List of Abbreviations
BE – bilirubin encephalopathy
GA – gestational age
MRI – magnetic resonance imaging
IB – indirect bilirubin
TB – total bilirubin
ET – exchange transfusion
VLBW – very low birth weight
DB – conjugated (direct) bilirubin
PT – prothrombin time
PT – prothrombin index
FB – free bilirubin
CA – corrected age
TBI – transcutaneous bilirubin index
TcB – transcutaneous (bilirubin measurement)
UDPGT – uridine diphosphate glucuronosyltransferase
ELBW – extremely low birth weight
RBCs – red blood cell components of donor blood
Hb – hemoglobin
Ht – hematocrit
Terms and Definitions
Jaundice of the preterm newborn — yellow discoloration of the skin and/or sclera of varying severity; a clinical manifestation of an increase in blood bilirubin concentration above 120 µmol/L.
Hyperbilirubinemia of the preterm newborn (excluding infants born at 35/0 weeks of gestation or more) — an increase in serum total bilirubin concentration above 171 µmol/L, predominantly due to the unconjugated fraction.
Bilirubin encephalopathy of the premature newborn (BE) is a toxic-metabolic brain injury caused by an elevation in the total blood bilirubin concentration. Unlike term newborns and premature infants born at a gestational age of 35/0 weeks or more, BE in extremely premature infants (GA of 34 weeks or less) develops subacutely. Furthermore, the toxic effect of bilirubin on brain neurons and neuroglial cells can occur at serum total bilirubin (TB) concentrations below 342 µmol/L. The individual threshold for toxic-metabolic brain injury in hyperbilirubinemia is determined by the degree of morphofunctional maturity of the blood-brain barrier and is inversely proportional to GA. In some cases, signs of toxic-metabolic brain injury in extremely premature infants are detected with a delay in the form of hearing impairment resembling auditory neuropathy, motor developmental delay with athetosis or dystonia, upward gaze palsy due to oculomotor nerve paresis, and high-intensity signal in the globus pallidus on brain MRI performed during the first year of life; these may be interpreted as manifestations of chronic bilirubin encephalopathy.
Skin phototherapy is a method of treating indirect hyperbilirubinemia in premature newborns, which involves exposing the newborn's skin to light in the blue or blue-green emission spectra.
Standard phototherapy is a method of exposing the maximum possible body surface area of a premature newborn to artificial light sources that provide a standard spectral power on 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 body surface area of a premature newborn to artificial light sources that provide a standard spectral power on 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
Hyperbilirubinemia of prematurity is an elevation of the total bilirubin concentration in blood plasma or serum above 171 µmol/L (predominantly due to the indirect fraction), associated with impaired bilirubin conjugation in the liver due to its morphofunctional immaturity [1–3].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Bilirubin is a breakdown product of hemoglobin. During catabolism, globin is cleaved from heme, after which a part of the molecule is oxidized to form biliverdin, and then, under the action of biliverdin reductase, indirect ("free") bilirubin (FB) is formed from it [4,5]. The rate of bilirubin production in extremely premature infants is higher compared to term newborns and adults. After formation in the cells of the mononuclear phagocyte system, FB forms a weak chemical bond with albumin, in a complex with which it is transported via the blood to the liver, where it is conjugated with glucuronic acid molecules. Extremely premature infants exhibit relative hypoalbuminemia, which reduces the efficiency of bilirubin transport to the liver [6–9]. Bilirubin conjugation occurs in the endoplasmic reticulum of hepatocytes under the influence of uridine diphosphate glucuronosyltransferase (UGT1A1), resulting in the step-by-step formation of bilirubin monoglucuronide and then diglucuronide [10,11]. Due to the morphofunctional immaturity of the liver, UGT1A1 activity after birth develops significantly slower than in term newborns. This negatively affects the rate of bilirubin conjugation, excretion, and its subsequent elimination from the body.
The combination of low hepatic UGT1A1 activity with excessive hemolysis and relative hypoalbuminemia, along with immaturity of the blood-brain barrier, leads to a higher risk of developing bilirubin encephalopathy in extremely premature infants compared to term and late preterm newborns [12–14].
