to standard therapy (adjusted OR; 95% CI: 0.8–113.6) [133]. In 55% of infants with herpetic CNS involvement treated with high-dose acyclovir**, no overt neurological abnormalities are detected during the first 24 months of life [64].

The most frequently identified neurological sequelae include spastic hemi- and tetraparesis and epilepsy; polymorphic refractory seizures are characteristic, and microcephaly may develop [109]. It should be remembered that meningoencephalitis can present not only as isolated CNS involvement in neonatal HSV infection, but also as one of the manifestations of generalized (disseminated) congenital HSV infection [91]; in the latter case, the prognosis for the child's life and health is less favorable. The earlier signs of cerebral cortex involvement manifest from the onset of the disease (48 to 168 hours after symptom onset), the worse the prognosis [134].

The disseminated form of HSV infection, even against the background of adequate etiotropic therapy in newborns, especially preterm infants, can be fatal and cause a devastating disease [135] with mortality up to 30–41% [64,100]. In the absence of etiotropic therapy, mortality in the disseminated form is 80–90% [31,97,98]. Survivors of disseminated neonatal HSV infection subsequently experience severe neurological sequelae accompanied by delayed motor, speech, and physical development [31,109]. Newborns with fulminant liver failure due to hepatic involvement in congenital HSV infection may require liver transplantation [92,126]. The disseminated form may be complicated by the development of hemophagocytic lymphohistiocytosis [66,129,136] with a mortality rate of up to 42% [137].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

Evidence of congenital HSV infection is the presence of characteristic herpetic rashes.

The basis for establishing the diagnosis is the detection of HSV DNA in any biological material (vesicular fluid, scrapings from rashes, nasopharyngeal scrapings, conjunctival discharge, blood, cerebrospinal fluid (CSF)) in the first 6 weeks of life [5,6].

Polymerase chain reaction (PCR) is the method of choice and the "gold standard" regardless of anatomical location or viral type when testing any biological material (including CSF to assess CNS involvement in the infectious process) and has a sensitivity of 75% to 100% and a specificity of 71% to 100% [13,20,138–146]. A positive result for herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in cerebrospinal fluid by PCR is a sign of CNS involvement (classified as either the cerebral form or disseminated disease). A positive result for herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) by PCR in blood (quantitative/qualitative study) may be detected before the onset of clinical signs of infection [105] and does not determine the form of the disease, since viremia occurs in all clinical variants of the disease (localized [SEM disease], CNS involvement, and disseminated form) [13]. A positive molecular biological test result of a nasopharyngeal scraping for herpes simplex virus (Herpes simplex virus) in a newborn with pneumonia strongly suggests the presence of HSV infection. PCR has higher sensitivity compared to viral culture isolation [140,147].

Determination of class M antibodies (IgM) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) in blood can be used to establish the diagnosis of congenital HSV infection if PCR is unavailable or in doubtful cases as an additional test, but possible false-negative and false-positive results must be taken into account [20,148]. The sensitivity of classical enzyme-linked immunosorbent assay (ELISA) for detecting general HSV antibodies ranges from 89.1% to 98.0%, with a specificity of 82.8% to 100% [149,150]. Determination of class G antibodies (IgG) to herpes simplex virus type 1 (Herpes simplex virus 1) in blood and class G antibodies (IgG) to herpes simplex virus type 2 (Herpes simplex virus 2) in blood can be type-specific and help identify HSV-1 and HSV-2, unlike IgM antibodies [150].

The diagnosis of "Congenital infection caused by herpes simplex virus [herpes simplex]" cannot be established on the basis of detecting class IgG antibodies to HSV in a newborn, since neonatal IgG reflects passively transferred maternal antibodies, given the high serological prevalence of HSV antibodies in the general population [4,23]. Conclusive data on the diagnostic significance of IgG avidity for diagnosing congenital HSV infection in newborns are lacking in the literature.

The diagnosis of "Congenital infection caused by herpes simplex virus [herpes simplex]", indicating the clinical form, is established in a newborn upon confirmation of antenatal or intranatal HSV transmission and the presence of characteristic disease signs (Tables 2 and 3), the etiology of which is confirmed by the detection of herpes simplex virus DNA (HSV-1 and HSV-2) in biological materials using PCR.

The clinical form is established in accordance with the criteria listed in subsection 1.6 and systematized taking into account laboratory parameters in Table 3.

Table 3. Clinical and laboratory characteristics of the three forms of congenital HSV infection in newborns [4]. The range of diagnostic tests according to the nomenclature of medical services is presented in Appendix A3.2.

2.1 Complaints and Anamnesis

Comments: suspected previously suffered or acute HSV infection during pregnancy may be indicated by typical clinical manifestations (Table 1), fever during pregnancy in the absence of confirmation of the etiology of these clinical manifestations [28–33,152]. It is important to establish the time of maternal infection, since the risk of transmitting the infection to the newborn during primary HSV infection in a pregnant woman with virus shedding during delivery is 10–30 times higher than in a mother with recurrent genital infection [12,152]. The risk of HSV transmission to the newborn from a mother with no history of prior herpetic infection, but with active (fresh) infectious elements at the time of delivery, ranges from 25% to 60% [5,12,23,24]. High titers of IgG antibodies to HSV-1 in women in the second trimester of pregnancy are associated with late miscarriages and premature births, maternal anemia, chronic placental insufficiency, labor abnormalities, early neonatal complications (cerebral ischemia, respiratory distress syndrome), and characteristic skin rash. Low titers of IgG antibodies to HSV-1 in women in the third trimester of pregnancy are associated with premature birth, maternal anemia, chronic placental insufficiency, endometritis, complications of the early neonatal period, and localized skin rashes [151]. Detection of HSV types 1 and 2 DNA in the blood may be detected before the clinical signs of infection appear [105].

