Anemia of prematurity

Premature infants weighing less than 1.0 kg at birth (commonly referred to as extremely low birth weight (ELBW)) have completed a gestation of ≤29 weeks, and almost all will require red blood cell transfusions during the first weeks of life. Each week in the United States, approximately 10,000 babies are born prematurely (i.e., <37 weeks of gestation), with 600 (6%) of these preterm babies being extremely low birth weight. Approximately 90% of ELBW infants will receive at least one red blood cell transfusion. [1], [2]

Causes of the anemia of prematurity

The main factors contributing to the onset of anemia in the first year of life in premature babies or in children born with low birth weight are the cessation of erythropoiesis, iron deficiency, folate deficiency and vitamin E deficiency.

The reason for the development of early anemia of preterm infants in some infants may be a deficiency of folic acid, the reserves of which in a preterm newborn are very small. The need for folic acid in a rapidly growing premature baby is great. Folic acid depot is usually consumed within 2-4 weeks, which leads to a deficiency of this vitamin, aggravated by the appointment of antibiotics (suppressing the intestinal microflora and, therefore, the synthesis of folic acid), and the addition of an intestinal infection. Folic acid deficiency develops especially rapidly in a premature baby with its deficiency in the mother during pregnancy and lactation. With a lack of folic acid, hematopoiesis from normoblastic can turn into megaloblastic with ineffective erythropoiesis: megaloblastosis in the bone marrow, increased intraosseous destruction of erythrocytes, macrocytosis of erythrocytes in the blood.

In premature infants, vitamin E plays an important role in maintaining the stability of red blood cells, which protects membranes from oxidation and is involved in synthesis. The reason for the increased hemolysis of erythrocytes is explained by the deficiency of vitamin E. Its reserves in a premature baby at birth are low: 3 mg with a weight of 1000 g (in a full-term 20 mg with a weight of 3500 g), and its absorption in the intestine is insufficient. Thus, prematurity itself can be the cause of hypovitaminosis E. The absorption of vitamin E is adversely affected by asphyxia, birth trauma of the central nervous system, infections that are often found in premature babies. Artificial feeding with cow's milk increases the need for vitamin E, and the appointment of iron supplements dramatically increases its consumption. All this leads to a deficiency of vitamin E in the body of a premature baby during the first months of life, which results in increased hemolysis of erythrocytes.

Lack of trace elements, especially copper, magnesium, selenium can aggravate early anemia of prematurity.

[3],   [4], [5], [6], [7]

Pathogenesis

It was found that with the onset of spontaneous respiration, the saturation of arterial blood with oxygen increases from 45 to 95%, as a result of which erythropoiesis is sharply inhibited. At the same time, the level of erythropoietin (high in the fetus) decreases to undetectable. The shortened life span of fetal red blood cells also contributes to anemia. A significant increase in total blood volume, accompanying a rapid increase in body weight in the first 3 months of life, creates a situation that is figuratively called "bleeding into the circulatory system." During this early anemia of prematurity, the bone marrow and the reticuloendothelial system contain a sufficient amount of iron and its reserves even increase, since the volume of circulating red blood cells decreases. However, in premature infants in the first months of life, the ability to recycle endogenous iron is reduced, their iron balance is negative (excretion of iron in feces is increased). By the age of 3-6 weeks, the lowest hemoglobin level is 70-90 g / l, and in children with very low body weight, it is even lower.

Type of anemia	Mechanism	Maximum detection time, weeks
Early	Delayed erythropoiesis + increasing blood volume (mass)	4-8
Intermediate	Erythroposes below what is required for increasing blood volume	8-16
Late	Depletion of iron stores needed to saturate the increasing mass of red blood cells	16 and more
Megaloblastic	Folate deficiency due to its erratic balance + infection	6-8
Hemolytic	Deficiency of vitamin E during the special sensitivity of red blood cells to oxidation	6-10

The early phase ends when erythropoiesis is restored due to the secretion of erythropoietin, stimulated by the developed anemia. This is evidenced by the appearance of reticulocytes in the peripheral blood, in which they were not previously present. This phase is called intermediate. The decrease in hemoglobin level is mainly stopped due to the restoration of erythropoiesis (at the age of 3 months, hemoglobin, as a rule, is 100-110 g / l), but hemolysis and an increase in blood volume continue, which can delay the increase in hemoglobin concentration. However, iron reserves are now being consumed and will inevitably be less than normal in relation to birth weight. By the 16-20th week, iron reserves are depleted, and then hypochromic erythrocytes are first detected, indicating iron deficiency anemia, which leads to a further decrease in hemoglobin levels - late anemia of prematurity, if iron therapy is not started. From this description of the pathogenetic mechanisms, it is clear that iron administration can eliminate or prevent only late anemia.

In term babies, hemoglobin levels also fall during the first 8-10 weeks of life. This phenomenon is called physiological anemia of newborns. It is caused by the same mechanisms as early anemia of prematurity, but in term infants, the life span of erythrocytes is less shortened and the blood volume does not increase so quickly, therefore, the anemia is less profound. In premature infants with low body weight, the hemoglobin level can reach 80 g / l already at the age of 5 weeks, while in term infants, hemoglobin rarely drops below 100 g / l and its minimum level is detected at 8-10 weeks of life.

