Congenital anemia due to fetal blood loss and other congenital anemias of the newborn: clinical guidelines

List of Abbreviations

Hb – hemoglobin

HbF — fetal hemoglobin

Hct, Ht – hematocrit

IgG – class G immunoglobulins

MCH – mean corpuscular hemoglobin

MCHC – mean corpuscular hemoglobin concentration

MCV – mean corpuscular volume

RBC — red blood cells

SD – standard deviation

BP – blood pressure

CHD – congenital heart disease

G6PD — glucose-6-phosphate dehydrogenase

DIC – disseminated intravascular coagulation

VSD – ventricular septal defect

ASD – atrial septal defect

GI – gastrointestinal tract

IMV – invasive mechanical ventilation

ABDS – acid-base balance status

HC – healthcare organization

LBW — low birth weight

NSG – neurosonography

NICU — neonatal intensive care unit / neonatal pathology department

NICU – neonatal intensive care unit

CBV – circulating blood volume

ICU – intensive care unit

PK — pyruvate kinase

PCR – polymerase chain reaction

TTP — thrombotic thrombocytopenic purpura

US – ultrasound examination

CMV — cytomegalovirus

CNS – central nervous system

RR – respiratory rate

HR – heart rate

RBCC — red blood cell components

EchoCG – echocardiography

Terms and Definitions

Anemia is a hematological syndrome characterized by a decrease in hemoglobin concentration and/or hematocrit by more than 2 standard deviations from the mean hemoglobin and/or hematocrit values for a given postnatal age.

Posthemorrhagic anemia is a hematological syndrome characterized by a decrease in hemoglobin concentration and/or hematocrit by more than 2 standard deviations from the mean hemoglobin and/or hematocrit values for a given postnatal age due to blood loss.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Anemia is a hematological syndrome characterized by a decrease in hemoglobin concentration and/or hematocrit by more than 2 standard deviations from the mean hemoglobin and/or hematocrit values for a given postnatal age [1,2].

Posthemorrhagic anemia is a hematological syndrome characterized by a decrease in hemoglobin concentration and/or hematocrit by more than 2 standard deviations from the mean hemoglobin and/or hematocrit values for a given postnatal age due to blood loss [1,2].

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

Pathological anemia in newborns results from one or more of 3 main causes: blood loss (prenatal, internal, or external), increased red blood cell destruction (hemolysis), or inadequate red blood cell production (congenital deficiency or secondary suppression of erythropoiesis) [3].

Blood loss in the fetus can occur in the prenatal and intranatal periods. Transplacental blood loss can be either acute or chronic [4,5].

1. Blood loss.

Blood loss in the fetus can occur in the prenatal and intranatal periods. Transplacental blood loss can be either acute or chronic [4,5].

Main causes of blood loss.

1.1. Prenatal blood loss:

• Transplacental (fetomaternal hemorrhage);

• Intraplacental;

• Retroplacental;

• Fetofetal (monozygotic, monochorionic twins).

1.2. Intranatal blood loss:

• Pathology and damage of the umbilical cord (rupture of a normal umbilical cord, rupture of a varicosity or aneurysm of the umbilical cord, umbilical cord hematoma, rupture of abnormal vessels unprotected by Wharton's jelly, vasa previa);

• Placental pathology (placental abruption, placenta previa, multilobed placenta with fragile vessels leading to the main placenta, placental damage during Cesarean section, vascular trauma during amniocentesis, placental chorioangioma);

• Hemorrhagic syndrome in the mother due to thrombocytopenia or coagulation factor deficiency.

1.3. Intrauterine or intranatal fetal hemorrhage:

• External blood loss (gastrointestinal bleeding);

• Internal bleeding (intracranial, intraventricular, subaponeurotic, subarachnoid, subdural, intraabdominal (liver or spleen rupture, subcapsular hematomas of parenchymal organs), retroperitoneal (adrenal hemorrhage), pulmonary hemorrhage).

Risk factors for anemia include low-lying placenta, premature birth, and emergency Cesarean section [6]. Severe anemia occurs in 10% of all infants born with placenta previa [7,8], which, along with prematurity, is a major risk factor for perinatal death [9,10].

2. Hemolytic anemias [5,11]:

2.1. Congenital erythrocyte defects:

a. Membranopathies:

• hereditary spherocytosis;

The disease is caused by a mutation in one or more genes encoding erythrocyte membrane cytoskeletal proteins and transmembrane proteins: α-spectrin (SPTA1), β-spectrin (SPTB), ankyrin-1 (ANK1), anion exchanger 1 (band 3) (SLC4A1), and protein band 4.2 (EPB42). In 75% of families, hereditary spherocytosis is inherited in an autosomal dominant manner. In the remaining cases, there is usually no family history, either due to autosomal recessive inheritance or the presence of a de novo autosomal dominant mutation. Autosomal recessive hereditary spherocytosis can be caused by biallelic mutations in any of the five genes, whereas autosomal dominant spherocytosis is observed only with mutations in the SPTB, ANK1, and SLC4A1 genes [11].