• In case of signs of intrauterine infection detected antenatally by fetal ultrasound and MRI, it is recommended to examine the newborn after birth for the timely diagnosis and treatment of congenital HSV infection [4, 51,52].

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

Comments: specific ultrasound signs of HSV infection in the fetus are presented in Table 2. The range of examination includes: determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in the cerebrospinal fluid, determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in the blood, qualitative/quantitative study; molecular biological study of a nasopharyngeal scraping for herpes simplex virus (Herpes simplex virus).

2.2 Physical Examination

• A newborn with suspected congenital HSV infection is recommended a pediatric visual examination to identify clinical manifestations characteristic of congenital HSV infection [98,114,154].

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

Comments: the main clinical signs characteristic of congenital HSV infection are presented in Tables 2 and 3. Most often, newborns with congenital HSV infection upon examination may exhibit symptoms such as typical skin lesions (vesicles, pustules, erosions), eye lesions, oral mucosal lesions, characteristic symptoms of meningoencephalitis (CNS depression, seizures, bulging anterior fontanelle), jaundice, hepatomegaly, fever, lymphadenopathy, hypotrophy, hemorrhagic rash, respiratory failure, and signs of perfusion impairment.

• In the presence of clinical signs of congenital infection, it is recommended to examine the newborn for HSV infection as soon as possible for the timely diagnosis and treatment of congenital HSV infection [90,98,99].

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

Comments: since the clinical picture of neonatal herpes is diverse and does not always have specific manifestations, a high level of clinical vigilance regarding HSV infection is required in the newborn. The main clinical signs most characteristic of congenital HSV infection are presented in Tables 2 and 3.

2.3 Laboratory Diagnostics

• As the primary diagnostic method in newborns with suspected congenital HSV infection, it is recommended to use the determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood by PCR, qualitative/quantitative study; determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in vesicular fluid, scrapings from rashes by PCR; determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in cerebrospinal fluid by PCR; determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in conjunctival discharge by PCR; determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in corneal scrapings by PCR; molecular biological study of a nasopharyngeal scraping for herpes simplex virus (Herpes simplex virus) in the first 6 weeks of life for etiological verification of the viral infection [4,5,13,65,105,138–140].

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

Comments: HSV DNA in the blood by PCR is detected in 78% of cases for SEM disease, in 64% of cases for the cerebral form, and in 100% of cases for the disseminated form [155]. The specimen for HSV testing must be collected before initiating aciclovir therapy**, no later than the first 24 hours of life (regardless of whether delivery was vaginal or by Caesarean section) [100]. Since CNS disease can be occult, any patient with suspected HSV infection should undergo a lumbar puncture to detect herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in the cerebrospinal fluid by PCR as soon as clinically feasible, provided there are no contraindications to lumbar puncture [156]. CNS HSV infection can occur even with a normal cell count and normal biochemical characteristics in the CSF, especially in the early stages of infection; therefore, detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in the cerebrospinal fluid by PCR should be performed even with normal CSF parameters.

• If histological signs of placental involvement characteristic of HSV infection are detected during pathological examination of the placenta, it is recommended to perform qualitative/quantitative determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in the blood by PCR for the newborn, as well as a molecular biological study of a nasopharyngeal swab for herpes simplex virus (Herpes simplex virus) as soon as possible after the identification of specific placental changes for the timely diagnosis and treatment of congenital HSV infection [4,45,53,71].

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

Comments: HSV DNA in the blood of newborns may be detected before the onset of clinical signs of infection [105].

• If the newborn presents with laboratory and/or instrumental signs characteristic of HSV infection, it is recommended to perform qualitative/quantitative determination of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in the cerebrospinal fluid and blood by PCR, along with a molecular biological study of a nasopharyngeal swab for herpes simplex virus (Herpes simplex virus), as soon as possible after the identification of specific symptoms for the timely diagnosis and treatment of congenital HSV infection [4].

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

Comments: the spectrum of possible laboratory and instrumental changes is presented in Tables 2 and 3. A positive test result from a nasopharyngeal sample of a newborn with pneumonia strongly suggests a disseminated HSV infection [153].

• If PCR is unavailable, as well as in dubious cases for the evaluation of newborn infants with suspected congenital HSV infection, it is recommended to determine class M antibodies (IgM) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) in the blood, class G antibodies (IgG) to herpes simplex virus type 1 (Herpes simplex virus 1) in the blood, and class G antibodies (IgG) to herpes simplex virus type 2 (Herpes simplex virus 2) in the blood for the etiological verification of the viral infection [132,150,152].

