Infection Specific to the Perinatal Period: Clinical Guidelines

List of Abbreviations

ABT – antibiotic therapy

AB – antibiotic

BP – blood pressure

BPD – bronchopulmonary dysplasia

BP – water-free interval / rupture-to-delivery interval

IAI – intraamniotic infection

IVH – intraventricular hemorrhage

CI – congenital infection

HSV – herpes simplex virus

CHD – congenital heart disease

IUI – intrauterine infection

CP – cerebral palsy

GI – gastrointestinal tract

IUGR – intrauterine growth restriction

FGR – fetal growth restriction

SPI – infection specific to the perinatal period

IMV – invasive mechanical ventilation

IL – interleukin

UTI — urinary tract infection

ABDS – acid-base balance status

US – urinary system

HC – healthcare organization

IEM – inherited inborn errors of metabolism

NI – neutrophil index

NSG – neurosonography

CBC – complete blood count

UA – urinalysis

VLBW – very low birth weight

NPUDI – neonatal and premature infant pathology department

NICU – neonatal intensive care unit

PI – perinatal infection

PVL – periventricular leukomalacia

ICU – intensive care unit

PCT – procalcitonin test (acute-phase inflammatory protein)

PPHN – persistent pulmonary hypertension of the newborn

PN – parenteral nutrition

PCR – polymerase chain reaction

RDS – respiratory distress syndrome

RCT – randomized controlled trial

MAS – meconium aspiration syndrome

CSF – cerebrospinal fluid

CRP – C-reactive protein (acute phase inflammatory protein)

GBS – group B Streptococcus

SIRS – systemic inflammatory response syndrome

TTN – transient tachypnea of the newborn

US – ultrasound examination

CMVI – cytomegalovirus infection

CNS – central nervous system

RR – respiratory rate

HR – heart rate

ECG – electrocardiography

ELBW – extremely low birth weight

EchoCG – echocardiography

SpO2 – oxygen saturation, blood oxygen saturation measured by pulse oximetry

Terms and Definitions

Infection specific to the perinatal period (ISPP) is an infectious process (inflammation) arising in various organs and/or systems of the fetus from 22 full weeks (154 days) or of the newborn up to and including the 7th day (168 hours) of extrauterine life, during which clinical and pathomorphological changes characteristic of an infectious disease occur in the body of the intrauterine fetus and/or newborn infant, detected antenatally or after birth.

Perinatal infection (PI) is an infectious disease of the fetus and/or newborn arising predominantly as a result of intrauterine infection due to hematogenous (transplacental), amniotic, ascending, or descending pathways of pathogen entry, which manifested from the 22nd week of gestation, as well as postnatally (upon early postnatal familial or hospital contact), with clinical manifestations of the disease during the early neonatal period.

Congenital infection (CI) is an infectious disease in which fetal infection and disease development, i.e., its clinical manifestation, occurred intrauterine (antenatally and/or intranatally) and by the time of birth the child presents with clinical, paraclinical, and other signs of an infectious process.

Other specified infection specific to the perinatal period – perinatal infection with a specified etiology and/or localization of the inflammatory focus.

Infection specific to the perinatal period, unspecified – perinatal infection with an unidentified pathogen.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Infection specific to the perinatal period or perinatal infection is an infectious process (inflammation) arising in various organs and/or systems of the fetus and newborn infant in the period from 22 full weeks (154 days) to the 7th day inclusive (168 hours) of extrauterine life, during which clinical and pathomorphological changes characteristic of an infectious disease occurred in the body of the fetus and/or newborn, detected antenatally or after birth [1–4].

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

Perinatal infections occupy a leading place among the causes of morbidity, maternal, and perinatal mortality. Infections are among the main causes of pregnancy termination and premature birth.

The term "perinatal infections" is generally applied to infections transmitted from mother to child during intrauterine development (intrauterine/congenital), during childbirth (strictly perinatal, or intranatal), and immediately after birth (postnatal infections) with their manifestation in the early neonatal period of life.

The causative agents of perinatal infections are diverse [4–12]. These can be bacteria [Group B streptococcus, Escherichia coli, Enterobacter aerogenes, Klebsiella spp., Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, Streptococcus pneumoniae, Treponema pallidum, Listeria monocytogenes, Mycobacterium tuberculosis], viruses [Herpes simplex virus, Cytomegalovirus, Respiratory syncytial virus, Rubella and others], atypical pathogens [Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma pneumoniae and others], fungi [Candida spp.], protozoa [Toxoplasma gondii].

The principal difference between perinatal infections (PI) and congenital infections (CI) is the proven connection of the latter infection with the maternal organism.

During a physiological pregnancy, the fetus is well protected by the placenta and fetal membranes from the effects of various pathogenic and opportunistic microorganisms. However, a pathological course of pregnancy, caused primarily by infectious factors, facilitates the penetration of pathogens into the fetal body, overcoming placental barriers (transplacentally or via an ascending route), contributing to the development of an inflammatory reaction upon microbial invasion.

In the vast majority of cases, fetal infection begins with damage to the placenta. An infectious and inflammatory process in the placenta and fetal membranes—intraamniotic infection (IAI)—adversely affects fetal viability, disrupting the transplacental metabolism that meets the fetus's needs. The placental membrane is permeable to antibodies and microorganisms, including bacteria, protozoa, and viruses. Pathogenic microorganisms enter the chorionic villi of the placenta with the bloodstream, fixate in them, and form a focus of inflammation. Even if the mother's disease is not accompanied by the penetration of the pathogen into the fetal body, the toxic effect of the pathogen's metabolic products is manifested [13].

The negative impact of antenatal infection on the condition of the fetoplacental complex largely depends on the gestational age at the time of infection, the type of pathogen, its virulence, the massiveness of contamination, the primary or secondary nature of the infectious process in the pregnant woman, the routes of infection penetration to the fetus, the degree of spread, the intensity of the inflammatory process, and the severity and character of changes in the pregnant woman's immune response.