• hereditary elliptocytosis (caused by autosomal dominant mutations in genes encoding α- or β-spectrin (SPTA1, SPTB) or protein band 4.1 (EPB41))

• hereditary stomatocytosis;

• hereditary xerocytosis;

• infantile pyknocytosis;

• pyropoikilocytosis (caused by autosomal dominant mutations in genes encoding α- or β-spectrin (SPTA1, SPTB) or protein band 4.1 (EPB41));

• Southeast Asian ovalocytosis (the disease results from homozygosity for mutations in the SLC4A1 gene);

b. Hemoglobinopathies:

• α-thalassemia:

- deletion of a single α-globin gene (silent carrier);

- deletion of two α-globin genes (α-thalassemia trait);

- deletion of three α-globin genes (hemoglobin H ₄ and Bart's hemoglobin);

- deletion of four α-globin genes (most often resulting in prenatal death or death shortly after birth).

• δβ-thalassemia;

• εγδβ-thalassemia;

• β-thalassemia;

• Unstable hemoglobin variants (Hb Köln, Hb F Poole, Hb Hasharon, etc.).

c. Enzymopathies:

• Pyruvate kinase (PK) deficiency;

Pyruvate kinase deficiency is inherited in an autosomal recessive manner and is caused by bi-allelic mutations in the PKLR gene, which encodes the pyruvate kinase enzyme.

• Glucose-6-phosphate dehydrogenase deficiency (mutations in the G6PD gene);

• Other rare enzyme deficiencies: glucosephosphate isomerase, hexokinase, pyrimidine 5'-nucleotidase, phosphofructokinase, phosphoglycerate kinase, triosephosphate isomerase).

2.2. Acquired erythrocyte defects:

a. immune:

• Autoimmune hemolytic anemia in the mother;

• Hemolytic disease of the fetus and newborn (Rh, ABO, minor antigens);

b. non-immune:

• Infection (cytomegalovirus, toxoplasma, herpes simplex, rubella, malaria, syphilis, bacterial sepsis, including E. coli);

• Microangiopathic hemolytic anemia with or without disseminated intravascular coagulation (DIC): disseminated herpetic infection, Coxsackie B infection, Gram-negative septicemia, renal vein thrombosis, thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome, congenital hemangiomas;

• Vitamin E deficiency;

• Metabolic diseases (galactosemia, osteopetrosis).

3. Impaired erythrocyte production [3,5,11]:

3.1. Congenital:

• Diamond-Blackfan anemia;

• Dyskeratosis congenita;

• Fanconi anemia;

• Aase syndrome;

• Pearson syndrome;

• Sideroblastic anemia;

• Congenital dyserythropoietic anemias.

3.2. Acquired

• Viral infections (viral hepatitis, HIV, cytomegalovirus, parvovirus B19, rubella, syphilis)

• Malaria

• Anemia of prematurity.

Most of the presented nosologies manifest as congenital anemia.

1.3 Epidemiology of the Disease or Condition

Neonatal anemia due to blood loss (loss > 30 ml of blood) occurs in 1 in 400 pregnancies, and severe anemia (> 100 ml) in 1 in 2,000 pregnancies.

In 30% of monochorionic pregnancies, twin-to-twin transfusion syndrome occurs, resulting in anemia in one of the twins [9], and in 15% of cases, transfusion occurs with a hemoglobin difference between twins exceeding 50 g/L [12].

The incidence of Diamond-Blackfan anemia in children in Russia is 0.63 ± 0.034 per 100,000 live births with an equal sex ratio (1:1). The average annual prevalence of Diamond-Blackfan anemia in Russia was 5.75 ± 0.87 per 100,000 live-born children. The global prevalence of Diamond-Blackfan anemia is estimated at 5–7 cases per 1 million live births [11,13].

Hereditary spherocytosis is the most common red blood cell membranopathy, causing symptomatic anemia in 1 in 2,000 to 1 in 5,000 live births in parents of Northern European descent [11].

The prevalence of hereditary elliptocytosis is estimated at 1 in 2,000 to 1 in 4,000 of the population, but these figures vary significantly across different countries worldwide. For example, hereditary elliptocytosis is more common in malaria-endemic areas, particularly among individuals of African and Mediterranean descent [11].

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects about 400 million people worldwide, mainly in Mediterranean countries, Africa, and China. The vast majority of affected individuals are males, while females are carriers. However, females can also be affected with a frequency of 1 in 5 million [3]. In contrast to G6PD deficiency, pyruvate kinase (PK) deficiency is quite rare; the estimated incidence is 1 in 20,000 among individuals of European descent [11].

Alpha-thalassemia is one of the most common inherited disorders, with a global carrier prevalence of approximately 5%. The most clinically significant form of this disease predominantly affects families of Southeast Asian descent, where carrier prevalence reaches up to 40%, although it is also common in parts of India and the Mediterranean (Greece, Turkey, Cyprus, and Sardinia) [11].

The prevalence of anemias caused by congenital infections depends on the prevalence of the infections themselves. For example, perinatally acquired syphilis remains a major problem in many countries, estimated to affect 713,600–1,575,000 pregnancies worldwide [11]. The epidemiology of congenital cytomegalovirus infection is presented in the clinical guidelines "Congenital Cytomegalovirus Infection" [14].

1.4 Features of Coding the Disease or Condition

P61.3 Congenital anemia due to fetal blood loss.

P61.4 Other congenital anemias, not elsewhere classified.

Subsequently, upon clarifying the cause of congenital anemia, the disease coding is transformed into the corresponding code of the identified nosology.

1.5 Classification of the disease or condition

Congenital posthemorrhagic anemias of newborns are classified as follows [15]:

- by time of onset: antenatal, intranatal (during labor), postnatal (immediately after birth);

- by rate of development: acute and chronic.