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

Comments: the study is performed using ELISA (or chemiluminescent immunoassay (CLIA)) indicating the sensitivity threshold values 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) [150]. Specific IgM in the first days of life indicate a primary infection, but it should be borne in mind that in congenital infections IgM may not be detected, so negative results should not be a reason to dismiss the diagnosis. The presence of IgG alone is not a marker of infection in newborns, as these may be maternal antibodies passively carried by the infant. A diagnostic criterion will be an increase or lack of decrease in the level of specific IgG in the infant's blood serum over the course of the disease [132,152]. The initial blood test for serological diagnosis in a newborn must be performed prior to the administration of immunoglobulins (ATC code J06B).

• Newborns with suspected congenital HSV infection are recommended to undergo a complete blood count (CBC) with differential to detect laboratory signs of HSV infection (anemia, thrombocytopenia, thrombocytosis, leukocytosis, leukopenia, neutropenia) [28,92,99,114,117,121,157].

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

• When treated with direct-acting antivirals (ATC code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATC code J05AB), newborns with congenital HSV infection are recommended to undergo a blood leukocyte count and differential leukocyte count to determine the absolute neutrophil count in order to monitor treatment safety [101,131,133, 189].

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

Comments: to monitor potential neutropenia that may develop during HSV infection therapy, the absolute neutrophil count should be assessed twice a week during initial parenteral therapy [101]. Subsequently, during maintenance therapy, neutrophil counts should be performed at weeks 2 and 4 of maintenance therapy, and monthly thereafter [101]. If necessary, monitoring of tests may be performed more frequently at the physician's discretion.

The absolute neutrophil count often recovers without intervention during therapy or after its completion [133, 189].

• A newborn with the disseminated form of congenital HSV infection is recommended to undergo a coagulogram (screening hemostasis test), including the determination of blood fibrinogen level, activated partial thromboplastin time, prothrombin (thromboplastin) time in blood or plasma, and international normalized ratio (INR) for the timely diagnosis and treatment of disseminated intravascular coagulation [104,125].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• Newborns with suspected congenital HSV infection, as well as those with suspected organ involvement caused by congenital HSV infection, are recommended to undergo a routine biochemical blood test (determination of alanine aminotransferase activity in the blood, aspartate aminotransferase activity in the blood, total bilirubin level in the blood, conjugated (direct) bilirubin level in the blood, and creatinine level in the blood) to identify laboratory signs of HSV infection and the severity of organ damage [28,92,99,125,128,192].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3) for the determination of alanine aminotransferase and aspartate aminotransferase activity in the blood.

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4) for the determination of total and conjugated bilirubin levels.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5) for the determination of blood creatinine level.

Comments: laboratory changes characteristic of HSV infection are presented in Table 3. Appropriate parameters of the routine biochemical blood test are used to detect organ involvement. An increase in blood ALT activity in newborns exceeding the upper limit of normal by more than 2 times can be considered a suspicious sign of disseminated herpetic infection [153]. An increase in blood ALT and AST activity may reach 10-fold or more [114]. A 10-fold increase in blood AST activity compared to the upper limit of normal is associated with increased mortality [159].

• When treated with direct-acting antivirals (ATC code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATC code J05AB), newborns with congenital HSV infection are recommended to undergo a routine biochemical blood test (determination of alanine aminotransferase activity in the blood, aspartate aminotransferase activity in the blood, total bilirubin level in the blood, conjugated (direct) bilirubin level in the blood, creatinine level in the blood, urea level in the blood, sodium level in the blood, and potassium level in the blood) to monitor treatment efficacy and safety for timely adjustment of the antiviral dose [28,92,99,117,127,128,133,160,161,189-191].

GCP BLEL 3Grade of recommendation B (level of evidence – 3) – for determining alanine aminotransferase and aspartate aminotransferase activity in the blood, assessing total and conjugated bilirubin levels in the blood, and testing blood creatinine and urea levels

GCP CLEL 4Grade of recommendation C (level of evidence – 4) – for testing blood sodium and potassium levels

Comments: considering the nephrotoxicity of aciclovir**, serial monitoring of blood creatinine levels is required during treatment once or twice a week [161]. If necessary, blood creatinine testing may be performed more or less frequently at the physician's discretion, determined based on the clinical assessment of the patient's condition.

• Newborns with suspected cerebral congenital HSV infection or any form of confirmed congenital HSV infection are recommended to undergo microscopic examination of cerebrospinal fluid, cell counting in a counting chamber (determination of pleocytosis), cerebrospinal fluid glucose testing, and cerebrospinal fluid protein testing for the timely diagnosis and treatment of herpetic meningoencephalitis [28,92,99,114,117,121,157,195].

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

Comments: lumbar puncture for suspected CNS viral infection must be performed as soon as possible [156]. Signs of herpetic meningoencephalitis include pleocytosis with mononuclear predominance, elevated CSF protein levels, and decreased CSF glucose levels.