Antenatally, the infectious agent reaches the fetus hematogenously (transplacentally) or via infected amniotic fluid through an ascending (from the cervical canal) or descending (from the fallopian tubes) pathway, transmembranously (through the fetal membranes in endometritis, placentitis), iatrogenically (during medical manipulations), or by contact [6, 14]. Most microorganisms identified in children with PI have relatively low virulence. It is hypothesized that upon entering the uterine cavity, they stimulate the infiltration and activation of neutrophils and lead to an increased synthesis and release of pro-inflammatory cytokines, prostaglandins, and matrix metalloproteinases. These changes promote cervical ripening, membrane rupture, uterine contractions, and premature rupture of membranes [4, 14, 15].

It is known that the inflammatory process is a complex local and general protective-adaptive mechanism arising in response to damage or the action of a pathogenic "irritant" and manifesting in reactions aimed at eliminating the products and agents of damage. It begins with the development of an acute-phase response, accompanied by an increase in the plasma concentration of acute-phase inflammatory proteins, the production of which occurs in the liver and is regulated by cytokines [16].

Perinatal infection and the development of a systemic inflammatory response in the fetus with activation of its immune system often lead to preterm birth and proven intraamniotic infection [17–21]. Newborns born to mothers with chorioamnionitis are at high risk for developing neonatal sepsis [22–25], bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) [26–29], and neonatal death [30, 31].

It has been noted that the systemic inflammatory response in the fetus contributes to the development not only of a generalized infectious process, including sepsis, but also of non-infectious neuroinflammation, contributing to the formation of PVL with gliosis and neuronal damage, the development of IVH, and PVL. In addition, the risk of long-term consequences (BPD, cerebral palsy [CP], retinopathy of prematurity, sensorineural hearing loss) and infant death increases [32].

High-risk factors for fetal infection include inflammatory diseases of the uterus and its appendages, colpitis, bacterial vaginosis, oligohydramnios or polyhydramnios, a burdened obstetrical and gynecological history (repeated artificial abortions with a complicated post-abortion period, habitual miscarriage, congenital malformations, and antenatal fetal death), placental insufficiency, intrauterine growth restriction and fetal developmental delay, the use of immunosuppressive therapy, surgical correction of cervical incompetence, and immunodeficiency states [2].

A particularly significant risk factor for fetal infection is maternal infectious disease diagnosed during the current pregnancy, colonization of maternal biological niches by various pathogenic microorganisms, including group B hemolytic streptococcus, and chorioamnionitis during labor.

Intranatal risk factors include premature rupture of membranes, prolonged anhydrous period, preterm birth, birth asphyxia, and meconium aspiration [33].

Depending on gestational age, the development of an infectious condition in the fetus may manifest as congenital malformations, preterm delivery, intrauterine growth restriction, fetal demise, and clinical signs of infection immediately after birth and/or after several hours or days (if infection occurred intranatally).

The inflammatory process may be localized in a specific organ or assume a systemic (generalized) character; in a number of situations, the entry of an infectious agent into the macroorganism is not necessarily accompanied by clinical manifestations, indicating an asymptomatic or subclinical course of the infection [1-7].

The transformation of a perinatal infection into a generalized process is driven by factors that reduce the body's reactivity, specifically the development of intrauterine and intranatal hypoxia, as well as primary and secondary immunodeficiencies [34-36].

A statistically significant association with the development of infections specific to the perinatal period (ISDPP) and the severity of consequences has been proven for such factors as the timing of infection during pregnancy, the pattern of infection (primary/recurrent/chronic), the duration of maternal membrane rupture, the mode of delivery, socioeconomic conditions, and breastfeeding [37].

All triggering factors must be taken into account to prevent intrauterine infection. The elimination of their potential impact should be carried out from the preconception stage and throughout pregnancy and childbirth.

1.3 Epidemiology of the Disease or Condition

Over the period from 2017 to 2020 in the Russian Federation (Order of Rosstat No. 674 dated December 23, 2024, "On Approval of the Federal Statistical Observation Form No. 32 'Information on Medical Care Provided to Pregnant Women, Women in Labor, and Puerperas' and Guidelines for Its Completion"), the incidence of infections specific to the perinatal period in newborns was about 1.4% [5]. The infectious morbidity in obstetric hospitals among preterm infants born with a birth weight of 1000 g or more was about 8%, and among preterm infants with extremely low birth weight (ELBW) it was about 27%; mortality in these groups was 1.6% and 21%, respectively.

According to N.P. Shabalov (2020), infections specific to the perinatal period are recorded in 2.3% of live births and account for 6% of cases of early neonatal morbidity [6].

Infections specific to the perinatal period are subject to recording and registration in the infectious diseases logbook at the place of their detection within medical organizations, as well as in territorial bodies authorized to exercise federal state sanitary and epidemiological supervision [38].

1.4 Features of Coding the Disease or Condition

P39.8 Other specified infections specific to the perinatal period

P39.9 Infection specific to the perinatal period, unspecified

P37.9 Congenital infectious or parasitic disease, unspecified

In cases where congenital, perinatal, and parasitic infections are specified (as to etiology and focus), the codes of the corresponding nosological forms of infections are used — P23, P37.0-37.5, P39.0-39.4, which are described/indicated in the relevant clinical guidelines.

1.5 Classification of the disease or condition

There is no approved general classification of ISDPP, including viral infections, but each infection with a specified etiology and/or nosological form has its own clinical classification. In this regard, ICD-10 code P39.8 should be used to code infections if a newborn in the first week of life exhibits clinical and laboratory signs of an inflammatory response with the identification of a pathogen, a specified infection (viral, bacterial, parasitic, fungal, mixed [polymicrobial, viral-bacterial]) and/or the presence of a focus of infection not specified in the clinical guidelines and ICD-10.

Codes P39.9 and P37.9 (unspecified) should be used when a newborn in the first week of life exhibits clinical, laboratory, and/or morphological signs of an inflammatory response without pathogen identification or localization of the inflammatory focus.