1.6 Clinical presentation of the disease or condition

Clinical symptoms of anemia are non-specific: examination reveals lethargy, poor sucking, marbling, pallor of the skin and mucous membranes in combination with various disorders of other organs and systems depending on the cause of the anemia; tachypnea/bradypnea, apnea, need for oxygen therapy, decreased efficacy of ongoing respiratory therapy, including the need to increase mechanical ventilation parameters; drowsiness or altered neurological status; tachycardia > 180 bpm, heart auscultation may reveal muffled heart sounds and a systolic murmur.

In chronic blood loss, skin pallor is present, the severity of which depends on the degree of anemia, although the child's condition may remain compensated due to normovolemia. In the neonatal period, such anemia is frequently observed in chronic fetomaternal transfusions [4].

In rapid and massive blood loss during the intranatal period or immediately after birth, the child may develop hypovolemic shock. Hypovolemic shock is characterized by a sharp decrease in circulating blood volume (CBV), cardiac output, and tissue perfusion. Shock manifests as severe circulatory disorders, presenting with peripheral vasoconstriction, low cardiac output; decreased pulse pressure and venous pressure, tachycardia, tachypnea with the use of accessory muscles (intercostal retractions, sinking of the lower third of the sternum, tension of the anterior abdominal wall muscles, nasal flaring), symptoms of acute respiratory distress syndrome, and central nervous system depression. When these symptoms develop, the newborn infant requires emergency care due to the high risk of mortality or severe central nervous system damage associated with both hypoxic and circulatory disorders in the brain against the background of anemia and hypovolemia.

In the neonatal period, erythrocyte G6PD deficiency manifests primarily as pronounced unconjugated hyperbilirubinemia, and may present as grade 1 hemolytic anemia with severe unconjugated hyperbilirubinemia. Although most affected newborns are males, screening for neonatal jaundice occasionally identifies female carriers, as these children can also sometimes develop severe neonatal jaundice. The peak of clinical manifestations occurs on days 2–3 of life. Although the cause of hyperbilirubinemia in infants with G6PD deficiency sometimes reflects accelerated erythrocyte destruction, more often there is no overt erythrocyte destruction. In most cases, jaundice predominates over anemia in the clinical picture. If the fetus has erythrocyte G6PD deficiency and the mother ingests medications or foods during pregnancy that induce a strong oxidative process, hemolysis may develop prenatally. The degree of fetal distress is dose-dependent: the more the mother has ingested, the more pronounced the hemolysis. It may also manifest in newborns aged several weeks with a sudden and profound drop in Hb levels due to acute oxidative hemolysis, often in combination with an infection (or drugs/chemicals). A family history of anemia is usually absent, but a family history of neonatal jaundice may be present [3,11].

Approximately a quarter of patients with erythrocyte pyruvate kinase (PK) deficiency are affected prenatally or immediately from birth, manifesting as profound anemia (up to hydrops fetalis), intrauterine growth restriction, and severe hemolytic anemia from the first days of life. After birth, all newborns with erythrocyte PK deficiency exhibit severe jaundice (unconjugated hyperbilirubinemia) and severe anemia from the first hours of life. In isolated cases, newborns may develop severe liver disease progressing to hepatocellular failure [3].

Infantile pyknocytosis is more common in premature infants, and if the condition occurs in twins, both are usually affected. It is characterized by a sudden onset of severe anemia at 2–4 weeks of age, usually with a drop in Hb levels by 40–50 g/L over several days; transfusion is frequently required (usually only 1–2 transfusions); it then gradually resolves by 2–3 months of age [11].

Diamond–Blackfan anemia is a congenital partia red cell aplasia that most commonly presents in the first three months of life. Fanconi anemia, conversely, extremely rarely presents in the neonatal period and early childhood, and in addition to anemia, children present with thrombocytopenia and leukopenia (Table 1).

Table 1. Clinical and laboratory manifestations of congenital bone marrow failure syndromes in early childhood. (FA, Fanconi anemia; CD, congenital dyskeratosis; DBA, Diamond-Blackfan anemia; SDS, Shwachman-Diamond syndrome; HH, Hoyeraal-Hreidarsson syndrome; RS, Revesz syndrome) [3].

Most newborns with Pearson syndrome have low birth weight, metabolic lactic acidosis, and exocrine pancreatic insufficiency; functional liver and kidney disorders are also frequently observed [11].

Slightly over half of all newborns with congenital syphilis will have Coombs-negative hemolytic anemia, which may persist for weeks after treatment. Although fatal outcomes are rare, severe cases may manifest as hydrops fetalis. Congenital toxoplasmosis may also manifest as severe neonatal hemolytic anemia and/or hydrops fetalis. Despite the prevalence of malaria among pregnant women, congenital anemia is very rare, even in malaria-endemic countries, and extremely rare in non-endemic countries, likely due to protective maternal IgG antibodies. Congenital malaria presents with anemia, jaundice, hepatosplenomegaly, and non-specific signs such as poor feeding, lethargy, and fever. Typically, the first signs of malaria appear on days 10–28 after birth, although cases presenting within a few hours of birth or by 8 weeks of age have been reported. Parvovirus B19 is responsible for 6–7% of non-immune hydrops fetalis cases and is the most common cause of this condition. Affected fetuses or newborns usually exhibit marked reticulocytopenia (often <10 ×109/L), and in severe cases, thrombocytopenia also develops. In addition to parvovirus B19, infections such as cytomegalovirus (CMV), toxoplasmosis, congenital syphilis, rubella, and herpes simplex can cause anemia resulting from decreased erythrocyte production, although these cases typically show mild anemia and reticulocytopenia [11].