• During treatment with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide analogues group, excluding reverse transcriptase inhibitors (ATX code J05AB), newborns with herpetic meningoencephalitis are recommended to undergo microscopic examination of cerebrospinal fluid, cell counting in a counting chamber (determination of pleocytosis), cerebrospinal fluid glucose testing, and cerebrospinal fluid protein testing to detect laboratory signs of meningoencephalitis and monitor treatment efficacy [113].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• Newborns with herpetic meningoencephalitis and disseminated HSV infection are recommended to undergo microbiological (culture) blood testing for sterility and microbiological (culture) cerebrospinal fluid testing for aerobic and facultatively anaerobic opportunistic microorganisms to rule out bacterial sepsis [4,114,192].

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

Comments: bacteriological blood and CSF tests must be performed to rule out other diseases that may present with similar clinical symptoms (bacterial sepsis and meningoencephalitis).

• Newborns with suspected cerebral congenital HSV infection or any form of confirmed congenital HSV infection are recommended to test for herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in cerebrospinal fluid by PCR to determine CNS involvement [114,156].

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

Comments: lumbar puncture must be performed as soon as possible if CNS HSV infection is suspected.

• During treatment with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide analogues group, excluding reverse transcriptase inhibitors (ATX code J05AB), newborns with localized HSV infection (SEM disease) are recommended to have qualitative/quantitative herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA testing in blood by PCR, herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA testing in conjunctival discharge by PCR, herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA testing in corneal scrapings by PCR, and serial molecular biological testing of nasopharyngeal scrapings for herpes simplex virus (Herpes simplex virus) to monitor treatment efficacy [23,138,155,162].

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

• During treatment with direct-acting antivirals (ATX code J05A) of the nucleoside and nucleotide analogues group, excluding reverse transcriptase inhibitors (ATX code J05AB), newborns with herpetic meningoencephalitis and disseminated HSV infection are recommended to undergo qualitative/quantitative herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA testing in cerebrospinal fluid by PCR and serial herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA testing in blood by PCR to monitor treatment efficacy [23,114,138,155,162].

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

Comments: the goal of treatment is to suppress viremia and eliminate the virus from CSF. Repeated CSF PCR is indicated for herpetic encephalitis near the end of the treatment course. If viral DNA persists in the CSF, treatment is extended for 7 days followed by serial monitoring of herpes simplex virus types 1 and 2 DNA in cerebrospinal fluid by PCR until a negative result is obtained [23,163]. HSV DNA in blood and CSF may persist for 1–2 weeks after treatment initiation or longer [138,155].

2.4 Instrumental Diagnostics

• A newborn with suspected or confirmed congenital HSV infection is recommended to undergo neurosonography to detect CNS lesions [4,132,152,164].

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

Comments: neurosonography reveals periventricular echogenicity increases, degenerative changes with cystic malacia formation (periventricular leukomalacia) in the frontal regions, thickening of the choroid plexuses of the lateral cerebral ventricles and sulci, encephalomalacia of the basal ganglia and thalamus, intraventricular and intracerebral hemorrhages, diffuse brain changes predominantly in the basal ganglia, and corpus callosum hypoplasia. From day 5 of the disease, areas of decreased density (necrosis) are identified, most commonly in the cortical or subcortical regions of the frontal, temporal, and less frequently parietal and occipital lobes of the brain [152,164].

• A newborn with confirmed congenital HSV infection presenting with neurological disorders and ultrasound brain abnormalities is recommended to undergo brain computed tomography (CT) or brain magnetic resonance imaging (MRI) to clarify the scope and nature of structural CNS damage [43,113,114,119–122,134,165–167].

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

Comments: early CT and MRI findings may be subtle and difficult to detect, requiring serial follow-up. Involvement of the cortical grey matter and subcortical white matter of the temporo-insular regions, basal ganglia, capsules, brainstem, and cerebellum predominates. The cortex is damaged initially, followed by involvement of the subcortical white matter in the early phase of infection [168]. Hemorrhagic changes are better visualized on MRI than on CT. These imaging methods are performed provided the specific medical organization has the technical capability.

• A newborn with confirmed congenital HSV infection presenting with neurological disorders is recommended to undergo electroencephalography (EEG) to detect abnormal electrical brain activity [113,114,165,169,170].

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

Comments: the typical EEG pattern consists of recurrent, uniform, "sharp-and-slow wave" complexes originating in one or both temporal lobes, repeating at regular intervals of 2–3 seconds. These complexes appear between days 2 and 15 of disease onset. They are observed in 2/3 of all confirmed cases of neonatal herpes. Pronounced intermittent high-amplitude slow waves over the temporal lobes may be detected on EEG, and slowing patterns have also been described [114,165,169,170]. EEG should be performed prior to prescribing anticonvulsant and sedative therapy due to its effect on EEG results. Performing this study depends on the capabilities of the specific medical organization.

• A newborn with confirmed congenital HSV infection and suspected organ involvement is recommended to undergo a comprehensive abdominal ultrasound, renal ultrasound, echocardiography, and chest X-ray to detect it [4,114,135,152,154,171,172].

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

Comments: echocardiography in newborns with neonatal herpes may reveal inadequate cardiac chamber filling, decreased cardiac output, pulmonary hypertension, patent ductus arteriosus with a left-to-right shunt, and pericardial effusion [135,171]. Chest X-ray may reveal bilateral interstitial infiltrates and a diffuse alveolar pattern [172].

