Neonatal Jaundice: Clinical Guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time assay

BD – bilirubin diglucuronide

BE – bilirubin encephalopathy

GA – gestational age

INR – international normalized ratio

IB – indirect bilirubin

DB – conjugated (direct) bilirubin

TSB – total serum bilirubin

EBT – exchange blood transfusion

PT – prothrombin time

PT – prothrombin index

TcB – transcutaneous (bilirubin measurement)

UDPGT – uridine diphosphate glucuronosyltransferase

CNS – central nervous system

RBCs – red blood cell components of donor blood

Hb – hemoglobin

Ht – hematocrit

Terms and Definitions

Jaundice is a clinical manifestation of elevated serum bilirubin concentration in a newborn, characterized by yellow discoloration of the skin and/or sclera of varying severity. Depending on the time of onset, severity, and duration, jaundice can be a sign of both a physiological increase in blood bilirubin concentration during early neonatal adaptation (a borderline normal state) and a manifestation of various congenital (including hereditary), perinatal, and postnatal diseases.

Neonatal jaundice is a term for specific perinatal conditions manifesting as jaundice in the neonatal period, caused by the excessive accumulation of indirect bilirubin in the blood under the influence of various pathological factors not associated with isoimmunization or preterm birth at less than 35 weeks of gestation.

Neonatal hyperbilirubinemia (in term and late preterm infants born at 35/⁰ weeks of gestation or more) is an increase in total serum bilirubin concentration exceeding 256 µmol/L;

Neonatal bilirubin encephalopathy is a toxic-metabolic brain injury caused by an elevated blood bilirubin concentration (primarily the indirect fraction) against the background of other metabolic disorders. In term and late preterm infants, it develops acutely in severe hyperbilirubinemia (exceeding 340 µmol/L) and is characterized by rapid central nervous system depression, specific neurological symptoms, and/or seizures.

Skin phototherapy is a method of treating indirect hyperbilirubinemia in newborns, which involves exposing the newborn's skin to light in the blue or blue-green spectrum.

Standard phototherapy is a method of exposing the maximum possible surface area of a newborn infant's body to artificial light sources providing a standard spectral irradiance at the skin surface of 8–10 µW/cm²/nm in the light emission range of 425–475 nm (using a neonatal phototherapy illuminator or a neonatal fiber-optic phototherapy system).

Intensive phototherapy is the exposure of the maximum possible surface area of a newborn infant's body to artificial light sources providing a standard spectral irradiance at the skin surface of more than 30 µW/cm²/nm in the light emission range of 425–475 nm (using a neonatal phototherapy illuminator or a neonatal fiber-optic phototherapy system).

Exchange blood transfusion is the partial or complete removal of blood from the recipient's bloodstream with simultaneous replacement by an adequate volume of donor blood components.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Neonatal jaundice (except for jaundice caused by isoimmunization and preterm birth at less than 35 weeks of gestation) is associated with the effect of various pathological factors on the newborn's body: hemorrhages, polycythemia, swallowed maternal blood, and others [1–4]. The appearance of jaundice is caused by a pathological increase in the concentration of indirect (unconjugated) bilirubin in the blood.

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

The primary source of free bilirubin (FB) formation in the body of a newborn infant is hemoglobin (Hb) from erythrocytes destroyed within the mononuclear phagocyte system, primarily in the liver and spleen [5].

FB is highly lipid-soluble but poorly water-soluble. Through the biochemical transformation of hemoglobin from aging erythrocytes, 75–80% of free bilirubin is formed in the body. The remaining 20–25% is formed as a result of the destruction of immature erythrocyte forms directly in the bone marrow, as well as from the heme moiety of iron-containing enzymes and myoglobin.

After formation in the cells of the mononuclear phagocyte system, FB binds to albumin and is transported by the blood to the liver, where it is conjugated with glucuronic acid molecules.

FB can be displaced from its bond with blood albumin by chemically more active compounds (drugs, unesterified fatty acids). Impairment of the bilirubin-binding capacity of albumin in neonatal hyperbilirubinemia is one of the main factors facilitating the penetration of bilirubin across the blood-brain barrier. The binding strength of bilirubin to albumin is significantly reduced in hypoxemia, hypercapnia, and metabolic acidosis [6,7].