The risk of BE in extremely premature infants further increases in the presence of the following factors:
- severe congenital and neonatal infection [15];
- severe neonatal asphyxia (Apgar score of less than 4 points) (Appendix G1), arterial hypotension, apnea, need for mechanical ventilation (MV) [16];
- severe metabolic acidosis (arterial blood pH less than 7.15 for more than 1 h) [17];
- hypothermia (rectal temperature less than 35°C) [12];
- extensive soft tissue trauma during delivery (ecchymoses, massive cephalohematomas), periventricular, intraventricular, and subarachnoid hemorrhages [18];
- polycythemia syndrome [7,19];
- G-6-PD (glucose-6-phosphate dehydrogenase) deficiency [20,21].
1.3 Epidemiology of the Disease or Condition
Neonatal jaundice occurs in 80% of premature newborns. The global incidence of neonatal jaundice among newborns ranges from 8.31 to 31.49% [22].
1.4 Features of Coding the Disease or Condition
P59.0 – Neonatal jaundice associated with preterm delivery.
1.5 Classification of the disease or condition
There is no specific classification.
1.6 Clinical presentation of the disease or condition
Hyperbilirubinemia of prematurity is characterized by [1,23]:
- jaundice appearing in an infant born before 35 weeks of gestation during the early neonatal period at an age older than 24 hours of life;
- an increase in total blood plasma or serum bilirubin concentration by more than 171 µmol/L/day, predominantly at the expense of the indirect fraction.
In extremely premature infants, jaundice differs in intensity (rate of increase) and clinical course from jaundice in term infants, and timely diagnosis is difficult due to concurrent diseases and/or conditions in the neonatal period [24].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for establishing the diagnosis of neonatal jaundice
The diagnosis of hyperbilirubinemia of prematurity is established based on: medical history, visual assessment of skin and scleral color, laboratory test data (determination of the transcutaneous bilirubin index; study of free and bound bilirubin levels in the blood).
2.1 Complaints and Anamnesis
When taking the medical history of a patient with suspected hyperbilirubinemia of prematurity, attention should be paid to body weight and gestational age, perinatal risk factors: congenital and perinatal infections, birth trauma, severe neonatal asphyxia, postnatal arterial hypotension, apnea, need for mechanical ventilation (MV), etc.
2.2 Physical Examination
It is recommended to perform a therapeutic visual inspection of the premature infant to detect symptoms of jaundice associated with preterm delivery [25].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Therapeutic visual inspection includes: examination of the skin and mucous membranes (changes in skin and mucous membrane color), palpation in diseases of the hematopoietic and blood systems (spleen), and palpation in diseases of the liver and biliary tract.
2.3 Laboratory Diagnostics
It is recommended to test the total blood bilirubin level using a direct reagent-free two-wavelength photometry method (micromethod), including as part of a comprehensive panel on an acid-base balance, blood gas, electrolyte, glucose, and lactic acid analyzer, in a premature infant with suspected hyperbilirubinemia [26].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: The experience of using non-invasive (transcutaneous) methods for determining bilirubin in extremely premature infants is limited. When total bilirubin levels in capillary blood, determined by the direct reagent-free two-wavelength photometry method, exceed 171 µmol/L, venous blood sampling is necessary to perform a chemical colorimetric method for determining bilirubin as part of a standard general therapeutic biochemical blood test, in order to study the level of total, free, and bound bilirubin in the blood. The measurement accuracy of capillary blood plasma total bilirubin by portable analyzers and automatic biochemical analyzers is comparable up to a maximum plasma/serum bilirubin concentration of 280 µmol/L.
If it is impossible to test the total blood bilirubin level during the first three days of life using the capillary (micro-) method and in the absence of local protocols for using non-invasive (transcutaneous) methods for determining bilirubin in extremely premature infants, the indication for a chemical colorimetric method to determine bilirubin concentration in venous blood is the visual detection and progression of jaundice.
It is recommended to perform a general therapeutic biochemical blood test with determination of total, free, and bound bilirubin levels in the blood in a premature infant with suspected hyperbilirubinemia, when capillary blood total bilirubin levels are below threshold values adjusted for GA at 48–72 hours of life, to determine management tactics [27–29].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to perform a complete blood count (CBC) with differential in a newborn with hyperbilirubinemia to rule out excessive hemolysis, polycythemia, and an acute inflammatory response to infection [27,30].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: In a complete blood count (CBC) with differential, it is necessary to evaluate red blood cell parameters (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, as well as platelet, leukocyte, and neutrophil counts, and the neutrophil index.