Symptoms of the anemia of prematurity

Symptoms of early anemia of prematurity are characterized by some pallor of the skin and mucous membranes; with a decrease in hemoglobin below 90 g / l, pallor increases, motor activity and activity during sucking decrease slightly, systolic murmur may appear at the apex of the heart. The course of early anemia in most children is favorable.

Late anemia of prematurity, due to a high need for iron in connection with a more intense than in full-term, the rate of development, clinically manifests itself as an ever-increasing pallor of the skin and mucous membranes, lethargy, weakness, loss of appetite. Reveal muffling of heart sounds, systolic murmur, tachycardia. In the clinical analysis of blood - hypochromic anemia, in severity correlating with the degree of prematurity (mild - hemoglobin 83-110 g / l, moderate - hemoglobin 66-82 g / l and severe - hemoglobin less than 66 g / l - anemia). In a blood smear, microcytosis, anisocytosis, polychromasis are determined. The content of serum iron is reduced, the coefficient of saturation of transferrin with iron is reduced.

[8], [9], [10]

 

Treatment of the anemia of prematurity

Characteristics of iron preparations for enteral use, produced in liquid form

Iron preparations	Release form	Elemental iron	Additional information
Aktiferrin drops	30 ml vials	In 1 ml - 9.8 mg Fe 2+	1 ml of the drug corresponds to 18 drops
Hemofer, drops	10 ml pipette vials	1 drop - 2.2 mg Fe 2+	1 ml of the drug corresponds to 20 drops
Maltofer drops	30 ml vials	In 1 ml - 50 mg of iron in the form of a polymaltose complex of Fe 3+ hydroxide	1 ml of the drug corresponds to 20 drops
Totem	10 ml ampoules	50 mg in 1 ampoule	Contains 1.3 mg elemental manganese and 0.7 mg elemental copper in 1 ampoule

Since early anemia refers to conditions reflecting the developmental process, treatment is usually not required for it, with the exception of providing adequate nutrition for normal hematopoiesis, especially the intake of folic acid and vitamin E, B vitamins, ascorbic acid.

Blood transfusions are usually not performed, however, if the hemoglobin level is below 70 g / L and the hematocrit is less than 0.3 L / L or concomitant diseases, it may be necessary to transfuse small volumes of red blood cells (the volume of blood transfusion should ensure an increase in hemoglobin to 90 g / L). More massive blood transfusions can delay the process of spontaneous recovery due to inhibition of erythropoiesis.

For the treatment of late anemia of prematurity, the correct organization of nursing is important - rational nutrition, walking and sleeping in the fresh air, massage, gymnastics, prevention of intercurrent diseases, and so on.

Therapy with iron preparations inside is prescribed at the rate of 4-6 mg of elemental iron per 1 kg of body weight per day.

The duration of treatment with iron preparations depends on the severity of the anemia. On average, the recovery of red blood counts occurs in 6-8 weeks, however, treatment with iron preparations in premature infants should be continued for 6-8 weeks until the iron stores in the depot are restored. Therapy with maintenance doses of iron preparations (2-3 mg / kg / day) should be continued prophylactically until the end of the first year of life.

Simultaneously with iron preparations, it is advisable to prescribe ascorbic acid, vitamins B ₆  and B ₁₂. With persistent intolerance to iron preparations administered orally, with a severe degree of iron deficiency anemia, intramuscular administration of iron preparations (ferrum-lek) is indicated.

• Recombinant erythropoietin for the treatment of anemia of prematurity

Recognition of low plasma erythropoietin (EPO) levels and normally responsive erythrocyte progenitor cells in preterm infants provides a rational basis for considering recombinant human erythropoietin (r-HuEPO) as a treatment for anemia of prematurity. Since an insufficient amount of erythropoietin in plasma is the main cause of anemia, and not a subnormal response of bone marrow erythroid precursors to erythropoietin, it is logical to assume that r-HuEPO will correct EPO deficiency and effectively treat anemia of prematurity. Regardless of the proposed logic, r-HuEPO is not widely used in clinical neonatal practice, as its effectiveness is not complete. On the one hand, clonogenic precursors of neonatal erythroids respond well to r-HuEPO in vitro and r-HuEPO, and iron effectively stimulates erythropoiesis in vivo, as evidenced by an increase in the number of reticulocytes and erythrocytes in the blood of newborn recipients (i.e., efficacy at the bone marrow level). On the other hand, when the main goal of r-HuEPO therapy is to eliminate red blood cell transfusions, r-HuEPO often fails to do so (i.e., clinical efficacy has not always been successful) [11]. [12]

Prevention

Preventive measures include timely sanitation of foci of infection and treatment of toxicosis in pregnant women, adherence to the regimen and proper nutrition of the pregnant woman.

Natural feeding and the prevention of sideropenia in the mother are important (with sideropenia in the mother, her milk contains iron 3 times less than the norm, copper - 2 times, other microelements are reduced or absent), optimal conditions for nursing a premature baby and prevention of diseases in him. In order to prevent hypovitaminosis E, it is recommended that all children weighing less than 2000 g in the first 3 months of life be given vitamin E orally at a dose of 5-10 mg / day. For the prevention of folate deficiency in the last trimester of pregnancy and premature babies, it is recommended to prescribe folic acid at a dose of 1 mg per day in courses of 14 days. Prevention of iron deficiency in premature babies is carried out from 2 months of age throughout the first year of life. Iron preparations are prescribed by mouth at the rate of 2-3 mg of elemental iron per 1 kg of body weight per day.