The conjugation process in hepatocytes is catalyzed by the microsomal enzyme uridine diphosphate glucuronosyltransferase (UDPGT). Bilirubin diglucuronide (BD), formed as a result of bilirubin conjugation, is a water-soluble substance with lower neurotoxicity than free bilirubin [8,9]. BD is excreted with the bile flow into the lumen of the duodenum, followed by the formation of mesobilirubin and mesobilinogen (urobilinogen). From the small intestine, part of the formed substances is reabsorbed through the intestinal wall, enters the portal vein, and is carried by the bloodstream to the liver, where it is completely broken down into di- and tripyrroles [10]. Most of the mesobilinogen from the small intestine enters the large intestine, where it is reduced to stercobilinogen by anaerobic microflora and eliminated from the body [11].

The key features of bilirubin metabolism in newborns are [1,2,12]:

• the rate of FB formation is 2 times higher than in adults, which is due to a large number of circulating red blood cells, a shorter erythrocyte lifespan, and the presence of

• fetal hemoglobin;

• lower plasma albumin levels compared to adults, which impedes its transport to the liver.

• extremely low activity of hepatic UDPGT after birth, which gradually increases to 30–50% of adult enzyme activity during the first month of life;

• visible staining of the skin and sclera in hyperbilirubinemia in newborns occurs at a minimal bilirubin concentration 1.5–2 times higher than the corresponding level in adults.

Excessive hemolysis pathogenetically associated with ecchymoses (bruises), hemorrhages, infections, polycythemia, as well as the action of drugs and toxins transferred from the mother's body or directly entering the newborn's body, and the swallowing of maternal blood, creates prerequisites for the development of clinically significant indirect hyperbilirubinemia, which can lead to bilirubin encephalopathy (kernicterus).

1.3 Epidemiology of the Disease or Condition

Jaundice occurs in more than 60% of term and more than 80% of late preterm newborns. The incidence of severe neonatal jaundice among hospitalized newborns in different regions of the world ranges from 8.31 to 31.49% [13].

1.4 Features of Coding the Disease or Condition

P58.0 – Neonatal jaundice due to bruising

P58.1 – Neonatal jaundice due to hemorrhage

P58.3 – Neonatal jaundice due to polycythemia

P58.5 – Neonatal jaundice due to swallowed maternal blood

P58.8 – Neonatal jaundice due to other specified excessive hemolysis

P58.9 – Neonatal jaundice due to excessive hemolysis, unspecified

P59.8 – Neonatal jaundice from other specified causes

P59.9 – Neonatal jaundice, unspecified

1.5 Classification of the disease or condition

Neonatal jaundice refers to transient disorders of bilirubin metabolism of various etiologies with a predominance of overproduction of indirect bilirubin from blood erythrocytes. Depending on the clinical conditions in which they develop, they are classified according to ICD-10 (see section 1.4)

1.6 Clinical presentation of the disease or condition

Pathological jaundice caused by the accumulation of indirect bilirubin in the blood, not associated with isoimmunization and preterm birth at 34 weeks of gestation or less, is characterized by the presence of at least one of the following signs: [1]

• early onset (before 24 hours of life);

• pronounced discoloration of the skin of the torso and extremities;

• increase in blood total bilirubin concentration exceeding 256 µmol/L;

• progression after 3–4 days;

• prolonged persistence after birth (more than 3 weeks of life).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of neonatal jaundice

The diagnosis of neonatal jaundice in newborns is established based on:

1) clinical and anamnestic screening: identification of the newborn risk group;

2) clinical and laboratory examination: visual monitoring of the time of onset and rate of progression of jaundice; determination of the transcutaneous bilirubin index; blood total bilirubin assay; blood free and conjugated bilirubin assay.