The severity of α-thalassemia depends on the number of affected α-globin genes. When both parents are carriers of α0-thalassemia, their offspring may be homozygous for α0 and inherit no normal α-globin genes; deletion of all four α-globin genes leads to Hb Bart's hydrops fetalis, which has the most severe manifestations and practically always presents prenatally with severe anemia in the second trimester and hydrops fetalis with a mean Hb concentration of 64 g/L. Because the main hemoglobin produced by affected fetuses is hemoglobin Bart's (tetramers of fetal globin γ-chains, γ4), this condition is called hemoglobin Bart's hydrops fetalis syndrome to distinguish it from hydrops fetalis with severe anemia caused by other factors. The main clinical signs of this syndrome include severe pallor with jaundice, heart failure, hydrothorax and hydropericardium, ascites, hepatosplenomegaly, and respiratory distress [11].

Most newborns with hereditary spherocytosis will have jaundice, although it is usually not severe and easily managed with phototherapy. However, newborns with hereditary spherocytosis who also carry the Gilbert syndrome trait—a common polymorphism in the promoter region of the uridine diphosphate-glucuronosyltransferase (UGT1A1) gene—frequently develop severe jaundice and may require exchange transfusion to prevent kernicterus. The Hb level in hereditary spherocytosis is usually normal at birth, but approximately one-third of newborns develop marked anemia during the neonatal period. As a rule, the anemia is moderate (70–100 g/L). Autosomal recessive forms of hereditary spherocytosis are usually very severe and present with hydrops fetalis or severe neonatal hemolytic anemia. In Southeast Asian ovalocytosis, jaundice is typical, and mild anemia or no anemia is noted. In hereditary pyropoikilocytosis, a prominent, persistent transfusion-dependent hemolytic anemia is typically observed in the neonatal period. Overhydrated hereditary stomatocytosis may present with hydrops fetalis. The clinical manifestations of hereditary elliptocytosis and related syndromes are complex in the sense that at least three distinct types of this disorder are recognized, and any of them can manifest in the neonatal period. The most frequent manifestation, especially in newborns of African descent, is common autosomal dominant hereditary elliptocytosis, which rarely causes any clinical symptoms other than the presence of elliptocytes on the blood smear. Therefore, the disease is discovered incidentally in the neonatal period, and the diagnosis is made based on a blood smear taken for another reason, such as infection screening. Newborns who are homozygous or compound heterozygous carriers of mutations leading to hereditary elliptocytosis have severe, transfusion-dependent anemia that manifests in utero or in the first few days after life. Hereditary elliptocytosis with infantile poikilocytosis is the second most severe form of elliptocytosis in the neonatal period. Typically, such newborns exhibit moderately severe hemolytic anemia with marked poikilocytosis as well as elliptocytes. Occasionally, sufficiently severe jaundice develops, requiring exchange transfusion [11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing fetal blood loss anemia

The diagnosis of posthemorrhagic anemia can be confirmed if laboratory diagnostic signs of anemia are identified in combination with documented blood loss [16].

Main criteria for diagnosing anemia:

A decrease in red blood cell count, hemoglobin concentration, and/or hematocrit level by more than 2 standard deviations below the mean values for erythrocytes, hemoglobin, and/or hematocrit for the given postnatal age [1].

Hemoglobin and hematocrit values according to the child's postnatal age are presented in Table 2 [17].

Table 2. Venous blood hemoglobin, hematocrit, and erythrocyte values in newborns [16–18] (modified from Dallman P.R. et al., 1977, Girelli G. et al., 2015).

Auxiliary diagnostic criteria for neonatal anemia

Indices of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) [18].

Table 3. Indices of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in newborns (venous blood) [18](modified from Dallman P.R. et al., 1977, Girelli G. et al., 2015).

Chronic post-hemorrhagic anemia is microcytic, hypochromic, normo- or moderately hyperregeneratory. In acute blood loss (e.g., during delivery), hematocrit, hemoglobin, red blood cell count, and reticulocyte count may remain within normal limits in the first few hours, since the loss of formed elements and plasma occurs in parallel, and consequently, the concentration of red blood cells per unit volume remains the same as before the hemorrhage. Acute post-hemorrhagic anemia is a normocytic, normochromic, hyperregeneratory anemia.

The main diagnostic criteria for red blood cell membranopathies and enzymopathies are a family history and characteristic red blood cell morphology on a blood smear (Table 4).

Table 4. Characteristic red blood cell morphology in membranopathies and enzymopathies.

2.1 Complaints and Anamnesis

Comments: Maternal risk factors for post-hemorrhagic anemia include:

• intrauterine interventions during pregnancy;

• umbilical cord or placental hematoma;

• placenta previa, placental accreta;

• maternal history of anemia of varying severity before and during pregnancy;

• multiple monochorionic pregnancy;

• presence of an acute infection in the mother or exacerbation of a chronic one;

• precipitous labor;

• operative delivery;

• placental abruption.

To diagnostically investigate other congenital anemias, it is advisable to study the family history, clarifying the presence of anemias or jaundice in relatives.