1.6 Clinical presentation of the disease or condition

Early clinical symptoms of congenital/perinatal infections generally lack specific manifestations [5, 6, 39]. Immediately after birth, newborns may exhibit conditions indicating an adverse course of the intrauterine period, specifically signs of intrauterine growth restriction (IUGR), morphofunctional immaturity, congenital malformations, multiple dysmorphisms, and birth in a state of asphyxia against the background of chronic intrauterine hypoxia. From the first hours or days of life (72 hours), signs of clinical deterioration increase as manifestations of infectious toxicosis: thermoregulation disorders (unstable temperature (≥38,5⁰C or ≤36,0⁰C), inability to maintain body temperature independently), skin mottling, pallor with a grayish tint, perioral cyanosis and/or acrocyanosis, sclerema, jaundice of unclear genesis, early and prolonged yellowness of the mucous membranes and skin, polymorphic hemorrhagic rash (isolated, punctate petechiae, ecchymoses, confluent erythema, large hemorrhagic and necrotic foci from birth or in early stages, of various localization), other manifestations of hemorrhagic syndrome (gastric, pulmonary hemorrhage, macrohematuria, bleeding from skin puncture sites). The newborn may show a decreased or absent suck reflex, refusal to feed, lethargy, muscular hypotonia, hyperesthesia, irritability, or depression. Episodes of hypoglycemia or hyperglycemia, edema syndrome, respiratory disorders (apnea and/or tachypnea, increased oxygen demand, need for respiratory support), manifestations of cardiovascular insufficiency (bradycardia [mean HR less than 110 bpm] and/or tachycardia [mean HR over 180 bpm], other rhythm disturbances, arterial hypotension [mean arterial pressure below the 5th percentile for gestational age]) are noted. Gastrointestinal dysfunction is possible (enteral feeding intolerance, abdominal distension, weakened or absent bowel sounds on auscultation). In the presence of manifest/severe infection specific to the perinatal period, the following symptoms and syndromes may occur: sepsis-like syndrome (differential diagnosis with early neonatal sepsis is performed), hepatosplenomegaly, cytopenia (most often mono — leukopenia, thrombocytopenia), pneumonitis, hydrothorax, hepatitis (most commonly cholestatic), pathological jaundice, enterocolitis/hemocolitis, ascites.

Clinical manifestations of infection in intrauterine (antenatal) or intranatal infection in a newborn infant most often manifest in the first 72 hours of life (early infections); in the group of infants born with extremely low birth weight, manifestation may be delayed up to 5–7 days of life. In 85% of cases, symptoms of the infectious disease appear in the first 24 hours of life, often 6–8 hours after birth (very early infections); in 5% they develop within 24–48 hours; in 10% signs of infection emerge on days 2–3 of life. In preterm infants, the initial clinical manifestations begin from birth with respiratory distress symptoms, which masks them as neonatal respiratory distress syndrome.

General clinical signs in the diagnosis of an infectious-inflammatory process in newborns caused by perinatal infection present with non-specific symptoms. It is essential to perform a differential diagnosis with other infectious nosological forms, primarily including early neonatal sepsis and congenital pneumonia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of an infection specific to the perinatal period

To confirm the diagnosis of ISDPP, the following are necessary [4, 14, 15, 17-21]:

1) Detailed collection of the mother's obstetric-gynecological history and complaints (see sections 1.2, 2.1);

2) Visual therapeutic examination of the newborn with the identification of one or more symptoms of the disease (see section 1.6. Clinical Presentation);

3) Laboratory and instrumental investigations to rule out a focus of infection (lungs, urinary system, gastrointestinal tract [GIT], central nervous system [CNS]).

To confirm the realization of perinatal infection, the infant undergoes laboratory testing, and signs of the infectious process are evaluated [5, 40-45]:

1. Complete blood count (CBC) with differential:

   - leukopenia less than 5 × 10⁹/L or leukocytosis on days 1–2 of life greater than 30 × 10⁹/L; days 3–7 of life greater than 20 × 10⁹/L;

   - neutropenia: days 1–2 less than 5000/µL; days 3–5 less than 2000/µL; day 7 less than 1700/µL;

   - neutrophilia: greater than 20 × 10⁹/L on days 1–2 of life; greater than 7–9 × 10⁹/L on days 3–7 of life;

   - neutrophil index (NI): greater than 0.2;

   - neutrophil morphology (studied in doubtful cases): toxic granularity, vacuolization, appearance of Döhle bodies (basophilic inclusions in the cytoplasm);

   - thrombocytopenia: assessed using nomograms, depending on the gestational and chronological age of the infant.

2. Laboratory markers of systemic inflammatory response syndrome (SIRS) in a general routine biochemical blood test [5, 6, 46-53]:

   - elevated blood C-reactive protein (CRP) level (reference range according to the test system, method, and analyzer type) and other SIRS markers approved by the specific medical organization (MO) (procalcitonin, presepsin, etc.); given that newborns experience a physiological rise in C-reactive protein during the first 2 days of life, it is best performed no earlier than 24 hours after birth.

3. Metabolic changes:

   - episodes of glucose intolerance (at least twice, with an age-appropriate glucose infusion rate): hypoglycemia < 2.6 mmol/l; hyperglycemia > 10 mmol/l;

   - metabolic acidosis with lactatemia (serum lactate > 2 mmol/l).

4. In the presence of hemorrhagic syndrome: coagulogram (exploratory hemostasis assay).

In the early neonatal period, it is necessary to differentiate suspected infection manifested in the perinatal period (SIMP) from the following conditions and nosological entities of confirmed etiology:

- Intrauterine infections (congenital CMV infection, HSV types 1, 2, 6, toxoplasmosis);

- Neonatal sepsis;

- Neonatal respiratory distress syndrome (RDS);

- Congenital pneumonia;

- Meningitis;

- Carditis;

- Necrotizing enterocolitis;

- Congenital malformations (CM): of the heart, lungs, diaphragmatic hernia, intestines, kidneys;

- Inborn errors of metabolism (IEM);

- Inborn metabolic disorders;

- Asphyxia;

- Transient tachypnea of the newborn (TTN);

- Neonatal meconium aspiration;

- Persistent pulmonary hypertension of the newborn (PPHN).