2.1 Complaints and Anamnesis

When taking the history of a patient with suspected neonatal jaundice, attention should be paid to risk factors and a burdened perinatal history: the likelihood of congenital and perinatal infections, birth injuries, polycythemia (due to intrauterine growth restriction, diabetic fetopathy, etc.), as well as the potential use of medications or exposure of the fetus and newborn to toxins (including those crossing from the maternal organism) during pregnancy and childbirth, and the possibility of swallowing a significant volume of maternal blood.

The following newborns should be classified as being at high risk for the development of neonatal jaundice caused by a pathological increase in serum unconjugated bilirubin: [14–17]

- with an elevated hemoglobin concentration or increased hematocrit of peripheral or venous blood;

- infants with rapid progression of jaundice;

- infants in whom the progression of jaundice is accompanied by a progressive decrease in hemoglobin concentration or a drop in hematocrit;

- infants with suspected swallowed blood syndrome;

- infants in whom neonatal jaundice has developed against the background of bruising (ecchymoses), cephalohematoma, bleeding, congenital and acquired infectious diseases, or maternal exposure to medications or toxins.

2.2 Physical Examination

Comments: The therapeutic visual examination includes: inspection of the skin and mucous membranes (changes in skin and mucosal color), palpation for diseases of the blood and hematopoietic system (spleen), and palpation for diseases of the liver and biliary tract. Early onset of jaundice (within the first 24 hours of life), rapid progression, or an increase in jaundice after 4 days against the background of developing anemia or polycythemia strongly indicate excessive hemolysis. Initially, a yellow color appears on the skin of the infant's face and torso. Further increase in bilirubin concentration, regardless of the cause, leads to the spread of jaundice and staining of the skin of the extremities. An increase in bilirubin concentration above 255–306 µmol/L is accompanied by staining of the palms and soles.

2.3 Laboratory Diagnostics

Comments: In the complete blood count (CBC), the following parameters must be evaluated: red blood cell count, total hemoglobin level, hematocrit (to rule out polycythemia as a cause of excessive hemolysis, or anemia as a consequence of excessive hemolysis); and platelet count in the presence of hemorrhagic syndrome.

Comments: Indications for standard laboratory testing of blood total bilirubin and free and conjugated bilirubin levels: in all newborns with jaundice within the first 24 hours; in newborns with signs of hemolysis or other known risk factors for pathological jaundice; in full-term and late preterm infants if the transcutaneous bilirubin index is: greater than 140 µmol/L at 24–48 hours of age; greater than 200 µmol/L at 48–72 hours of age; greater than 250 µmol/L at over 72 hours of age.

Comments: All infants receiving skin phototherapy must undergo blood total bilirubin assays, and free and conjugated bilirubin assays no later than 24 hours after the initiation of skin phototherapy, and no later than 12 hours if there are indications for intensive care. The frequency and timing of subsequent blood total bilirubin tests during skin phototherapy are determined by the severity of hyperbilirubinemia: when the blood total bilirubin concentration approaches the threshold for exchange blood transfusion (EBT) – at least once every 12 hours (2–3 times a day); in other cases – at least once a day. Skin phototherapy may be discontinued if the serum total bilirubin concentration falls below the threshold values for skin phototherapy, taking into account postnatal and gestational/corrected age.

In the neonatal unit of an obstetric hospital, bilirubin levels are monitored once, 12 hours after the completion of the skin phototherapy session. If the infant's condition is satisfactory and the bilirubin concentration remains below the values requiring repeated skin phototherapy, discharge from the hospital within the next 24 hours may be considered. In other cases, it is necessary to decide whether continued treatment is required in the neonatal ward or NICU (depending on the severity of the infant's condition and the rate of rebound hyperbilirubinemia).

Comments: The most significant changes in newborns with neonatal jaundice caused by bruising or bleeding pertain to prothrombin complex parameters: prolongation of PT, often by 4 times or more, a marked decrease in prothrombin index (PTI), and an increase in INR ≥ 4; prolongation of APTT is also characteristic.