2.5 Other Procedures

• A newborn with confirmed congenital HSV infection is recommended to undergo an initial/follow-up examination (consultation) by an ophthalmologist to detect visual system lesions [34,68,108–111].

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

Comments: a follow-up examination (consultation) by an ophthalmologist is necessary dynamically to assess treatment results and identify complications of herpetic eye disease.

• A newborn with confirmed congenital HSV infection is recommended to undergo an initial/follow-up examination (consultation) by a neurologist to detect neurological disorders [6,38,173].

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

Comment: to detect neurological disorders in newborn infants with HSV infection receiving inpatient nursing care, follow-up examinations (consultations) by a neurologist should be performed at least once every 2 weeks.

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

3.1 Conservative Treatment

Etiotropic therapy

Early initiation of antiviral therapy reduces the risk of serious complications and mortality; therefore, it should be started immediately if the diagnosis of neonatal HSV infection is reasonably suspected. Antiviral therapy is prescribed immediately prior to laboratory test results (but after material sampling) when neonatal HSV infection is suspected, if the infant has characteristic clinical symptoms, if the mother has a primary HSV infection in the last 6 weeks of pregnancy, or if the pregnant woman has clinical manifestations of HSV infection upon admission for delivery [1,99,133,174–176].

Treatment of congenital HSV infection is carried out with direct-acting antiviral drugs (ATX code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB). Aciclovir**(ATX code J05AB) (an inhibitor of HSV-1 and HSV-2 DNA polymerase) is the first-line drug in the treatment of neonatal HSV infection [5,160,174]. Systemic treatment with aciclovir**(ATX code J05AB) is well tolerated by most newborns. The most significant side effects of aciclovir**(ATX code J05AB) therapy include the development of transient neutropenia, less commonly nephrotoxicity, and injection site damage (infiltrates with superficial or deep ulcerations, phlebitis); therefore, preference should be given to intravenous administration of aciclovir**(ATX code J05AB) via central venous access. Monitoring of blood creatinine levels, blood urea levels, and ALT and AST activity is necessary.

Persistence of HSV DNA during aciclovir**(ATX code J05AB) treatment may indicate viral resistance to this drug [42,113,177], which is extremely rare.

In the treatment of congenital HSV infection, in the absence of intravenous aciclovir**(ATX code J05AB) or in case of resistance to it, alternative antiviral drugs of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB), may be used: #ganciclovir**, #valaciclovir**. It is used for life-threatening indications in all forms of HSV infection after obtaining informed parental consent. As a first-line alternative therapy, intravenous #ganciclovir**(ATX code J05AB) should be prescribed [155,178]. #Ganciclovir** (ATX code J05AB) inhibits HSV DNA polymerase and thereby its replication. #Ganciclovir**(ATX code J05AB) is used for life-threatening disease courses in newborns and the risk of disability (damage to the central nervous system, lungs, myocardium, liver, eyes). The drug may cause a myelotoxic effect with the development of severe neutropenia, thrombocytopenia, and exhibits teratogenic, mutagenic, and carcinogenic activity [178–180].

#Valaciclovir** (ATX code J05AB) in newborns and infants (as suppressive therapy for congenital HSV infection) is used with caution (efficacy and safety of use have not been established). After administration, the drug is rapidly and almost completely transformed into aciclovir**(ATX code J05AB) [113].

Achieving negative PCR results in CSF, blood, nasopharyngeal swab, cornea, conjunctival discharge, and stabilization of the condition is the direct goal of therapy in the acute period of the clinical form.

The decision to discontinue the main etiotropic therapy or prolong it is made based on PCR results (negative result for HSV DNA), clinical, laboratory, and instrumental assessment, and the dynamics of the disease (by decision of the medical council). If HSV DNA persists in the blood or CSF, treatment is extended for 7 days, followed by monitoring of HSV DNA at the end of the additional weekly course.

• A newborn infant with a well-founded suspicion of congenital HSV infection, prior to receiving HSV test results, is recommended empirical therapy with direct-acting antiviral drugs (ATX code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB) - aciclovir** (infusion solution) at a daily dose of 60 mg/kg, divided into three administrations - every 8 hours (3 times a day) by continuous intravenous administration of drugs for timely main etiotropic treatment [1,3,127,133,175,176,181].

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

Comments: empirical therapy with aciclovir** (ATX code J05AB) is started immediately before obtaining laboratory test results, but after sampling material if there is a suspicion of congenital HSV infection in the newborn; if the newborn has characteristic clinical symptoms; if the mother has a primary HSV infection in the last 6 weeks of pregnancy; if the pregnant woman has clinical manifestations of HSV infection [133]. Delayed (late) initiation of aciclovir** (ATX code J05AB) therapy increases the risk of death in newborns with neonatal herpetic infection [175,176], therefore empirical therapy with aciclovir** (ATX code J05AB) for newborns undergoing testing for HSV infection is completely justified [175,176].