To identify potential infectious causes of anemia, clarify the course of pregnancy, the presence of chronic infectious diseases in the mother, travel to endemic countries, and the use of medications and substances capable of causing hemolysis in the fetus in G6PD deficiency.

2.2 Physical Examination

• A newborn infant with suspected congenital anemia is recommended to undergo a visual therapeutic examination [1,11].

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

Comments: See Section 1.6 "Clinical Presentation". In congenital anemias due to inadequate red blood cell production, attention should be paid to the presence of malformations and dysmorphic stigmata (Table 1).

2.3 Laboratory Diagnostics

• A newborn infant with suspected congenital anemia is recommended to undergo a complete (clinical) blood count with assessment of red blood cells, hemoglobin, hematocrit evaluation, and reticulocyte count to determine further management tactics [18–29].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

Comments: For reliable determination of hemoglobin levels and hematocrit evaluation, it is most optimal to use venous blood parameters, since in edema syndrome capillary blood parameters may be falsely low.

• A newborn infant with congenital anemia and suspected congenital red blood cell defects is recommended to have a blood smear reviewed to analyze anomalies in red blood cell, platelet, and leukocyte morphology to confirm the diagnosis [11,21,24,25,27,28].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

Comments: see Table 4.

• A newborn infant with congenital anemia is recommended to undergo a direct antiglobulin test (direct Coombs test) to rule out an immune hemolytic anemia [3,11].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• A newborn infant with anemia accompanied by the development of skin jaundice is recommended to have blood levels of total bilirubin, unconjugated and conjugated bilirubin measured to confirm non-immune hemolysis and determine further management for hyperbilirubinemia [3,11].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• To evaluate gas exchange disturbances, signs of tissue hypoxia, metabolic disorders, and to determine further management tactics for symptomatic therapy in a newborn infant with signs of congenital anemia accompanied by respiratory and/or hemodynamic disorders, it is recommended to perform blood gas and acid-base balance (ABB) analysis and blood lactate measurement [22,30–36].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

Comments: determination of blood lactate depends on the capabilities of the medical organization's laboratory.

• To rule out coagulopathies and determine further hemostatic therapy tactics in a newborn infant with congenital anemia combined with hemorrhagic syndrome, it is recommended to perform a coagulogram (screening hemostasis test) [18,37–40].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: coagulogram testing depends on the capabilities of the medical organization's laboratory. Thromboelastography and/or thromboelastometry may be used as additional hemostasis test methods if available at the specific medical organization.

• If the condition worsens during and after a blood transfusion, the newborn is recommended to undergo blood acid-base balance and serum potassium and calcium level testing to detect transfusion reactions and complications of blood transfusion [41,42].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Hyperkalemia is a consequence of red blood cell hemolysis. If hyperkalemia (6.5–7.0 mmol/L) is detected, the transfusion should be stopped. Hypocalcemia, metabolic acidosis, or alkalosis are usually associated with citrate toxicity and require timely correction [42].

• Following a blood transfusion in a newborn, it is recommended to perform a complete (clinical) blood count and urinalysis no earlier than 2 hours and no later than 24 hours after the blood transfusion to evaluate efficacy and detect complications [43].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: Evaluation of transfusion efficacy is based on achieving target hematocrit and/or hemoglobin values.

• In a newborn with anemia and suspected viral or bacterial etiology of the anemia, it is recommended to perform determination of Toxoplasma DNA (Toxoplasma gondii) by PCR in peripheral and umbilical cord blood, determination of Cytomegalovirus DNA (Cytomegalovirus) by PCR in peripheral and umbilical cord blood (quantitative test), determination of Parvovirus B19 DNA (Parvovirus B19) by PCR in peripheral and umbilical cord blood (quantitative test), determination of Herpes simplex virus types 1 and 2 DNA (Herpes simplex virus types 1, 2) by PCR in blood (quantitative test), determination of Rubella virus RNA (Rubella virus) by PCR in peripheral and umbilical cord blood (quantitative test), molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1), and microbiological (culture) blood testing for sterility, in order to identify the etiology of the anemia and determine further treatment strategy [11].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• A newborn infant with congenital anemia of unclear etiology and suspected hereditary hemolytic or aplastic anemia is recommended a panel of tests for anemia of undetermined etiology or a panel for the diagnosis of hemolytic anemia [11,29].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: Panels may include molecular genetic testing for mutations in various genes responsible for the development of hemolytic and aplastic anemias.

2.4 Instrumental Diagnostics

• To rule out internal organ hemorrhage, a newborn with signs of anemia is recommended to undergo ultrasound examinations: neurosonography (NSG), abdominal ultrasound (comprehensive), and ultrasound of the kidneys and adrenal glands [44–51].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

• To determine further management tactics for a newborn infant with congenital anemia combined with hypovolemic shock, it is recommended to perform echocardiography (Echocardiogram) [45,52–54].

GCR BLEL 3Recommendation Grade B (Level of Evidence — 3).