2.4 Instrumental Diagnostics

Comment: Determination of the transcutaneous bilirubin index (TBI) in newborns is the measurement of total bilirubin using special devices based on light reflected from the skin and subcutaneous tissues. In the range of total bilirubin concentrations from 100 to 255–280 µmol/L, there is a direct linear correlation between skin and serum bilirubin levels in full-term and preterm infants with a gestational age of more than 35 weeks. When the TBI exceeds 255 µmol/L, the linear correlation between skin and serum bilirubin decreases, which requires re-checking the bilirubin level using standard laboratory methods. TBI determination is valid prior to the initiation of skin phototherapy. To assess the efficacy of skin phototherapy, it is valid to measure TBI 30 minutes after the end of skin phototherapy only on covered skin areas (forehead).

To determine the risk of developing pathological hyperbilirubinemia, it is advisable to use percentile curves (Appendix A3.2). The first test should be performed at 24-36 hours of life. If risk zone 2 (below average) is identified, a repeat test is indicated in 24 hours; if risk zone 3 (above average) is identified, in 12 hours; and in the case of zone 4 (high risk), in 4-6 hours.

2.5 Other Procedures

Comment: Given that hyperbilirubinemia is a significant risk factor for hearing loss, newborns who have received skin phototherapy undergo hearing testing using otoacoustic emissions.

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

3.1 Conservative Treatment

Comments: in full-term and late preterm infants (gestational age of 35 weeks or more) with unconjugated hyperbilirubinemia in the early neonatal period, management is based on determining threshold values of total serum bilirubin depending on postnatal age in hours (Appendix A3.3).

Depending on the type of light source, the following types of skin phototherapy are distinguished:

• conventional – using a single light source (blue fluorescent lamps are most commonly used);

• LED (light emitting diode) phototherapy – using light-emitting diodes, providing lower bodily fluid losses;

• fiberoptic phototherapy – using a single neonatal fiberoptic phototherapy system through which the light beam passes to a flexible glowing surface on which the infant is placed or which can be wrapped around the infant (does not require eye protection);

• combination phototherapy – performed using two or more light sources (two or more units or a combination of photodynamic therapy lamps/skin phototherapy lamps), generally used to increase the efficacy of skin phototherapy in the absence of special medical equipment for high-dose ("intensive") phototherapy.

• Intensive (including combination) skin phototherapy is indicated for the treatment of both term and preterm newborns if the total serum bilirubin concentration is less than 50 µmol/L below the threshold value for exchange transfusion.

Technique of phototherapy using a neonatal phototherapy illuminator or neonatal fiberoptic phototherapy system:

• the undressed infant is placed in a closed-type neonatal incubator or an adjustable heated infant bassinet (the choice of mode depends on the infant's gestational age and thermoregulation characteristics, while the infant's body temperature should be within 36.6-37.0 ºC);

• the infant's eyes and the genitalia of male infants must be protected with protective phototherapy goggles and a disposable infant diaper;

• the phototherapy source is positioned above the infant at a height of 50-55 cm; if the infant is in a closed-type incubator, the distance from the upper wall of the closed-type incubator to the phototherapy lamp should be 5.0 cm;

• every 1-2 hours of phototherapy, it is necessary to change the infant's position relative to the light source by alternately turning them onto their back or abdomen;

• body temperature must be measured every 2 hours;

• during phototherapy, one must not rely on skin color and transcutaneous bilirubinometer readings;

• in some infants, an allergic rash may appear in response to phototherapy, stool frequency and color may change, and a bronze skin tint may develop, all of which disappear without a trace after skin phototherapy is discontinued.

Continuous skin phototherapy is carried out around the clock continuously; only breaks for feeding and procedures (no more than 30 minutes) are permitted. The need for additional fluids during skin phototherapy should only be considered if daily weight loss exceeds 5% or when breast milk is insufficient for adequate feeding. In cases of rapidly worsening jaundice, it is necessary to re-evaluate the total serum bilirubin level 12 hours after the start of skin phototherapy and perform a follow-up total serum bilirubin test 12 hours after the end of skin phototherapy.

3.2 Surgical Treatment

Comments: Total bilirubin levels requiring exchange transfusion in full-term and late preterm infants (GA 35+ weeks) in the early neonatal period are presented in Appendix A3.3.