In case of clinical suspicion of congenital HSV infection, immediate administration of aciclovir**(ATX code J05AB) is required to avoid disseminated disease, since vesicles or other signs of HSV infection may be absent in 40% of cases [159,181]. Empirical treatment should never be omitted in the presence of characteristic clinical symptoms of congenital HSV infection in a newborn solely based on the absence of a history of herpetic infection in the maternal history. Unfortunately, up to 80% of mothers who transmitted HSV to the fetus do not report a history of genital herpes [3]. Asymptomatic newborns whose mothers have active manifestations of HSV infection should be managed with contact precautions until the end of the incubation period (day 14) or until samples taken from the infant after the first 24 hours of life are negative. Some experts do not recommend contact precautions if the exposed infant was born by Caesarean section and membrane rupture occurred < 4–6 hours before delivery [153].

• A patient with a localized form of congenital HSV infection (SEM disease) is recommended therapy with direct-acting antiviral drugs (ATX code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB) (aciclovir**) (infusion solution) at a daily dose of 60 mg/kg, divided into three administrations - every 8 hours (3 times a day) by continuous intravenous administration of drugs for a duration of 14 days for the main etiotropic treatment [1,100,133].

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

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

• A patient with cerebral and disseminated forms of congenital HSV infection is recommended therapy with direct-acting antiviral drugs (ATX code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB) (aciclovir**) (infusion solution) at a daily dose of 60 mg/kg, divided into three administrations - every 8 hours (3 times a day) by continuous intravenous administration of drugs for a duration of 21 days for the main etiotropic treatment [1,100,133].

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

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

• A patient with any form of congenital HSV infection is recommended to continue treatment with direct-acting antiviral drugs (ATX code J05A) of the nucleosides and nucleotides group, excluding reverse transcriptase inhibitors (ATX code J05AB) - #aciclovir** orally at a dose of 300 mg/m² per administration 3 times a day for 6 months after completing the full course of parenteral therapy in order to improve neurological outcomes and prevent relapses [131].

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

Comments: the dose should be adjusted monthly taking into account changes in the child's body weight [131].

• In patients with any form of congenital HSV infection, if intravenous acyclovir (ATC code J05AB) is unavailable for life-saving indications, alternative therapy with direct-acting antivirals (ATC code J05A) of the nucleoside and nucleotide analogues class, excluding reverse transcriptase inhibitors (ATC code J05AB) – #ganciclovir** (6 mg/kg every 12 hours intravenously for infants aged ≤ 90 days, and 5 mg/kg every 12 hours intravenously for infants aged > 90 days) or #valaciclovir** (300 mg/m²/dose orally 3 times a day) – is recommended as primary etiotropic treatment [1,113,133,155,178].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4) for #valaciclovir**

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5) for #ganciclovir**

Comments: The decision to prescribe reserve drugs is made jointly (by a medical panel) on an individual basis.

• In an infant with congenital HSV infection receiving direct-acting antivirals (ATC code J05A) of the nucleoside and nucleotide analogues class, excluding reverse transcriptase inhibitors (ATC code J05AB) (acyclovir**) (infusion solution), #(acyclovir**) (oral form) who develops severe neutropenia (< 500 cells/µL) due to the myelotoxic effect of antiviral therapy, it is recommended to temporarily reduce the dose by half or suspend treatment until the absolute neutrophil count recovers [131,133,189].

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

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

The developmental care regime involves creating optimal conditions for nursing newborns.

Feeding of newborns with HSV infection is carried out either with breast milk or with an adapted infant formula for term, preterm, and low-birth-weight infants, depending on gestational age, if breastfeeding is not feasible.

Medical Nutrition Therapy

• Newborns with any form of congenital HSV infection are recommended to continue breastfeeding with maternal milk, provided there are no herpetic lesions on the breast surface, to supply the body with essential nutrients (proteins, fats, carbohydrates, vitamins, and trace elements) [58–61,182].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Individual case reports have demonstrated the occurrence of HSV infection in newborns associated with maternal herpetic lesions localized on the breast [58–61]. When a mother has herpetic lesions on the breast, HSV DNA is detected within it, found in mononuclear cells (cells contained in breast milk) as well as in the epithelial cells of the breast [183–185]. Mothers with active herpetic lesions on the breast should temporarily (until complete healing of skin lesions) discontinue breastfeeding from the affected breast.

Pathogenetic therapy

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

Symptomatic therapy

Symptomatic therapy involves prescribing medicinal products depending on the clinical manifestations of the infectious process (antihemorrhagic, hemostatic, anticonvulsant, sedative, cardiotonic, vasopressor, volume expander therapy).

• In an infant with congenital HSV infection receiving direct-acting antivirals (ATC code J05A) of the nucleoside and nucleotide analogues class, excluding reverse transcriptase inhibitors (ATC code J05AB) (acyclovir**) (infusion solution), #(acyclovir**) (oral form) who develops severe neutropenia (< 500 cells/µL) that does not resolve with the temporary discontinuation of direct-acting antivirals (ATC code J05A), the administration of colony-stimulating factors (ATC code L03AA) – #filgrastim** (solution for intravenous and subcutaneous administration) is recommended to manage neutropenia at a dose of 5–10 mcg/kg/day subcutaneously or intravenously, daily until the target absolute neutrophil count is achieved [133,193].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4) – for the prescription of colony-stimulating factors

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5) – for the dose of colony-stimulating factors

Comments: Therapy is prescribed following consultation (examination, assessment) by a hematologist. The target absolute neutrophil count is 1000 cells/µL or more. The most frequently used regimen is 1–3 days. An increase in neutrophils is observed within 24–48 hours in most cases [193].