2.1 Complaints and Anamnesis

Comments: maternal risk factors for perinatal-៊ីspecific infections include:

- presence of an acute or exacerbation of a chronic infectious and inflammatory disease;

- obstetric invasive diagnostic or therapeutic procedures;

- presence of clinical signs of acute and persistent infections, including bacterial infections, before or during labor;

- prolonged or frequent hospital stays of the mother during the current pregnancy, repeated courses of antibacterial, hormonal, and/or cytotoxic therapy;

- maternal laboratory findings prior to delivery: elevated CRP, leukocytosis (excluding leukocytosis following recent corticosteroid administration);

- detection of pathogens in the maternal birth canal, primarily group B Streptococcus (GBS) or its antigens;

- premature rupture of membranes (latent period ≥ 18 hours);

- maternal fever during labor ≥ 38° C lasting for more than 2 hours;

- intrauterine interventions during pregnancy;

- maternal antibacterial therapy immediately prior to delivery or during labor with broad-spectrum penicillins or reserve antimicrobial agents;

- clinical manifestations of chorioamnionitis or other intraamniotic infection;

- maternal consumption of raw meat, raw eggs, raw milk, or unwashed vegetables and fruits, or contact with cat feces during pregnancy (Toxoplasma gondii);

- vaginal delivery in the presence of a primary maternal herpes simplex virus type 1 or type 2 infection (herpes simplex virus);

- seronegative mothers who develop a primary infection during pregnancy (cytomegalovirus) or reactivation of cytomegalovirus infection in seropositive pregnant women (see Clinical guidelines "Congenital cytomegalovirus infection");

- maternal HIV infection;

- consumption of dairy and insufficiently heat-treated products (Listeria monocytogenes);

- bacteriuria during pregnancy.

The main symptoms of chorioamnionitis in any combination include febrile fever (body temperature 38.0°C), maternal tachycardia (100 bpm), fetal tachycardia (160 bpm), purulent or purulent-sanguinolent vaginal discharge, sometimes with a foul odor [66, 69]. From a diagnostic perspective, pathomorphological examination of the placenta and/or pathomorphological examination of biopsy (surgical) material of the placenta is of great importance, revealing characteristic inflammatory changes in the vessels of the fetal part of the placenta and the umbilical cord wall (deciduitis, funisitis, vasculitis, infiltration of placental tissues), which indicates a possible realization of the infectious process in the newborn and serves as an additional criterion for verifying the diagnosis of intrauterine infection or SIMP (pathomorphological examination of the placenta and/or pathomorphological examination of biopsy (surgical) material of the placenta is mandatory to confirm the diagnosis) [34, 35, 38, 66, 70, 71]. Signs of chorioamnionitis include inflammation of the fetal membranes, amniotic fluid, and decidual tissue.

Additional risk factors for SIMP realization [33, 67] include:

- gestosis and other maternal pregnancy complications;

- vitamin D deficiency;

- premature rupture of membranes;

- meconium-stained amniotic fluid with a specific odor;

- preterm labor;

- fetal distress;

- perinatal hypoxia and intrapartum asphyxia;

- family history of child mortality from severe bacterial infections under 3 months of age (suspected primary immunodeficiency).

When taking the maternal history, it is important to confirm the infection via microbiological (culture) testing of female genital discharge (and/or amniotic fluid) for aerobic and facultatively anaerobic microorganisms, and to administer rational antimicrobial therapy to reduce neonatal morbidity and purulent-septic complications in the mother [66, 72].

It is also necessary to review maternal vaccination records, epidemiological history, occupational hazards (working in childcare facilities, with animals, etc.), travel history, especially during pregnancy (characteristic of Epstein-Barr virus (EBV) infection, malaria, dengue fever, Zika viruses, etc.), history of exanthematous diseases during pregnancy; features of the current pregnancy course: thrombocytopenia of undetermined etiology, threatened and preterm labor, congenital malformations, fetal growth restriction (FGR), fetal hydrops, prior missed miscarriages and antenatal demise, placental insufficiency, poly- and oligohydramnios.

Neonatal factors include prematurity and intrauterine growth restriction (IUGR), especially the dysplastic type, multiple dysmorphic features, congenital malformations, and structural anomalies.

2.2 Physical Examination

• In newborns with suspected SIMP manifestation, it is recommended to perform a physical examination by organ systems [5, 6, 8, 9, 49, 50, 56, 58, 87, 119-129].

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

Comments: see section 1.6. Clinical Presentation.

2.3 Laboratory Diagnostics

• In newborns with suspected SIMP, it is recommended to perform a complete blood count (CBC) with differential leukocyte count (leukocyte formula), platelet count, calculation of the neutrophil index (NI), and absolute neutrophil count to detect inflammatory changes, with a repeat test at 48-72 hours of life and upon completion of the antibiotic course to decide on discontinuing or continuing (switching) antibacterial therapy [8, 73-78, 88].

To calculate the neutrophil index:

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

To perform a complete blood count (CBC) with differential leukocyte count (leukocyte formula) and platelet count:

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: an elevated NI and a low absolute neutrophil count are predictors of infection in newborns. The sensitivity of the absolute neutrophil count is 78%, specificity is 73%; the sensitivity of the NI is 78%, specificity is 75% [75-78, 88-90].

• In newborns with suspected SIMP, it is recommended to perform a microbiological (culture) blood test for sterility from the umbilical cord or peripheral vein and determine the susceptibility of microorganisms to antimicrobial chemotherapy drugs to detect and identify the pathogen, rule out neonatal sepsis, and determine the strategy of antibacterial therapy [58, 73, 81-83, 86-88, 91-93].

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

Comments: a rapid culture method (RCM – Shell vial assay) is preferred, if available at the medical organization.

Microbiological (culture) blood test for sterility (including cord blood) has high sensitivity and specificity for diagnosing intrauterine infection of bacterial etiology [93]. Modern microbiological tests make it possible to distinguish true bacteremia from contamination in blood culture (taking into account the capabilities of the medical organization). Blood culture is considered negative for Gram-negative microorganisms if no growth is observed within 48 hours, and for Gram-positive microorganisms if no colony growth is observed within 72 hours. At the same time, blood culture is highly likely to be considered contaminated if colony growth appears later than 72 hours of incubation. Modern systems allow identification of the pathogen in 77%, 89%, and 94% of cases respectively, at 24 hours, 36 hours, and 48 hours after blood collection. The absence of a positive blood culture result does NOT exclude the presence of an infectious process in the newborn (taking into account the capabilities of the medical organization).