It is recommended to test blood levels of total bilirubin, unconjugated and conjugated bilirubin in a preterm infant with hyperbilirubinemia dynamically after the initiation of therapy [31].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: All infants receiving skin phototherapy must undergo testing of blood total bilirubin, unconjugated and conjugated bilirubin levels no later than 24 hours after the start of skin phototherapy, and in the presence of indications for intensive care, no later than 12 hours. The frequency and timing of subsequent blood total bilirubin tests during skin phototherapy are determined by the severity of hyperbilirubinemia: when bilirubin concentrations approach the threshold for exchange transfusion (ET), testing should be performed 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 initiating skin phototherapy, taking into account postnatal and gestational/corrected age.
2.4 Instrumental Diagnostics
It is recommended to perform neurosonography in a preterm infant with hyperbilirubinemia to rule out intraventricular hemorrhage [32].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform a comprehensive abdominal ultrasound, renal and adrenal ultrasound in a preterm infant with hyperbilirubinemia to detect abdominal organ pathology and rule out internal bleeding [27,33–37].
GPP CLOE 5Grade of Recommendation C (Level of Evidence – 5) – for comprehensive abdominal ultrasound.
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4) – for renal and adrenal ultrasound.
It is recommended to determine the transcutaneous bilirubin index in a preterm infant with suspected hyperbilirubinemia for dynamic monitoring of bilirubin levels in order to minimize phlebotomy losses [38–43].
GRC CLOE 2Grade of Recommendation C (Level of Evidence – 2).
Comment: Determination of the transcutaneous bilirubin index (TBI) is the measurement of total bilirubin reflecting light from the skin and subcutaneous tissues using specialized devices. TBI determination is a fast, reliable, and painless method for diagnosing hyperbilirubinemia in extremely preterm infants; however, during ongoing skin phototherapy, TBI values should not be relied upon exclusively. When TBI exceeds 255 µmol/L, the linear correlation between skin and serum bilirubin concentrations decreases, requiring verification of bilirubin levels by standard laboratory methods. TBI determination is reliable prior to the initiation of skin phototherapy. To assess the efficacy of skin phototherapy, TBI is validly applied 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
It is recommended to perform an initial examination (evaluation, consultation) by a neurologist in a preterm infant with hyperbilirubinemia upon the appearance of neurological symptoms to diagnose central nervous system disorders and determine further management tactics [3,44].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to perform a hearing test using otoacoustic emissions in a preterm infant with hyperbilirubinemia after completion of skin phototherapy [45–47].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: Considering that hyperbilirubinemia is a significant risk factor for hearing loss, preterm 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
It is recommended to initiate skin phototherapy in a preterm infant with hyperbilirubinemia to reduce the risk of bilirubin encephalopathy [48–50].
GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).
Comments: In preterm infants, the likelihood of bilirubin encephalopathy develops at lower bilirubin concentrations than in term newborns and depends on blood bilirubin concentration and the infant's birth weight (Appendix A3.3). In infants born with very low birth weight (VLBW) and extremely low birth weight (ELBW), bilirubin encephalopathy can occur even after a moderate increase in serum total bilirubin concentration (in the range of 171–255 µmol/L).
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 body fluid losses;
- fiberoptic phototherapy – using a single neonatal fiberoptic phototherapy system through which the light beam passes to a flexible emitting surface on which the infant is placed or wrapped (does not require eye protection);
- combination phototherapy – performed using two or more light sources (two or more units or a combination of photodynamic therapy/skin phototherapy lamps), typically used to increase phototherapy efficacy when specialized medical equipment for high-dose ("intensive") skin phototherapy is unavailable.
- intensive (including combination) 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 initiating exchange transfusion.
In preterm infants with a gestational age of 34 weeks or less, standard skin phototherapy is advisable for the prevention of bilirubin neurotoxicity (Appendix A3.3.1). However, in the event of high blood bilirubin levels and/or a rapid rise of bilirubin to critical levels, intensive skin phototherapy should be initiated to reduce the risk of chronic bilirubin encephalopathy (Appendix A3.3.2). Skin phototherapy is continued until blood total bilirubin, unconjugated and conjugated bilirubin tests show concentrations below the values that indicated the initiation of skin phototherapy. In cases of rapid progression of jaundice, a repeat blood total bilirubin test must be performed 12 hours after the start of skin phototherapy, along with a follow-up blood total bilirubin test 12 hours after the end of skin phototherapy.