Upon the appearance of clinical signs of acute bilirubin encephalopathy (kernicterus), an exchange transfusion is performed regardless of laboratory total serum bilirubin results.

Technique of exchange transfusion:

- place the infant in a pre-warmed open-type neonatal incubator or closed-type neonatal incubator;

- secure the infant's limbs by reliable swaddling, keeping the abdominal skin exposed;

- place a umbilical catheter with a pre-attached stopcock for intravenous infusion systems (three-way stopcock) with strict adherence to asepsis and antisepsis rules and secure it;

- in the presence of contraindications for umbilical vein catheterization, exchange transfusion is performed via any other central vein;

- donor blood components must be pre-warmed to a temperature of 36-37⁰ C;

- the volume of a single replacement (single blood removal) and single replenishment (single administration of donor blood components) depends on the infant's body weight, gestational age, and severity of condition (in term infants – 10-20 mL/kg, in preterm infants – 5-10 mL/kg with mandatory monitoring of hemodynamics, respiration, and renal function);

- the first portion of removed blood must be collected to test for free and conjugated bilirubin levels in the blood;

- next, successive gradual removal of the infant's blood and subsequent replenishment of the removed volume are performed;

- the rate of a single replacement is 3-4 mL/min;

- for every 2 syringes of red blood cell-containing donor components (RBCs), 1 syringe of fresh frozen plasma is administered;

- after every 100 mL of replacement medium (RBCs and plasma), intravenously administer calcium gluconate** (ATX code A12AA03) – 10% solution 0.3 mL/kg or calcium chloride (ATX code B05XA) 10% solution 0.3 mL/kg, pre-diluted in 5.0 mL of dextrose** (ATX code B05CX) 5% solution (strictly between syringes containing RBCs!);

- before the end of the procedure, blood is sampled for bilirubin;

- as a result of the procedure (taking into account the blood sampled for biochemical testing), the total volume of administered donor blood components must equal the total volume of the infant's blood removed.

Absolute efficacy of the exchange transfusion is indicated by a more than 2-fold decrease in bilirubin by the end of the procedure.

3.3 Other Treatment

The therapeutic and protective regimen involves creating optimal conditions for nursing newborns.

Feeding of infants with neonatal jaundice is carried out either with breast milk or a standard infant formula for feeding from birth (or a specialized infant formula for feeding preterm and low-birth-weight infants depending on gestational age) if breastfeeding is not possible.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation depends on the extent of central nervous system damage due to bilirubin encephalopathy and neurological complications.

5. Prevention and Dispensary Observation

5.1 Prevention

An important condition for the prevention of hyperbilirubinemia in newborns is creating optimal conditions for the early neonatal adaptation of the child. All healthy and conditionally healthy newborns need early (starting from the first hour of life) and regular breastfeeding. In cases of contraindications to early breastfeeding or excessive initial weight loss by the 3rd–4th day of life, newborns must be provided with supplementary feeding using an adapted infant formula for newborns (or a specialized infant formula for premature and low-birth-weight infants, depending on gestational age). In all cases of neonatal illness, it is necessary to ensure the maintenance of an optimal body temperature and provide the body with a sufficient amount of fluids and nutrients. [5]

5.2 Dispensary monitoring

Follow-up dispensary observation of a child who has undergone neonatal jaundice due to excessive hemolysis consists of:

1. dispensary appointment (examination, consultation) with a district pediatrician;

2. serial monitoring of total and direct bilirubin levels in the blood every 24–48 hours;

3. due to the high incidence of late-onset anemia, which may require a red blood cell transfusion, after discharge from the hospital it is necessary to monitor the total hemoglobin level in the blood every 2–4 weeks (more frequently if clinically indicated) during the first 3 months of life;

4. the issue of routine vaccinations is decided on an individual basis, taking into account the contraindications listed in the vaccine package inserts.

6. Organization of Medical Care

Indications for inpatient admission to a medical organization: presence of jaundice requiring skin phototherapy, or the appearance/progression of jaundice combined with changes in neurological status (lethargy, refusal to feed, etc.)