• In a newborn with suspected specific intrauterine/perinatal infection (SIPI) who undergoes tracheal intubation, it is recommended to perform a microbiological (culture) sputum test for aerobic and facultatively anaerobic microorganisms, a microbiological (culture) sputum test for fungi (yeasts and molds), and determination of antimicrobial susceptibility to identify the pathogen, rule out pneumonia, and determine the antimicrobial therapy strategy [73, 81-83, 86, 87, 94].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: a rapid culture method (RCM – Shell vial assay) is preferred if available at the medical organization.

• If there are risk factors for SIPI or clinical and/or laboratory signs of infection in the mother, a newborn with suspected SIPI is recommended to undergo selective screening for infectious pathogens (Epstein-Barr virus, Cytomegalovirus, Parvovirus B19, HHV6, Herpes simplex virus types 1, 2, Varicella-Zoster virus, Rubella virus, Listeria monocytogenes, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus spp., Toxoplasma gondii, Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum, Ureaplasma spp., Chlamydia spp., Treponema pallidum) to identify SIPI pathogens (Appendix A.3.2) [5, 6, 15, 47, 88, 91, 185].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: the range of main tests is presented in Appendix A.3.2.

Blood PCR testing depends on the technical capabilities of the medical organization's laboratory. If quantitative testing is unavailable, qualitative testing is acceptable.

Upon receiving molecular genetic test results confirming the etiology of the infectious process, further management of the child is carried out in accordance with existing clinical guidelines for specific nosologies.

• In a newborn with suspected SIPI, it is recommended to test the serum C-reactive protein (CRP) level with a follow-up test in 48–72 hours to detect signs of systemic inflammatory response syndrome (SIRS) and at the end of the antimicrobial therapy course to determine the antibacterial therapy strategy (discontinuation or continuation of therapy) [95–104].

GCR BLEL 2Grade of Recommendation B (Level of Evidence - 2)

Comments: reference values are determined by the method used and the type of analyzer in the medical organization.

CRP begins to be produced 4-6 hours after the development of the infectious process, doubles after 8 hours, and reaches its peak at 36-48 hours. Evaluation of CRP in the first 6-8 hours after birth has a low sensitivity of 35-50% and 30% false-positive results [45, 46, 98, 99]. Therefore, CRP testing should be performed 24-48 hours after birth (earlier if indicated), and follow-up monitoring no earlier than 24-36 hours dynamically, which increases the sensitivity of this test to 74-98% and specificity to 71-94% [5, 45, 98-101]. An increase in CRP levels in the first 24-48 hours after birth can be influenced by non-infectious conditions in the newborn: trauma, meconium aspiration syndrome, ischemic tissue injury, and hemolysis [100-103]. Elevated CRP is an early sign of bacterial infection in term infants; in preterm infants, such a correlation has not been clearly proven (sensitivity 68.5%, specificity 85.5%) [102].

Determination and evaluation of other SIRS markers to rule out a generalized infectious process (neonatal sepsis) is carried out taking into account the capabilities of the medical organization:

- blood presepsin testing (sensitivity 80-94%, specificity 75-100%). It is known that the presepsin level does not depend on: gestational age, body weight, early postnatal age, or delivery mode. Blood presepsin and interleukin-6 tests are not used to determine further antimicrobial therapy strategies (discontinuation, switching, prolonging the course), but only for the early diagnosis of infectious diseases [53, 105-111, 116-118];

- blood interleukin-6 (IL-6) determination (sensitivity 83-95%, CI 71-90%, specificity 87-95%, CI 78-93%) [112, 113].

- blood procalcitonin (PCT) testing is evaluated according to the threshold value depending on age (hours) after birth (sensitivity 87–94%, specificity 74–90%). In newborns, a physiological increase in PCT is observed during the first 48 hours of life; a sign of infection is PCT greater than 2.5 ng/mL in the first 72 hours, and greater than 2.0 ng/mL after 72 hours [50]. PCT levels rise in the first days after trauma, surgery, severe burns, and in patients with invasive fungal infections [114, 115].

Determination and correct assessment of inflammatory markers, and the use of a combination of the above markers in the diagnostic process, increase the likelihood of establishing an infectious disease in a newborn [16, 95-118].

• In a newborn with suspected SIPI and neurological disorders characteristic of central nervous system infection, it is recommended to perform a lumbar puncture, microscopic examination of the cerebrospinal fluid, cell counting in a counting chamber (cytosis determination), and cerebrospinal fluid protein testing to rule out meningitis/encephalitis [58, 93, 94].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: before performing a lumbar puncture, it is necessary to stabilize the newborn's condition (respiratory therapy, treatment of shock, seizures, hemorrhagic syndrome).

• In a newborn with suspected SIPI and neurological disorders characteristic of central nervous system infection, it is recommended to perform a microbiological (culture) test of cerebrospinal fluid for aerobic and facultatively anaerobic opportunistic microorganisms, and determination of Herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in cerebrospinal fluid by PCR [5, 6, 58, 94].

For microbiological (culture) testing of cerebrospinal fluid for aerobic and facultatively anaerobic opportunistic microorganisms: Level of Recommendations C (Level of Evidence - 3)

For the determination of Herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) in cerebrospinal fluid by PCR:

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: determination of Herpes simplex virus types 1 and 2 DNA in cerebrospinal fluid by PCR depends on the technical capabilities of the regional medical organization's laboratory. If quantitative testing is unavailable, qualitative testing is acceptable.

Upon receiving molecular genetic test results confirming the etiology of the infectious process, further management of the child is carried out in accordance with existing clinical guidelines for specific nosologies.

• In a newborn with SIPI, to rule out urinary tract infection, it is recommended to perform a general (clinical) urinalysis [73, 86, 93, 185].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• In a newborn with suspected SIPI, to rule out urinary tract infection in case of pathological changes in the general (clinical) urinalysis, it is recommended to perform a microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms [58, 73, 86, 93].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

2.4 Instrumental Diagnostics

• In a newborn with suspected SIPI and respiratory disorders, it is recommended to perform a chest X-ray to rule out pneumonia [5, 6, 47-49, 73, 91, 119-124].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: it is necessary to determine the cause of respiratory disorders in the newborn and establish the appropriate diagnosis: congenital pneumonia, respiratory distress syndrome of the newborn, meconium aspiration syndrome, congenital malformations (CM) of the heart, CM of the lungs, interstitial lung diseases, etc.