3.2 Surgical Treatment
It is recommended to initiate an exchange transfusion in a preterm infant with hyperbilirubinemia when blood total bilirubin levels rise to the threshold requiring exchange transfusion and/or phototherapy is ineffective [17,25,51,52].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: When skin phototherapy is ineffective, exchange transfusion is the primary surgical treatment for hyperbilirubinemia threatening the development of bilirubin encephalopathy. Detailed indications for exchange transfusion based on gestational age, postnatal age in hours, and blood total bilirubin levels are convenient from a practical standpoint (Appendix A3.3.3). Given the high risk of complications from exchange transfusion in extremely preterm infants, the final decision to perform the procedure in infants born before 32 weeks of gestation must be made by a medical concilium.
Technique of exchange transfusion:
- place the infant in a pre-warmed open-type neonatal incubator or a closed-type neonatal incubator with a conversion feature to an open type;
- 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 36–370C;
- the volume of a single replacement (single blood withdrawal) and a single replenishment (single administration of donor blood components) depends on the infant's body weight, gestational age, and clinical severity (10–20 mL/kg for term infants, 5–10 mL/kg for preterm infants under mandatory monitoring of hemodynamics, respiration, and renal function) [1];
- 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 (red blood cell suspension and plasma), intravenously administer calcium gluconate** (ATC code A12AA03) – 10% solution 0.3 mL/kg or calcium chloride (ATC code B05XA) 10% solution 0.3 mL/kg, pre-diluted in 5.0 mL of dextrose** (ATC code B05CX) - 5% solution (only between syringes containing red blood cell suspension!);
- 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 preterm infants with manifestations of neonatal jaundice associated with premature birth is carried out either with breast milk or with a special infant formula for 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 CNS 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 extremely preterm newborns is the creation of optimal conditions for the early neonatal adaptation of the infant. In all cases of neonatal disease, it is necessary to ensure the maintenance of optimal body temperature and supply the body with an adequate amount of fluids and nutrients.
5.2 Dispensary monitoring
Follow-up care (dispensary observation) of a preterm infant who has suffered from neonatal jaundice associated with premature birth consists of:
dispensary appointment (examination, consultation) with a district pediatrician;
serial monitoring of total blood bilirubin levels, as well as free and conjugated bilirubin levels in the blood;
due to the high incidence of late anemia, which may require an RBC transfusion, total blood hemoglobin levels must be measured every 2–4 weeks (more frequently if clinically indicated) during the first 3 months of life after hospital discharge;
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) Total blood bilirubin levels were assessed after the completion of skin phototherapy using two consecutive measurements with a 12-hour interval.
4) There are no other contraindications to discharge.
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 capacity of blood albumin to tightly bind 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), nonsteroidal anti-inflammatory and antirheumatic drugs (ATC code M01A), other analgesics and antipyretics (ATC code N02B), beta-lactam antibacterial drugs, penicillins (ATC code J01C), and other beta-lactam antibacterial drugs (ATC code J01D) (first-generation cephalosporins [ATC code J01DB], etc.).
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1. | Determination of total blood bilirubin was performed using a direct reagent-free two-wavelength photometry method (micromethod). | Yes/no |
2. | General biochemical blood test performed, including measurement of total bilirubin, free bilirubin, and conjugated bilirubin levels in the blood | Yes/no |
3. | Complete (clinical) blood count performed | Yes/no |
4. | Neurosonography performed | Yes/no |
5. | Ultrasound examination of the abdominal cavity (comprehensive), ultrasound examination of the kidneys and adrenal glands were performed. | Yes/no |
6. | Skin phototherapy was performed. | Yes/no |
7. | General therapeutic biochemical blood analysis was performed with serial assessment of total blood bilirubin levels, as well as free and conjugated bilirubin levels in the blood after the initiation of therapy. | Yes/no |
8. | In cases of ineffective skin phototherapy and/or the appearance of clinical symptoms of acute encephalopathy (muscle hypertonus, opisthotonos, fever, "brain" cry), an exchange blood transfusion was performed. | Yes/no |
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Morris B.H. et al. Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight // N. Engl. J. Med. 2008. Vol. 359, № 18. P. 1885–1896.
Wennberg R.P. et al. Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns // Pediatrics. 2006. Vol. 117, № 2. P. 474–485.
Kuint J. et al. Excessively high bilirubin and exchange transfusion in very low birth weight infants // Acta Paediatr. 2011. Vol. 100, № 4. P. 506–510.
Appendix A1. Working Group Composition
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.