2.5 Other Procedures

• If feto-maternal transfusion is suspected, it is recommended to measure the maternal blood level of fetal hemoglobin within the first 2 hours of life [55–57].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

Comments: if laboratory diagnostics are available in the specific medical facility. Diagnostic methods for fetomaternal hemorrhage include: determining fetal erythrocytes in maternal blood using the Kleihauer-Betke test or flow cytometry [58]. The Kleihauer-Betke test has insufficient sensitivity and low reproducibility or accuracy (coefficient of variation 50–100%). Calculating the percentage of fetal and maternal cells is used to assess fetomaternal hemorrhage [55]: Percentage of fetal cells = number of fetal cells × 100 / total number of erythrocytes. The Kleihauer-Betke test determines the presence of fetal blood in maternal blood with a threshold of 5 ml. If 1% of erythrocytes in the maternal blood smear are fetal, the fetal blood loss is approximately 50 ml. In case of ABO incompatibility between mother and fetus, fetal hemoglobin (HbF) entering the maternal circulation may be rapidly lysed by maternal antibodies. If the mother has persistent fetal hemoglobin or other maternal hemoglobinopathies leading to elevated HbF levels, the Kleihauer-Betke test will be false positive, and flow cytometry is used for the quantitative assessment of fetomaternal hemorrhage. Determining the number of fetal erythrocytes in maternal blood using flow cytometry is the fastest and most sensitive method. Sensitivity reaches 100% [59].

• A newborn infant with suspected congenital erythrocyte defects or congenital impaired erythrocyte production is recommended an initial consultation (examination) by a pediatric hematologist to determine further management and treatment strategies [3,11].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

• During blood transfusion and for at least 2 hours afterwards, the newborn is recommended to undergo monitoring of heart rate, blood pressure, respiratory rate, oxygen saturation of hemoglobin, urine output, urine color, and body temperature to enable the detection of transfusion reactions and complications [60].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

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

3.1. Conservative management

Etiotropic and pathogenetic therapy

• A newborn with a hemoglobin level of less than 120 g/L in the first 24 hours of life is recommended a blood transfusion of leukoreduced red blood cell components (RBCC) to correct anemia [61–66].

LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).

Comments: In anemia accompanied by hypovolemic shock due to acute blood loss immediately after birth, O (I) Rh (-) D-negative leukoreduced RBCC may be used [67].

The volume of the transfused leukoreduced red blood cell component typically ranges from 10 to 20 ml/kg [38,61].

The recommended transfusion duration is no more than 4 hours [61,62,68,69].

Potential risks and complications of blood transfusion [70]:

- Transfusion of an incorrect RBCC component (by blood group, Rh factor, etc.);

- Acute / delayed transfusion reaction;

-  Transmission of bacterial and viral infections;

- Transfusion-associated graft-versus-host disease – a rare but frequently fatal condition prevented by gamma-irradiation of blood products;

- Immune and non-immune hemolysis;

- Metabolic disorders (hyperkalemia, hypocalcemia) and acid-base balance disturbances;

- Transfusion-related acute lung injury ("TRALI") with the development of respiratory failure;

- TANEC – transfusion-associated necrotizing enterocolitis – enterocolitis developing within 48–72 hours after blood RBCC transfusion;

- Post-transfusion purpura, in which the platelet count drops catastrophically 5–9 days after transfusion;

- Allergic reactions;

- Volume overload;

- Iron overload;

- Apnea;

- Cardiac arrhythmias;

- Seizures;

- Embolism (air / thrombus);

- Hemodynamic disorders;

- Infection;

- Body temperature instability;

- Thrombocytopenia;

- Intraventricular hemorrhage.

• To correct anemia in a newborn with an Hb level of less than 80 g/L combined with hypovolemic shock (circulating blood volume loss of 20% or more), the blood transfusion volume may exceed 20 ml/kg, and the calculation of the transfused leukoreduced RBCC is recommended to be performed using the formula [18]:

target Ht – patient's Ht

Blood volume (mL) = ––––––––––––––––––––––– × neonate's blood volume

                                       Ht of RBC component

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Newborn blood volume: 80 ml/kg for term infants, 100 ml/kg for preterm infants, target Ht not less than 0.35.

To avoid complications of massive blood transfusion, the total RBC volume should not exceed 60% of the circulating blood volume.

The transfusion should be discontinued if the following adverse reactions occur [61]:

- tachycardia, bradycardia, or arrhythmia;

- tachypnea;

- increase in systolic blood pressure (BP) by more than 15 mm Hg, unless this is a desired effect;

- temperature rise above 38^°C and/or temperature increase ≥ 1^°C;

- cyanosis;

- skin rash, urticaria, hyperemia;

- hematuria/hemoglobinuria;

• A newborn with symptoms of anemia and/or a decrease in hemoglobin level to values requiring correction is recommended a blood transfusion of leukoreduced red blood cell components (RBCC) to achieve the target hemoglobin level, taking into account the need for respiratory therapy [63,64,71–74].

BIP ALEL 1Level of evidence A (level of data reliability - 1).

Comments: Indications for replacement blood transfusion of leukoreduced red blood cell components in newborns are presented in Table 5 [74].

Table 5. Hemoglobin concentrations (g/L) at which red blood cell (RBC) transfusion is recommended in newborn infants, depending on their respiratory status and postnatal age (modified from Whyte R., Kirpalani H., 2011) [74].

^★includes all types of respiratory therapy and support for adequate spontaneous breathing, including mask or diffuse oxygen delivery

The recommended hemoglobin levels as criteria for transfusion cannot be applied in cases of major surgical interventions, sepsis, shock, hemorrhage, or symptoms intrinsic to anemia (tachycardia, tachypnea) [18,75].