• In newborns with suspected intrauterine infection of the lower respiratory tract (ISDPT), it is recommended to perform echocardiography (EchoCG), neurosonography (NSG), comprehensive ultrasound examination of the abdominal organs (US), and ultrasound of the kidneys and adrenal glands to assess the function of organs and systems [5, 6, 47, 49, 120].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: in case of concomitant disorders of various organs and systems, Echo-CG, NSG, and ultrasound can facilitate the timely prescription and correction of symptomatic therapy. It is necessary to rule out various somatic diseases (primarily congenital malformations: congenital heart disease, CNS, gastrointestinal tract, and urinary system (US)).

• In newborns with organ and system dysfunction, for the purpose of vital function monitoring and differential diagnosis, it is recommended to perform continuous bedside monitoring: heart rate (HR) measurement, respiratory rate (RR) measurement, blood pressure measurement in peripheral arteries (BP, incl. SBP), pulse oximetry (SpO2), general thermometry, and urine volume determination [5, 6, 47-49, 120, 125-127].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: in case of concomitant dysfunctions of various organs and systems, these studies can facilitate the timely prescription and correction of syndromic and symptomatic therapy.

2.5 Other Procedures

They are used when indicated in comorbid patients in accordance with the scope established for the diagnosis of the comorbid disease/condition.

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

3.1 Conservative Treatment

1. Etiotropic empirical antibacterial therapy is prescribed to newborns with clinical and/or laboratory-instrumental signs of probable or proven, but etiology-unspecified, healthcare-associated infections of the skin and subcutaneous tissue (ISDPP).

2. Justified intensive (symptomatic/supportive) therapy is performed when indicated: correction of metabolic and hemostasiological disorders, and manifestations of organ dysfunction.

3. Symptomatic therapy.

4. Rational feeding (total parenteral nutrition, partial parenteral nutrition, breastfeeding, feeding with breast milk substitutes, including adapted formula).

Etiotropic therapy

• For a newborn with clinical and anamnestical risk factors, 1–2 or more clinical symptoms and/or laboratory-instrumental signs of probable or proven, but etiology-unspecified, congenital (perinatal) infection, it is recommended to prescribe empirical antibacterial therapy (systemic antibacterial drugs, ATX code J01) at an early stage [129–149].

GOW CLOE 5Grade of Recommendation C (Level of Evidence - 5)

Comments: antibacterial therapy (ABT) for suspected implementation of perinatal infections is indicated at an early stage after birth in the following categories of children: patients with very low and extremely low birth weight (VLBW, ELBW); newborns who required invasive mechanical ventilation from birth due to severity of condition, and newborns with neonatal seizures. It is advisable to initiate ABT no later than 2 hours of life, and for ELBW newborns - in the delivery room.

Newborns with a birth weight of more than 1500 g are prescribed ABT if there are indications based on the results of the initial clinical and laboratory examination. ABT initiated for suspected perinatal infection in the first 24 hours of life is discontinued if there is no clinical, laboratory, and instrumental evidence confirming infection within 48-72 hours of life (following serum C-reactive protein measurement, and blood procalcitonin measurement if available).

Once a diagnosis of "perinatal infection" is established, the empirical ABT regimen is continued until the results of microbiological testing are obtained (microbiological (culture) blood test for sterility, microbiological (culture) sputum test for aerobic and facultatively anaerobic microorganisms, microbiological (culture) cerebrospinal fluid test for aerobic and facultatively anaerobic opportunistic microorganisms, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms), screening for infectious pathogens (Epstein-Barr virus, Cytomegalovirus, Parvovirus B19, HHV6, Herpes simplex virus types 1, 2, Varicella-Zoster virus, Rubella virus, Listeria monocytogenes, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus spp., Toxoplasma gondii, Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum, Ureaplasma spp., Chlamydia spp., Treponema pallidum) (Appendix A.3.2) and evaluation of the clinical, laboratory, and instrumental examination results, followed by a decision on whether to discontinue or continue targeted ABT (according to the susceptibility of the isolated microflora).

Upon normalization of SIRS marker levels and the results of the newborn's clinical, laboratory, and instrumental examination, ABT is discontinued (regimen in Appendix A3.4).

Initial ABT regimens (Appendix A3.3) [129, 132, 133, 143, 144].

Regimen A: involves administering antibacterial therapy to newborns whose maternal history is unremarkable. It is advisable to prescribe empirical ABT using broad-spectrum penicillins (ATX code J01CA) (ampicillin**), in combination with other aminoglycosides (ATX code J01GB) (#gentamicin**[140, 141], amikacin**, netilmicin) or monotherapy with a combination of penicillins, including combinations with beta-lactamase inhibitors (ATX code J01CR) (Ampicillin + [Sulbactam]**). In case of renal impairment, it is advisable to address the discontinuation of other aminoglycosides (ATX code J01GB) on an individual basis, taking into account the available anamnestic data, laboratory, and microbiological examination results of the patient.

Regimen B: involves administering antibacterial therapy to newborns whose maternal history includes aggravating factors: chorioamnionitis, intrauterine interventions, prolonged rupture of membranes (more than 18 hours), elevated CRP, fever during labor lasting more than 2 hours, maternal ABT immediately before and during labor, group B Streptococcus isolated from the cervical canal. Regimen "B" may also be considered in cases where there are neonatal risk factors for infection (e.g., VLBW, ELBW, mechanical ventilation). In this case, it is advisable to prescribe a combination of penicillins, including combinations with beta-lactamase inhibitors (ATX code J01CR) (Ampicillin + [Sulbactam]**) and other aminoglycosides (ATX code J01GB) (#gentamicin**[140, 141], amikacin**, netilmicin).

Preference is given to parenteral administration of systemic anti-infective drugs (ATX code J) (intravenous drug administration). Amoxicillin + clavulanic acid**-containing medications (ATX code J01CR) should not be prescribed due to the potential adverse effect of clavulanic acid on the intestinal wall, especially in premature newborns.