Pain Management

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

Strategic measures for the prevention of congenital HSV infection aim to reduce the risk of vertical transmission of HSV and child infection during delivery through anticipatory guidance for expectant mothers and partners (reducing primary and recurrent infection in pregnant women), identifying pregnancies with a high risk of fetal HSV transmission, delivery by cesarean section, and administering antiviral therapy to pregnant women with HSV infection [12]. The most effective prevention method is informing pregnant women about hygiene practices to prevent infection, especially in late pregnancy, because the highest risk of neonatal infection occurs when the mother sheds HSV during delivery, which is most common in women who acquire genital herpes in the third trimester [153]. Women at high risk should be counseled on abstaining from or reducing oral-genital contact in the near term [186]. Acyclovir** (ATC code J05AB) is used as therapy aimed at preventing vertical transmission in pregnant women with acute or secondary active HSV infection.

Delivery by cesarean section in patients with active skin rashes or prodromal symptoms can reduce the risk of herpetics infection in newborns [163,182]. In addition to using acyclovir** (ATC code J05AB), all laboring women with genital herpes should have the number of vaginal examinations limited during labor and are prohibited from any invasive obstetric procedures (amniostomy, fetal scalp blood lactate testing) [186].

Management of pregnancy and labor in the presence of HSV infection is carried out in accordance with the clinical guidelines "Anogenital Herpetic Viral Infection".

Parents of newborns at risk for neonatal herpes must be informed about the clinical signs to monitor at home after hospital discharge [153].

Mothers shedding the virus, as well as infected newborns, must be isolated to prevent nosocomial transmission of HSV [63,187,188]. Mothers staying in the hospital should observe contact precautions until skin lesions are crusted over. Mothers with cold sores on their lips should wear a disposable medical mask when caring for an infant under 6 weeks of age until the lesions heal (crusted and dry). Mothers should not kiss their infant. Mothers with skin lesions must keep them covered when their newborn is nearby. When managing newborns with HSV infection, contact precautions with affected skin and mucous membrane areas must be observed until the lesions are crusted over [153].

Specific prevention of HSV infection has not been developed.

Dispensary follow-up (Active surveillance)

• Newborns with any form of congenital HSV infection are recommended to undergo a follow-up outpatient examination (consultation, assessment) by an ophthalmologist to evaluate the visual analyzer status, and to monitor for relapses and sequelae of HSV infection [1,6,111,194].

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

• Newborns with any form of congenital HSV infection are recommended to undergo a follow-up outpatient examination (consultation, assessment) by a neurologist to evaluate neurological disorders and long-term sequelae of congenital HSV infection [1,6,31,109,113,134].

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

6. Organization of Medical Care

A newborn with suspected congenital HSV infection must be transferred from the obstetric department to a specialized unit (department of pathology of newborns and preterm infants, neonatal intensive care unit of a children's hospital, perinatal center, etc.). Examination of the child can be performed both at the obstetric department stage and in specialized units (depending on the capabilities of specific medical organizations).

Treatment with parenteral forms of direct-acting antivirals (ATC code J05A) of the nucleoside and nucleotide analogues class, excluding reverse transcriptase inhibitors (ATC code J05AB), in newborn infants with any form of congenital HSV infection must be carried out in an inpatient setting.

Indications for discharging a patient from a medical organization:

1) Stable, satisfactory condition of the infant.

2) Stabilization of laboratory parameters and negative HSV PCR results (blood, CSF, eyes, nasopharynx).

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 – Candidate of Medical Sciences, Leading Research Fellow at the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics, Associate Professor at the Department of Neonatology of the Institute of Professional Education at the 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 of the Pediatric Faculty at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Council of the Russian Association of Neonatologists.

2. Nikolay N. Volodin – Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, President of the Association of Specialists in Perinatal Medicine, Care for Pregnant Women, Fetuses, Newborns, and Children under 3 Years of Age (ASPM+), Head of the Pediatrics Department at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Health of Russia.

3. Valeriy V. Gorev – Candidate of Medical Sciences, Chief Medical Officer of the Morozov Children's City Clinical Hospital of the Moscow City Health Department, Member of the Council of the Russian Association of Neonatologists.

4. Degtyarev Dmitry Nikolaevich – MD, 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, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Council Member of the Russian Society of Neonatologists.

5. Andrey L. Zaplatnikov – Doctor of Medical Sciences, Professor, Head of the Prof. V.V. Gavryushov Department of Neonatology, Professor at the Academician G.N. Speransky Department of Pediatrics at the Russian Medical Academy of Continuous Professional Education (RMANPO) of the Russian Ministry of Health.

6. Oleg V. Ionov – Doctor of Medical Sciences, Head of the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics at the 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 of the N.F. Filatova Clinical Institute of Children's Health at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chairman of the Council of the Russian Association of Neonatologists.

7. Anna L. Karpova – PhD in Medical Sciences, Anesthesiologist-Resuscitologist, Neonatologist, Moscow Doctor, Head of the Neonatal Inpatient Department at City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department; Associate Professor at the Professor V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; 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; Council Member of the Russian Society of Neonatologists.