The decision to perform elective transfusion should be made taking into account the risk-benefit assessment in comorbid diseases and conditions (e.g., progressive retinopathy, volume overload, active necrotizing enterocolitis, acute kidney injury, etc.).

Symptomatic therapy

Symptomatic therapy includes infusion therapy with crystalloid solutions to maintain normovolemia, hemostatic therapy in the presence of active hemorrhagic syndrome manifestations, and respiratory and cardiotonic therapy when indicated.

• In severe anemia due to blood loss in a newborn, for emergency correction of hypovolemia prior to RBC transfusion, it is recommended to administer electrolyte solutions (ATX code B05XA) – sodium chloride** 0.9% solution at a dose of 20 mL/kg [18,76,77].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

• In a newborn with unconjugated hyperbilirubinemia due to hemolysis, it is recommended to perform skin phototherapy to reduce bilirubin levels and prevent the development of kernicterus [78].

LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).

Comments: The unconjugated bilirubin level requiring phototherapy depends on gestational and postnatal age (see Appendix A3.2).

• In a newborn with unconjugated hyperbilirubinemia due to hemolysis, when skin phototherapy is ineffective and/or unconjugated bilirubin levels rise to those requiring exchange transfusion, it is recommended to perform an exchange transfusion to lower bilirubin levels and prevent the development of kernicterus [3,11,79].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: The unconjugated bilirubin level requiring an exchange transfusion depends on gestational and postnatal age (see Appendix A3.2).

3.2 Surgical Treatment

Surgical treatment depends on the topography and severity of hemorrhages.

3.3 Other Treatment

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

- Depending on the severity of the condition, a newborn requiring a blood transfusion should be transferred to the neonatal intensive care unit (NICU), neonatal step-down unit, or the neonatal pathology and premature infant department;

- The infant is indicated for care in a neutral thermal environment, limitation of sensory stimulation (protection from light, noise, and touch), and body temperature monitoring;

- The infant is indicated for adequate enteral and, if necessary, parenteral nutrition. Preference in enteral feeding is given to breast milk. In case of insufficient lactation or contraindications to breastfeeding on the part of the mother, the newborn is fed with an infant formula adapted for term newborns from birth or a specialized formula for premature and low-birth-weight infants.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Performed by relevant specialists (neurologist, ophthalmologist, surgeon, etc.) depending on concomitant pathology and complications.

5. Prevention and Dispensary Observation

• To prevent anemia in the newborn, it is recommended to perform delayed cord clamping and transection after 60–120 seconds if there is no need for immediate resuscitation of the mother or infant [80–82].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: An alternative to delayed cord clamping may be umbilical cord milking. Routine use of umbilical cord milking is not recommended for extremely premature infants due to insufficient evidence of its safety in extremely premature newborns [80].

• In prenatally diagnosed severe fetal anemia, it is recommended to perform intrauterine fetal blood transfusion with washed red blood cells to increase fetal hemoglobin levels and improve neonatal outcomes [11,83].

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

Comments: Criteria for severe fetal anemia and the procedure technique are presented in the clinical guidelines "Rhesus Immunization. Hemolytic Disease of the Fetus". The procedure of intrauterine fetal blood transfusion is performed in a Level III maternity hospital equipped with specialists proficient in this method.

Dispensary follow-up (Active surveillance)

Follow-up by relevant specialists depending on the topography of hemorrhages.

• Children with anemia due to congenital erythrocyte defects or congenital erythropoiesis failure are recommended a follow-up appointment (examination, consultation) with a hematologist [3].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

6. Organization of Medical Care

Blood transfusion in newborns is performed exclusively in inpatient settings. If a child is diagnosed with congenital erythrocyte defects or congenital impaired erythrocyte production, the patient must be transferred to a specialized hematology department. In cases of antenatal detection of severe fetal anemia, including when combined with non-immune fetal hydrops, when a decision is made to perform intrauterine fetal blood transfusions, the pregnant woman is transferred to a Level III inpatient facility staffed with specialists proficient in this treatment method.

Indications for discharging a patient from a medical organization:

1) Stable, satisfactory condition of the infant;

2) Stabilization of laboratory parameters with hemoglobin levels that do not require red blood cell (RBC) transfusion;

3) Absence of contraindications to discharge.

7. Additional Information

The prognosis for anemia resulting from fetal blood loss in the absence of comorbid conditions is generally favorable. In cases of severe anemia at birth due to blood loss, mortality is possible, as is the development of multiple organ dysfunction syndrome (particularly acute kidney injury) and central nervous system damage resulting from hemic hypoxia. The prognosis also depends on comorbid conditions and the localization of hemorrhages.

The outcome of anemias caused by viral infections resulting in fetal hydrops, as well as other congenital anemias, varies, up to and including fatal outcomes.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ekaterina N. Balashova – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov Department of Anesthesiology and Intensive Care, 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, Member of the Council of the Russian Society of Neonatologists

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

3. Degtyarev Dmitry Nikolaevich — Doctor of Medical Sciences, Professor, Deputy Director for Research at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Head of the Department of Neonatology at the Pediatric Faculty of the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists

4. Zubkov Viktor Vasilyevich — Doctor of Medical Sciences, Director of the Institute of Neonatology and Pediatrics, Head of the Department of Neonatology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Professor at the Department of Neonatology of the N.F. Filatova Clinical Institute of Children's Health at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists

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

6. Karpova Anna Lvovna — Candidate of Medical Sciences, Head of the Neonatal Inpatient Unit at the L.A. Vorohobov City Clinical Hospital No. 67 of the Moscow City Health Department, Associate Professor at the Professor V.V. Gavryushov Department of Neonatology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry of the Institute of Professional Development of the Yaroslavl State Medical University of the Ministry of Health of Russia, member of the Council of the Russian Society of Neonatologists.