It is inadvisable to include first-generation cephalosporins (ATX code J01DB), second-generation cephalosporins (ATX code J01DC), third-generation cephalosporins (ATX code J01DD), or fourth-generation cephalosporins (ATX code J01DE) in the initial antibacterial therapy regimen due to the lack of activity against Listeria monocytogenes and Enterococcus spp., as well as the risk of necrotizing enterocolitis (NEC) and invasive candidiasis in ELBW newborns [129, 133, 145-148].

Regimen C: administration of targeted antibacterial therapy.

Targeted antibacterial therapy is used if the mother has flora resistant to the drugs of starting antibacterial therapy regimens "A" and "B" and/or after receiving the results of microbiological testing (microbiological (cultural) blood test for sterility, microbiological (cultural) sputum test for aerobic and facultatively anaerobic microorganisms, microbiological (cultural) cerebrospinal fluid test for aerobic and facultatively anaerobic opportunistic pathogens, microbiological (cultural) urine test for aerobic and facultatively anaerobic opportunistic pathogens), testing for infectious pathogens (Epstein-Barr virus, Cytomegalovirus, Parvovirus B19, HHV6, Herpes simplex virus types 1, 2, Varicella-Zoster virus, Rubella virus, Listeria monocytogenes, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus spp., Toxoplasma gondii, Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum, Ureaplasma spp., Chlamydia spp., Treponema pallidum) (Appendix A.3.2) in the newborn with determination of microorganism susceptibility to antimicrobial chemotherapy drugs [149-152].

If the isolated pathogens are not susceptible to systemic antibacterial drugs (ATC code J01) of the initial regimen, it is necessary to switch to systemic antibacterial drugs (ATC code J01) to which susceptibility has been identified, or transition to local protocols taking into account the microbiological monitoring of the department where the patient is located.

In case of increasing laboratory activity, as well as when nosocomial infection is suspected during ongoing initial therapy, it is advisable to test the patient's biological material from all available loci, with mandatory microbiological (cultural) blood test for sterility, after which correction of antibacterial therapy should be performed.

The duration and tactics of antibacterial therapy are determined individually in each case and depend on the severity of the child's condition and the normalization of clinical, laboratory, and instrumental data [131-137, 152-154, 156-161].

Pathogenetically substantiated intensive care

Intensive care is carried out in accordance with clinical/methodological guidelines depending on the existing comorbid disease/condition (normalization of acid-base balance, correction of respiratory and hemodynamic disorders, etc.) [5, 6, 47-49, 162, 163, 179].Symptomatic therapy

Symptomatic therapy includes prescribing therapy depending on the clinical manifestations of the infectious process (hemostatic, anticonvulsant, sedative, etc.) and is carried out according to the relevant clinical/methodological guidelines depending on the clinical manifestations of the infectious process.

Rational feeding

• For a newborn with an infection specific to the perinatal period, it is recommended to initiate enteral nutrition as early as possible (breast milk is preferred); if necessary, total parenteral nutrition, partial parenteral nutrition, and feeding with adapted infant formulas are performed [180-184].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: adequate enteral nutrition is indicated for the newborn, with preference given to breast milk for enteral feeding. If breastfeeding is impossible (insufficient lactation or presence of contraindications to breastfeeding on the part of the mother and child), the newborn is fed with an adapted infant formula. If enteral nutrition is impossible, in order to provide the requirements for proteins, fats, carbohydrates, electrolytes, and fluid volume appropriate for the gestational age, parenteral nutrition (PN) is indicated. PN is performed using parenteral nutrition solutions (ATC code B05BA). The following are used: amino acids (ATC code B05BA01), lipid emulsions (ATC code B05BA02), carbohydrates (ATC code B05BA03), electrolyte solutions (ATC code B05XA), calcium preparations (ATC code A12AA).

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

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

Depending on the severity of the condition, a newborn with suspected infection specific to the perinatal period must be transferred to the neonatal intensive care unit (NICU), intensive care ward, or neonatal pathology department.

A preterm infant requires a thermoneutral environment, limitation of sensory stimulation (protection from light, noise, touch), body temperature monitoring (general thermometry) depending on thermoregulation, and prevention of pain syndrome.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is carried out depending on the comorbid pathology and complications by specialized professionals (neurologist, ophthalmologist, etc.).

5. Prevention and Dispensary Observation

Prevention of infections specific to the perinatal period includes timely detection and treatment of infectious diseases in the mother during pregnancy, which are described/indicated in the relevant clinical guidelines, and compliance with the rules and regulations of the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (chapter on the sanitary and epidemiological regime in obstetric hospitals and neonatal departments) [38, 80, 164-176, 186-194].

6. Organization of Medical Care

Treatment of newborns with infections specific to the perinatal period is carried out in a 24-hour inpatient setting (NICU, intensive care ward, neonatal pathology and newborn department, or newborn unit in pediatric hospitals).

Indications for discharging a patient from a medical organization:

1) The child's condition has stabilized, and there are no signs of organ or systemic failure;

2) Normalization of inflammatory markers;

3) Withdrawal of antibiotic therapy at least 24 hours prior to discharge, with a complete blood count (CBC) performed and mandatory interpretation on the day before discharge;

4) Absence of other contraindications to discharge.

7. Additional Information

The prognosis of the disease may vary depending on the gestational age at birth, the severity of the infectious process, its duration, and the patient's comorbidity.

In extremely premature infants, immunocompromised patients, and those who have suffered perinatal-specific infections, the risk of developing periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), disability, and death increases.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Balashova Ekaterina Nikolaevna – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov Department of Anesthesiology and Intensive Care of the 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, Associate Professor at the Department of Neonatology of the Institute of Professional Education, 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, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), member of the Council of the Russian Society of Neonatologists.

2. Belousova Tamara Vladimirovna – Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics and Neonatology, Novosibirsk State Medical University of the Russian Ministry of Health, Honored Doctor of Russia.

3. Bem Elena Venediktovna – Candidate of Medical Sciences, Assistant Professor at the Department of Neonatology with Courses in Neurology and Obstetrics and Gynecology, Faculty of Postgraduate and Additional Professional Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.