8. Marina A. Kovaleva – Head of the Neonatal and Premature Infant Intensive Care Unit, Yaroslavl Regional Clinical Perinatal Center.

9. Alexey V. Mostovoy – Doctor of Medical Sciences, Head of the Anesthesiology and Intensive Care Service, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Associate Professor at the V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education, Council Member of the Russian Society of Neonatologists.

10. Marina V. Narogan – Doctor of Medical Sciences, 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), Council Member of the Russian Society of Neonatologists.

11. Anastasia S. Petrova – PhD in Medical Sciences, Deputy Chief Physician for Pediatric Care, Moscow Regional Perinatal Center, Chief freelance specialist neonatologist of the Ministry of Health of the Moscow Region, Associate Professor at the Department of Obstetrics, Gynecology and Perinatology, A.I. Burnazyan Federal Medical Biophysical Center of the FMBA of Russia, Head of the Department of Neonatology, Research Institute of Childhood of the Ministry of Health of the Moscow Region, Council Member of the Russian Society of Neonatologists.

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 updates to these guidelines are presented for discussion in a preliminary version. An updated version for broad discussion was posted on the website of the Association of Specialists in Perinatal Medicine, Care for Pregnant Women, Fetuses, Newborns and Children under 3 Years of Age (ASPM+) www.aspm.pro, the Russian Society of Neonatologists (RSN) www.neonatology.pro, and the public discussion portal for clinical guidelines of the Russian Ministry of Health https://portalcr.minzdrav.gov.ru/ to ensure all interested parties have the opportunity to participate in discussing and improving 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 and intensivists,

3. pediatricians,

4. infectious disease specialists,

5. obstetricians-gynecologists,

6. neurologists,

7. medical students,

8. 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 were developed taking into account the following regulatory 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. Ministry of Health of the Russian Federation, Order No. 203n dated April 14, 2025 "On Approval of Criteria for Assessing the Quality of Medical Care".

3. International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10) (World Health Organization), 2019 version.

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with amendments dated October 26, 2022) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).

5. Order of the Russian Ministry of Health No. 222n dated April 17, 2025, "On Approval of the Procedure for Providing Medical Care in the Field of 'Neonatology'." (Registered with the Ministry of Justice of Russia on June 2, 2025, No. 82516).

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 Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care>.

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

8. State Register of Medicinal Products: https://grls.rosminzdrav.ru

Appendix. Spectrum of basic examinations for herpes simplex virus infection presented in the clinical guidelines

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Congenital herpes simplex virus (HSV) infection is registered with a frequency of approximately 1 in 3,200 to 1 in 10,000 live births. The development of congenital herpetic infection in a newborn can result from intrauterine infection or intrapartum infection directly through the natural birth canal.

Intrauterine herpetic infection can lead to non-immune hydrops fetalis and intrauterine fetal death.

Clinical manifestations after birth can present in three forms:

1. – localized form, limited to lesions of the skin, eyes, and oral mucosa;

2. – herpetic infection with predominant central nervous system (CNS) involvement;

3. – disseminated (generalized) herpetic infection involving multiple organs and systems.

The localized form of herpetic infection (lesions of the skin, eyes, and oral mucosa) is characterized by the appearance of small vesicular rashes on the skin with a tendency to coalesce and group; localized small ulcerations may appear on the oral mucosa, palate, and tongue; various eye lesions may develop, such as conjunctivitis, chorioretinitis, etc.

Clinical manifestations of herpetic infection in newborns with predominant CNS involvement include seizures, lethargy, increased irritability, tremor, feeding difficulties, thermal instability (fever or hypothermia), and a bulging anterior fontanelle.

Disseminated (generalized) herpetic infection is characterized by a severe general condition of the infant and involvement of multiple organs (lungs, heart, CNS, liver, etc.).

Children with CNS involvement due to congenital HSV infection may develop severe neurological sequelae.

Newborns with perinatal contact with herpes simplex virus (specifically, maternal active surface genital lesions) require careful monitoring for objective signs of herpetic infection.

The diagnosis of herpetic infection in newborns can be accurately established by detecting HSV DNA using the polymerase chain reaction. Various tests can be performed for this investigation, depending on the localization of the lesion (skin elements, eye discharge, nasopharyngeal scraping, blood, cerebrospinal fluid).

Newborns with herpetic infection undergo laboratory and instrumental evaluations, the scope of which is determined by the attending physician. Depending on indications, the following may be ordered: complete blood count (CBC), general biochemical blood test, cerebrospinal fluid analysis, neurosonography, complex abdominal ultrasound, renal ultrasound, echocardiography, brain CT or MRI, EEG, ophthalmologist and neurologist consultations.

Treatment of congenital herpetic infection is carried out with special direct-acting antiviral drugs (ATX code J05A) of the nucleoside and nucleotide analogues group, excluding reverse transcriptase inhibitors (ATX code J05AB), aimed at eradicating the herpes simplex virus. The treatment course is 14 or 21 days depending on the disease form, followed by oral administration for 6 months.

Preventive measures to prevent congenital HSV infection before and during pregnancy include observing personal hygiene, avoiding casual sexual contacts, and abstaining from oral-genital contact, especially in the third trimester of pregnancy.

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

Not applicable.