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

8. Olga I. Sapun – Head of the Neonatal Intensive Care Unit 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

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

10. Smetanina Natalya Sergeevna — Doctor of Medical Sciences, Professor, Deputy Director of the Institute of Hematology, Immunology and Cell Technologies at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, member of the National Hematological Society, member of the Russian Society of Pediatric Oncology and Hematology

11. Ryndin Andrey Yurievich — Candidate of Medical Sciences, Senior Researcher at the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Associate Professor at the Department of Neonatology of the N.F. Filatova Clinical Institute of Children's Health at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists

12. Narogan Marina Viktorovna — Doctor of Medical Sciences, Professor at the Department of Neonatology of the N.F. Filatova Clinical Institute of Children's Health at the I.M. Sechenov First Moscow State Medical University of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists

13. Sharafutdinova Diyana Rashidovna — Candidate of Medical Sciences, Anesthesiologist-Intensivist at the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Assistant at the Department of Neonatology of the N.F. Filatova Clinical Institute of Children's Health at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists

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 guidelines consisted of publications included in the Cochrane Library, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, e-Library, clinicaltrials.gov databases, 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 43 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 peer review;

· internal peer 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:

The latest changes to these guidelines are presented for discussion in a preliminary version. The updated version for broad discussion was posted on the websites of the Russian Society of Neonatologists (RSN) www.neonatology.pro, www.raspm.ru, https://portalcr.minzdrav.gov.ru/ so that all interested parties could participate in discussing and improving the guidelines.

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

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

Target audience for these clinical guidelines:

1. Neonatologists

2. Anesthesiologists-intensivists

3. Pediatricians

4. Obstetricians-gynecologists

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

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and rehabilitation methods (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 or upon the emergence of new information on patient management tactics for a given disease, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The proposals formed must take into account the results of a comprehensive evaluation of drugs and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

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 Protecting the Health of Citizens in the Russian Federation."

2. Russian Ministry of Health, Order No. 203n dated 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. Nomenclature of Medical Services (Ministry of Health and Social Development of the Russian Federation), 2020.

5. Order of the Ministry of Health of the Russian Federation No. 1170n dated October 28, 2020, "On approval of the rules for providing medical care to the population in the profile 'transfusiology'"

(Registered on November 27, 2020, No. 61123)

6. Decree of the Government of the Russian Federation No. 797 dated June 22, 2019, "On approval of the Rules for procurement, storage, transportation, and clinical use of donor blood and its components and on invalidating certain acts of the Government of the Russian Federation"

7. Methodological Letter of the Russian Ministry of Health No. 15-4/I/2-2570 dated 04.03.2020 "Resuscitation and stabilization of newborns in the delivery room". Ed. by E.N. Baybarina. Moscow: Ministry of Health of the Russian Federation; 2020.

8. List of Vital and Essential Medicines for 2020 (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019).

Appendix A3.2 Indications for phototherapy and exchange blood transfusion in newborns

Indications for phototherapy in newborn infants of various gestational ages [3,84].

Indications for exchange blood transfusion in newborn infants of various gestational ages [3,84].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Anemia can occur in newborns. Anemia is characterized by a significant decrease in the hemoglobin concentration in the baby's blood, as well as the red blood cell (erythrocyte) count. In newborns, anemia on the first day of life can result from fetomaternal hemorrhage, twin-to-twin transfusion syndrome in multiple pregnancies, or bleeding due to placenta previa, trauma, or placental abruption. In such cases, the newborn exhibits a decreased hemoglobin level, leading to so-called congenital anemia due to fetal blood loss. Anemia can also be caused by external and internal hemorrhages in the infant developing intrauterine or during labor, impaired hemoglobin synthesis, hereditary erythrocyte membrane disorders, hereditary hemolytic disorders, congenital anemias due to inadequate red blood cell production, and intrauterine viral or bacterial infections leading to anemia. Depending on the rate of onset, anemia can be acute or chronic. Anemia leads to generalized hypoxia in the infant, meaning insufficient oxygen delivery to organs and tissues, including the brain, which can have serious consequences for the baby's health. Anemia in children has the following signs: pale skin and mucous membranes, dyspnea, and tachycardia. Newborns with anemia may require treatment and monitoring in a neonatal intensive care unit (NICU) and intensive care management. To diagnose anemia and determine its causes, a comprehensive blood test and instrumental examination methods are performed. The primary treatment for severe anemia is blood component transfusion (red blood cells). To prevent anemia in the newborn, delayed cord clamping or cord "milking" is performed immediately after birth. It is also necessary to establish proper feeding, organize a routine schedule, and administer prescribed medications. The most easily absorbed iron is found in breast milk, making it the best prevention for anemia in children; iron supplements are prescribed when necessary (in agreement with the physician). Maintaining a positive attitude and supporting breastfeeding is crucial—these two factors are the key to success. After discharge, it is essential to monitor hemoglobin levels according to the doctor's recommendations.

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

Not applicable.