Indications for discharging a patient from a medical organization:

1) Satisfactory condition;

2) Stabilization of the child's condition has been achieved;

3) Blood testing for total bilirubin has been performed: monitoring serum total bilirubin levels after the completion of skin phototherapy via two consecutive measurements with a 12-hour interval;

4) There are no other conditions requiring inpatient treatment.

7. Additional Information

Factors influencing the outcome of the disease:

• Factors increasing blood-brain barrier permeability to bilirubin: blood hyperosmolarity, acidosis, cerebral hemorrhages, neuroinfections, arterial hypotension.

• Factors increasing the sensitivity of brain neurons to the toxic effects of unconjugated bilirubin: prematurity, severe asphyxia, malnutrition, hypoglycemia, anemia.

• Factors reducing the binding capacity of blood albumin for unconjugated bilirubin: prematurity, hypoalbuminemia, infection, acidosis, hypoxia, elevated levels of non-esterified fatty acids in the blood, use of sulfonamides (sulfonamides and trimethoprim [ATC code J01E]), use of furosemide** (ATC code C03CA01), antiepileptic drugs (ATC code N03A), non-steroidal anti-inflammatory and antirheumatic drugs (ATC code M01A), other analgesics and antipyretics (ATC code N02B), beta-lactam antibacterial drugs, penicillins (ATC code J01C), other beta-lactam antibacterial drugs (ATC code J01D) (first-generation cephalosporins [ATC code J01DB], etc.).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Elena Nikolaevna Baybarina – MD, Professor, Honored Scientist of the Russian Federation, Chief Researcher at the Department of Neonatal and Premature Infant Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Moscow, Russian Federation.

2. Ekaterina Nikolaevna Balashova – PhD, Leading Researcher at the Prof. A.G. Antonov ICU, Associate Professor at the Department of Neonatology, 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, Member of the Council of the Russian Society of Neonatologists

3. Nikolay Nikolaevich Volodin – Academician of the Russian Academy of Sciences, Professor, MD; President of the Russian Association of Perinatal Medicine Specialists, President of the Association of Specialists in Perinatal Medicine, Healthcare for Pregnant Women, Fetuses, Newborns, and Children under 3 Years of Age (ASPM+).

4. Petr Anatolyevich Goloshubov – Specialist at the Department of Regional Healthcare Analysis and Development, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Moscow, Russian Federation.

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

6. Anna Vladimirovna Degtyareva – MD, Professor, Head of the Department of Pediatrics, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University).

7. Viktor Vasilyevich Zubkov – MD, Director 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, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Member of the Council of the Russian Society of Neonatologists.

8. Anna Leonidovna Karavaeva – Head of Clinical Work at Neonatal Department No. 1, 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, Highest Category Physician, Member of the Russian Society of Neonatologists.

9. Mziya Ilyinichna Makieva – PhD, Head of Neonatal Department No. 2, Institute of Neonatology and Pediatrics, Assistant Professor at the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Highest Category Physician, Member of the Russian Society of Neonatologists.

10. Marina Viktorovna Narogan – MD, Leading Researcher at the Department of Neonatal and Premature Infant Pathology No. 1, Institute of Neonatology and Pediatrics, Professor at the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Member of the Council of the Russian Society of Neonatologists.

11. Irina Ivanovna Ryumina – MD, Professor, Head of the Department of Neonatal and Premature Infant Pathology No. 1, Institute of Neonatology and Pediatrics, Professor at the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health

12. Olga Alexandrovna Senkevich – MD, Professor, Head of the Department of Pediatrics, Neonatology, and Perinatology with a Course in Emergency Medicine, Institute of Continuing Professional Education and Accreditation, Far Eastern State Medical University of the Ministry of Health of the Russian Federation, Member of the Council of the Russian Society of Neonatologists.

13. Leyla Akakievna Timofeeva – PhD, Head of Neonatal Department No. 1, Institute of Neonatology and Pediatrics, Associate Professor at the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Highest Category Physician, Member of the Russian Society of Neonatologists.