Ekaterina N. Balashova – Cand. of Sci. (Med.), Leading Research Fellow, Prof. A.G. Antonov ICU, Associate Professor, 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.
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+).
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.
Elena V. Grosheva – Cand. of Sci. (Med.), Head of the Department of Pathology of Newborns and Preterm Infants No. 2, Institute of Neonatology and Pediatrics, Associate Professor, Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.
Dmitry N. Degtyarev – Dr. of Sci. (Med.), Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Head of the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Council of the Russian Society of Neonatologists.
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).
Ionov Oleg Vadimovich – MD, Head of the Prof. A.G. Antonov NICU, 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. Filatova 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), President of the Russian Society of Neonatologists.
Anna L. Karpova – Cand. of Sci. (Med.), Head of the Neonatal Hospital, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Associate Professor, Professor V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education (RMAPE) of the Russian Ministry of Health, Assistant Professor, Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Institute of Postgraduate Education, Yaroslavl State Medical University of the Russian Ministry of Health, Member of the Council of the Russian Society of Neonatologists.
Anna R. Kirtbaya – Dr. of Sci. (Med.), Head of Clinical Work, Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Russian Society of Neonatologists.
Olga A. Krog-Jensen – Cand. of Sci. (Med.), Neonatologist, Resuscitation and Intensive Care Unit No. 2, 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, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Russian Society of Neonatologists.
Lenyushkina Anna Alekseevna – PhD in Medical Sciences, Head of Clinical Work at ICU No. 2, 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, Council Member of the Russian Society of Neonatologists.
Marina V. Narogan – Dr. of Sci. (Med.), Leading Research Fellow, Department of Pathology of Newborns and Preterm Infants, 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, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, 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.
Irina V. Nikitina – Cand. of Sci. (Med.), Leading Research Fellow, ICU No. 2, 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, Department of Neonatology, Member of the Russian Society of Neonatologists.
Irina I. Ryumina – Dr. of Sci. (Med.), Professor, Head of the Department of Pathology of Newborns and Preterm Infants, 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 Russian Society of Neonatologists.
Olga I. Sapun – Head of Neonatal ICU No. 2, Children's Regional Clinical Hospital, Krasnodar, Chief Freelance Neonatologist of the Ministry of Health of Krasnodar Krai, Member of the Council of the Russian Society of Neonatologists.
Lyubov V. Ushakova – Cand. of Sci. (Med.), Head of the Department of Neonatal and Pediatric Neurology, 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.
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, 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 22 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:
Pediatricians,
Neonatologists;
Anesthesiologists-intensivists;
Pulmonologists;
General practitioners (family physicians);
Medical students;
Residents and interns.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
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)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
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)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
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:
Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.
Order of the Russian Ministry of Health No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."
International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization), 2019 version.
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)
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).
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"
State Register of Medicinal Products: https://grls.rosminzdrav.ru
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 preterm infants of various gestational ages based on transcutaneous bilirubin measurement [1].
Appendix A3.3 Indications for skin phototherapy and exchange blood transfusion in preterm newborns
Appendix A3.3.1 Indications for standard skin phototherapy in newborns ("New 2017 revised Kobe University treatment criteria") [1,24]
Age GA/PMA (weeks) | less than 24 hours | 24 to 48 hours | 48 to 72 hours | 72 to 96 hours | 96 to 120 hours | more than 120 hours |
|---|---|---|---|---|---|---|
Total serum bilirubin concentration, µmol/L. | ||||||
22-25 | 86 | 86 | 86 | 103 | 120 | 137 |
26-27 | 86 | 86 | 103 | 137 | 154 | 171 |
28-29 | 103 | 120 | 137 | 171 | 188 | 205 |
30-31 | 120 | 137 | 171 | 205 | 222 | 239 |
32-34 | 137 | 171 | 205 | 239 | 257 | 274 |
Appendix A3.3.2 Indications for intensive skin phototherapy in newborns ("New 2017 revised Kobe University treatment criteria") [1,24]
Age GA/PMA (weeks) | less than 24 h. | 24 to 48 h. | 48 to 72 h. | 72 to 96 h. | 96 to 120 h. | more than 120 h. |
|---|---|---|---|---|---|---|
Total serum bilirubin concentration, µmol/L. | ||||||
22-25 | 103 | 137 | 137 | 154 | 171 | 171 |
26-27 | 103 | 154 | 171 | 188 | 205 | 205 |
28-29 | 120 | 171 | 205 | 222 | 239 | 239 |
30-31 | 137 | 205 | 239 | 257 | 274 | 274 |
32-34 | 154 | 239 | 274 | 308 | 325 | 325 |
Appendix A3.3.3 Indications for exchange blood transfusion in newborns ("New 2017 revised Kobe University treatment criteria") [1,24]
Age GA/PMA (weeks) | less than 24 h. | 24 to 48 h. | 48 to 72 h. | 72 to 96 h. | 96 to 120 h. | more than 120 h. |
|---|---|---|---|---|---|---|
Total serum bilirubin concentration, µmol/L. | ||||||
22-25 | 137 | 171 | 205 | 222 | 222 | 222 |
26-27 | 137 | 171 | 205 | 239 | 257 | 257 |
28-29 | 154 | 205 | 239 | 274 | 308 | 308 |
30-31 | 171 | 239 | 274 | 308 | 342 | 342 |
32-34 | 171 | 274 | 308 | 342 | 376 | 376 |
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
Preterm hyperbilirubinemia is a condition characterized by an elevated blood bilirubin level.