4. Zelenin Nazar Martovich – Head of the Neonatal Intensive Care Unit of the Perinatal Center, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.

5. Ivanov Dmitry Olegovich – Doctor of Medical Sciences, Professor, Rector of the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Head of the Department of Neonatology with Courses in Neurology and Obstetrics and Gynecology, Faculty of Postgraduate and Additional Professional Education, Chief Neonatologist of the Russian Ministry of Health.

6. Izvekova Irina Yakovlevna – Doctor of Medical Sciences, Professor at the Department of Infectious Diseases, Novosibirsk State Medical University of the Russian Ministry of Health.

7. Myznikova Irina Vladimirovna – Head of the Department of Pathology of Newborns and Young Infants of the Perinatal Center, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Assistant Professor at the Department of Neonatology with Courses in Neurology and Obstetrics and Gynecology, Faculty of Postgraduate and Additional Professional Education.

8. Marina I. Levadneva – Head of the Department of Neonatal Physiology at the Perinatal Center of Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation; Assistant at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education.

9. Anna S. Nabieva – Candidate of Medical Sciences, Head of the Epidemiological Department at Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

10. Dmitry Yu. Ovsyannikov – Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics at Peoples' Friendship University of Russia.

11. Svetlana E. Pavlova – Assistant at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

12. Aleksandra S. Panchenko – Doctor of Medical Sciences, Professor at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

13. Larisa A. Fedorova – Candidate of Medical Sciences, Associate Professor at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

14. Larisa A. Romanova – Candidate of Medical Sciences, Associate Professor at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

15. Galina N. Chumakova – Doctor of Medical Sciences, Professor at the Department of Neonatology with Courses in Neurology and Obstetrics-Gynecology, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

16. Ekaterina E. Yakovleva – Candidate of Medical Sciences, Head of the Clinical Pharmacology Department, Associate Professor at the Department of Pharmacology with a Course in Clinical Pharmacology and Pharmacoeconomics, Saint Petersburg State Pediatric Medical University, Ministry of Health of the Russian Federation.

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 these guidelines included publications indexed in the Cochrane Library, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, eLibrary, and clinicaltrials.gov, as well as 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 30 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 reviewed.

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 as a draft version for discussion. The updated version for broad discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro and https://portalcr.minzdrav.gov.ru/ to enable all interested parties to participate 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. Pediatricians

3. Obstetricians-gynecologists

4. Anesthesiologists-Resuscitators

5. General practitioners (family physicians)

6. Medical students

7. Residents in clinical training specialties: neonatology, pediatrics, anesthesiology and critical care, obstetrics and gynecology

Table 1.Scale for evaluating levels of evidence (LoE) 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, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Related Documents

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 Healthcare Protection in the Russian Federation".

2. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "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 Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

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."

6. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs, 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. State Register of Medicines: https://grls.rosminzdrav.ru.

8. Order of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'."

Appendix A3.2 Main spectrum of molecular biological tests for infectious pathogens occurring in the perinatal period

This appendix contains the main range of medical services for the most common infectious disease pathogens. The panel may be expanded if the mother is diagnosed with uncommon infectious diseases.

Appendix A3.3 Antibacterial therapy

Doses, frequency, and routes of administration of systemic antibacterial drugs (ATC code J01) used in newborns are presented in accordance with the official product labeling (instructions for medical use).

Appendix A3.3.1. Dosing regimens for systemic antibacterial drugs (ATC code J01) approved for use in the neonatal period

When prescribing systemic antibacterial drugs (ATC code J01), one should follow the product labeling. If it is necessary to prescribe a systemic antibacterial drug off-label based on the susceptibility of isolated microflora for life-saving indications, approval by a medical commission/consilium and informed consent of the patient's legal representative are required.

Appendix A3.4 Adjustment of antibacterial therapy

Antibacterial therapy is adjusted/changed:

• if there is no clinical response to the prescribed systemic antibacterial drug (ATC code J01) within 48–72 hours;

• if adverse effects develop during the administration of the prescribed systemic antibacterial drug (ATC code J01) / drug combinations;

• when using systemic antibacterial drugs (ATC code J01) with cumulative toxicity and limited duration of use.

If convincing evidence confirming an infectious disease is not obtained, antibacterial therapy should be discontinued!

Discontinuation of antibacterial therapy:

Diagram

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Perinatal-specific infection is an infectious and inflammatory disease of the fetus and newborn infant during the first 7 days of life, caused by pathogenic microorganisms, most commonly of bacterial etiology. Infection occurs in utero or during childbirth.

In the fetus, the development of an infectious state may manifest as congenital malformations, preterm birth, growth restriction, and intrauterine fetal death. Clinical symptoms in the infant after birth may appear from the first hours of life or develop gradually, and manifestations of infection are non-specific. The infectious inflammatory process may be localized in a specific organ or assume a systemic (generalized) character; asymptomatic or subclinical courses are possible.

The newborn infant exhibits behavioral changes, feeding difficulties, and the development of organ and system failure, which requires investigation and inpatient treatment. The prognosis for an infant with this condition depends on the severity of the disease, the infectious pathogen, and the duration of the intrauterine infectious process. With timely diagnosis and treatment and in the absence of complications, the prognosis is favorable.

It has been known worldwide for many years that the most common causative agents of perinatal-specific infections are group B streptococcus and Escherichia coli, which are typically present in pregnant women. The fetus and newborn infant are much more susceptible to infection due to the immaturity of the immune system.

Regular monitoring and medical examination during pregnancy for potential infectious and inflammatory diseases of the urogenital system in women are essential. Treatment and eradication of the infection are necessary.

During pregnancy, the expectant mother must understand the danger of contracting bacterial and viral infections. Prevention consists of limiting the pregnant woman's attendance at mass gatherings (public transport, shopping malls, railway stations, airports), especially during the period of emerging viral epidemics.

Timely registration of a pregnant woman at the antenatal clinic, follow-up, compliance with all recommendations of the obstetriciangynaecologist, and adherence to preventive and epidemiological measures will help prevent the development of this disease.

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

Not applicable.