Anemia of prematurity

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

Causes anemia of prematurity

The main factors contributing to the development of anemia in the first year of life in premature infants or in children born with low birth weight are the cessation of erythropoiesis, iron deficiency, folate deficiency and vitamin E deficiency. The development of early anemia of prematurity is primarily due to the suppression of erythropoiesis.

The cause of early anemia of prematurity in some children may be a deficiency of folic acid, the reserves of which in a premature newborn are very small. The need for folic acid in a rapidly growing premature baby is great. The folic acid depot is usually used up within 2-4 weeks, which leads to a deficiency of this vitamin, aggravated by the administration of antibiotics (suppressing the intestinal microflora and, consequently, the synthesis of folic acid), and the addition of an intestinal infection. Folic acid deficiency develops especially quickly 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 intramedullary 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, protecting membranes from oxidation and participating in the synthesis of vitamin E. The cause of increased hemolysis of red blood cells is explained by a 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 baby 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, often found in premature babies. Artificial feeding with cow's milk increases the need for vitamin E, and the administration of iron preparations sharply increases its consumption. All this leads to a deficiency of vitamin E in the body of a premature baby in the first months of life, which results in increased hemolysis of red blood cells.

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

[ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Pathogenesis

It has been established that with the onset of spontaneous breathing, 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 lifespan of fetal erythrocytes also contributes to anemia. A significant increase in the total blood volume, accompanying a rapid increase in body weight in the first 3 months of life, creates a situation that has been figuratively called "bleeding into the circulatory system". During this early anemia of prematurity, the bone marrow and reticuloendothelial system contain a sufficient amount of iron, and its reserves even increase, since the volume of circulating erythrocytes decreases. However, premature infants in the first months of life have a reduced ability to reutilize endogenous iron, their iron balance is negative (iron excretion with feces is increased). By the age of 3-6 weeks, the lowest hemoglobin level is 70 - 90 g / l, and in very low birth weight infants it is even lower.

Type of anemia	Mechanism	Time of maximum detection, weeks
Early	Delayed erythropoiesis + increasing blood volume (mass)	4-8
Intermediate	Erythropoiesis below what is required for the increasing blood volume	8-16
Late	Depletion of iron stores needed to supply the increasing mass of red blood cells	16 and more
Megaloblastic	Folate deficiency due to its unstable balance + infection	6-8
Hemolytic	Vitamin E deficiency during periods of increased 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 present before. This phase is called the intermediate phase. The decrease in the hemoglobin level mainly stops due to the restoration of erythropoiesis (at the age of 3 months, hemoglobin is usually 100-110 g / l), but hemolysis and an increase in blood volume continue, which can delay the increase in the hemoglobin concentration. However, now the iron reserves are already used up and they will inevitably be less than normal in relation to the body weight at birth. By the 16th-20th week, the iron reserves are depleted, and then hypochromic erythrocytes are detected for the first time, indicating iron deficiency anemia, which leads to a further decrease in the hemoglobin level - late anemia of prematurity, unless iron therapy is started. From this description of the pathogenetic mechanisms it is clear that iron administration can only eliminate or prevent late anemia.

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

Symptoms anemia of prematurity

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

Late anemia of prematurity, caused by a high need for iron due to a more intense rate of development than in full-term infants, is clinically manifested by constantly increasing pallor of the skin and mucous membranes, lethargy, weakness, and loss of appetite. Muffled heart sounds, systolic murmur, and tachycardia are detected. A clinical blood test reveals hypochromic anemia, the severity of which correlates 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). A blood smear reveals microcytosis, anisocytosis, and polychromasia. The serum iron content is reduced, the transferrin saturation coefficient is reduced.

[ 8 ], [ 9 ], [ 10 ]

Treatment anemia of prematurity

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

Iron preparations	Release form	Amount of elemental iron	Additional information
Actiferrin, drops	Bottles of 30 ml	1 ml contains 9.8 mg Fe 2+	1 ml of the preparation corresponds to 18 drops
Hemofer, drops	10 ml bottles with a pipette	1 drop contains 2.2 mg Fe 2+	1 ml of the preparation corresponds to 20 drops
Maltofer, drops	Bottles of 30 ml	1 ml contains 50 mg of iron in the form of a polymaltose complex of Fe 3+ hydroxide	1 ml of the preparation corresponds to 20 drops
Totem	Ampoules of 10 ml	50 mg in 1 ampoule	Contains 1.3 3 mg of elemental manganese and 0.7 mg of elemental copper in 1 ampoule

Since early anemia is a condition that reflects the developmental process, treatment is usually not required, except for ensuring adequate nutrition for normal hematopoiesis, especially the intake of folic acid and vitamin E, B vitamins, and 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 there are concomitant diseases, transfusion of small volumes of red blood cells may be required (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 the suppression of erythropoiesis.

For the treatment of late anemia of prematurity, it is important to properly organize nursing care - rational nutrition, walks and sleep in the fresh air, massage, gymnastics, prevention of intercurrent diseases, and so on.

Oral iron therapy is prescribed at a 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 anemia. On average, the red blood cell counts are restored after 6-8 weeks, but 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 for prophylactic purposes until the end of the first year of life.

Along with iron preparations, it is advisable to prescribe ascorbic acid, vitamins B6 _and B12 _. In case of persistent intolerance to iron preparations prescribed orally, in case of severe iron deficiency anemia, intramuscular administration of iron preparations (ferrum-lek) is indicated.

• Recombinant erythropoietin for the treatment of anemia of prematurity

The recognition of low plasma erythropoietin (EPO) levels and normally responsive erythroid progenitor cells in preterm infants provides a rational basis for considering recombinant human erythropoietin (r-HuEPO) as a treatment for anemia of prematurity. Since insufficient plasma erythropoietin is the primary cause of anemia rather than a subnormal response of bone marrow erythroid progenitors to erythropoietin, it is logical to assume that r-HuEPO would correct the EPO deficiency and effectively treat anemia of prematurity. Regardless of the presumed logic, r-HuEPO has not been widely used in clinical neonatology practice because its efficacy is incomplete. On the one hand, neonatal clonogenic erythroid precursors respond well to r-HuEPO in vitro and to r-HuEPO, and iron effectively stimulates erythropoiesis in vivo, as evidenced by the increase in reticulocyte and red blood cell counts in neonatal recipients (i.e., efficacy at the bone marrow level). On the other hand, when the primary goal of r-HuEPO therapy is to eliminate red blood cell transfusions, r-HuEPO often fails to do so (i.e., efficacy at the clinical level has not always been successful) [ 11 ], [ 12 ]

Prevention

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

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