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 are rapidly and massively destroyed. It is also worth noting the low activity of the enzyme uridine diphosphate glucuronosyltransferase (UGT), which is associated with morphofunctional liver immaturity. 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 infant's body.
To identify symptoms of jaundice, a visual therapeutic examination is performed, which includes assessing changes in the color of the skin and mucous membranes. A more objective method for assessing the rate and degree of bilirubin accumulation in the infant's skin is percutaneous measurement of the transcutaneous bilirubin index using special devices. However, at high transcutaneous bilirubin concentrations, monitoring of venous bilirubin levels by standard laboratory methods is required.
Bilirubin encephalopathy is a severe condition associated with the toxic effect of high bilirubin concentrations on the newborn's brain. The combination of low hepatic UGT1A1 activity with excessive hemolysis and immaturity of the blood-brain barrier leads to a significantly higher risk of developing bilirubin encephalopathy in extremely preterm infants compared to term newborns. In order to reduce the pathologically high concentration of unconjugated bilirubin in the child's blood, as well as to prevent the toxic effect of bilirubin on the infant's brain, skin phototherapy is performed. The baby is placed in a special device where bilirubin is transformed under the influence of short light waves. As a result, the toxin is decomposed 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 excreted from the body.
If the infant's bilirubin level is very high or rises very rapidly, skin phototherapy alone will not be sufficient. In this case, an exchange transfusion is used for treatment, which reduces the amount of bilirubin in the infant's blood.
Hyperbilirubinemia in preterm infants is treatable — that is the most important thing. In each individual case, the management tactics for the infant depend on indications and symptoms. It is very important for parents to maintain a positive attitude and follow the pediatrician's recommendations; these factors are the key to success, so with effective treatment, the mother and baby can be discharged home very soon.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Apgar score assessment of the newborn
Russian name: Apgar newborn scoring system
Original name: The Apgar Score
Source (official developer site, validated publication): Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant-second report. JAMA. 1958; 168 (15): 1985–1988. doi:10.1001/jama.1958.03000150027007
Type: rating scale
Purpose:
Content (template)
Sign | 0 points | 1 point | 2 points |
|---|---|---|---|
HR | Absent | Less than 100 beats per minute | 100 or more beats per minute |
Respiration | Absent | Bradypnea, irregular | Active regular, loud cry and crying |
Muscle tone | Limbs hanging limp | Some flexion of limbs, weak movements | Active motion |
Reflex irritability (response to stimulation during upper airway suctioning, sole stimulation) | No response | Grimace | Cough or sneezing |
Skin color | Generalized pallor or generalized cyanosis | Pink body and blue extremities (acrocyanosis) | Entire body and extremities pink |
Key (interpretation) and notes: A score of 4–7 points at 1 minute after birth corresponds to moderate birth asphyxia (P21.1), and 0–3 points at 1 minute after birth corresponds to severe asphyxia (P21.0). Despite the fact that according to ICD-10 a total score of 7 points at 1 minute after birth corresponds to moderate asphyxia, it is inappropriate to assign this diagnosis, since an Apgar score of 7 points by the end of the 1st minute is not clinically and/or prognostically significant.
1 — Methodological letter «Resuscitation and stabilization of newborn infants in the delivery room». Ed. by E.N. Baybarina. Moscow: Russian Ministry of Health; 2020.