14. Tamara Kureyshevna Tsetsoeva – Specialist at the Department of Neonatal and Premature Infant Pathology No. 2, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

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, eLIBRARY, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and the European Society for Neonatology. The search depth was 34 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

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

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

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

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

Economic analysis:

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

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

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

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

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

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

Consultation and peer review:

Recent changes to these guidelines are presented for discussion in a preliminary version. An updated version for wide discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro, the Association of Specialists in Perinatal Medicine, Maternal, Fetal, Newborn and Child Health Care (ASPM+) www.raspm.ru, 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. Pediatricians,

2. Neonatologists;

3. Anesthesiologists-intensivists;

4. Pulmonologists;

5. General practitioners (family physicians);

6. Medical students;

7. Residents and interns.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, 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 rehabilitative 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 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

2. Order of the Russian Ministry of Health No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

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

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services" (Registered with the Russian Ministry of Justice on November 7, 2017, No. 48808)

5. Rules for the provision of medical care in the specialty "Neonatology" (Order of the Ministry of Health of the Russian Federation No. 921n dated November 15, 2012).

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 Drugs for Medical Use and the Minimum Assortment of Drugs Required for the Provision of Medical Care"

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

8. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 44 dated December 24, 2020, On Approval of Sanitary Rules SP 2.1.3678-20 "Sanitary and epidemiological requirements for the operation of premises, buildings, structures, equipment, and transport, as well as the conditions for the activities of business entities engaged in the sale of goods, performance of work, or provision of services."

Appendix A3.2 Determination of the risk of developing pathological hyperbilirubinemia based on transcutaneous bilirubin index measurement.

Determination of the risk of developing pathological hyperbilirubinemia in newborns of various gestational ages based on transcutaneous bilirubin measurement [1].

Appendix A3.3 Indications for skin phototherapy and exchange transfusion in newborns

Indications for standard skin phototherapy in newborns ("New 2017 revised Kobe University treatment criteria") [1, 52].

Indications for intensive skin phototherapy in newborns ("New 2017 revised Kobe University treatment criteria") [1, 52].

Indications for exchange transfusion in newborns ("New 2017 revised Kobe University treatment criteria") [1, 52].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Neonatal jaundice is a condition characterized by an elevated level of bilirubin in the blood.

The newborn's blood contains a high number of red blood cells with so-called fetal hemoglobin, which must be replaced by "regular" hemoglobin after birth. These red blood cells have a short lifespan and undergo rapid, massive destruction. The situation is further aggravated by the fact that the activity of the enzyme uridine diphosphate glucuronosyltransferase (UGT), which is necessary for bilirubin conjugation, is much lower in newborns compared to adults. In other words, the liver's resources are insufficient to neutralize and excrete all the bilirubin, causing unconjugated (insoluble, toxic) bilirubin to accumulate in the baby's body.

Neonatal jaundice differs from physiological jaundice in its time of onset, rate of progression, and clinical course. To identify symptoms of jaundice, a visual therapeutic examination is performed, which includes assessing changes in skin and mucosal color. A more objective method for assessing the rate and degree of bilirubin accumulation in the infant's skin is transcutaneous bilirubin measurement using specialized devices. However, at high transcutaneous bilirubin concentrations, venous bilirubin levels must be monitored using standard laboratory methods.

Bilirubin encephalopathy is a severe condition associated with the toxic effects of high bilirubin concentrations on the newborn's brain. Skin phototherapy is performed to reduce pathologically high concentrations of unconjugated bilirubin in the baby's blood and prevent its toxic effects on the brain. The baby is placed in a special device where short light waves transform the bilirubin. This breaks down the toxin into safe, water-soluble isomers that are easily processed by the liver and partially by the kidneys. Within a few hours, they are rapidly and naturally eliminated from the body.

If the baby's bilirubin level is extremely high or rises very rapidly, phototherapy alone is not sufficient. In such cases, an exchange transfusion is used to reduce the amount of bilirubin in the baby's blood.

Neonatal jaundice is treatable—this is the most important thing. In each individual case, the management tactics depend on the indications and symptoms. It is essential for parents to maintain a positive attitude and follow the pediatrician's recommendations; these factors are the key to success, meaning that with effective treatment, mother and baby can be discharged home very soon.

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

Not applicable.