Anemia of Prematurity
- Author: George Cassady, MD; Chief Editor: Ted Rosenkrantz, MD more...
All infants experience a decrease in hemoglobin concentration after birth. The transition from a relatively hypoxic state in utero to a relatively hyperoxic state with increased tissue oxygenation after birth leads to a decline in erythropoietin (EPO) concentration. For the term infant, a physiologic and usually asymptomatic anemia is observed 8-12 weeks after birth.
Anemia of prematurity (AOP) is an exaggerated, pathologic response of the preterm infant to this transition. AOP is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum EPO level, often despite a remarkably reduced hemoglobin concentration. Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia, as may blood loss and/or a reduced red cell life span.
AOP spontaneously resolves in many premature infants within 3-6 months of birth. In others, however, medical intervention is required. Although the physiology and pathophysiology for AOP are well studied, controversy surrounds the timing, method, and effectiveness of therapeutic interventions for AOP. This article reviews the pathophysiology of AOP, the means of reducing its impact on premature infants, and its treatment through blood transfusion or recombinant EPO therapy.
It is important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration.
The three basic mechanisms for the development of anemia of prematurity (AOP) include (1) inadequate RBC production, (2) shortened RBC life span, and (3) blood loss.
Inadequate RBC production
The first mechanism of anemia is inadequate RBC production for the growing premature infant. The location of EPO and RBC production changes during gestation. EPO synthesis initially occurs in the fetal liver but gradually shifts toward the kidney as gestation advances. By the end of gestation, however, the liver remains the major source of EPO.
Fetal erythrocytes are produced in the yolk sac during the first few weeks of embryogenesis. The fetal liver becomes more important as gestation advances and, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By about 32 weeks' gestation, the burden of erythrocyte production in the fetus is shared evenly by liver and bone marrow. By 40 weeks' gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.
Although EPO is not the only erythropoietic growth factor in the fetus, it is the most important. EPO is synthesized in response to anemia and consequent relative tissue hypoxia. The degree of anemia and hypoxia required to stimulate EPO production is far greater for the fetal liver than for the fetal kidney. EPO production may not be stimulated until a hemoglobin concentration of 6-7 g/dL is reached. As a result, new RBC production in the extremely premature infant, whose liver remains the major site of EPO production, is blunted despite what may be marked anemia. In addition, EPO, whether endogenously produced or exogenously administered, has a larger volume of distribution and is more rapidly eliminated by neonates, resulting in a curtailed time for bone marrow stimulation.
Erythroid progenitors in premature infants are quite responsive to EPO, but the response may be blunted if iron or other substrate or co-factor stores are insufficient. Another potential problem is that while the infant may respond appropriately to increased EPO concentrations with increased reticulocyte counts, rapid growth may prevent the appropriate increase in hemoglobin concentration.
Shortened RBC life span or hemolysis
Also important in the development of AOP is that the average life span of a neonatal RBC is only one half to two thirds that of an adult RBC. Cells of the most immature infants may survive only 35-50 days. The shortened RBC life span of the neonate is a result of multiple factors, including diminished levels of intracellular adenosine triphosphate (ATP), carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.
Finally, blood loss may contribute to the development of AOP. If the neonate is held above the placenta for a time after delivery, fetal-placental transfer of blood may occur. Conversely, delayed cord clamping may lessen the degree of AOP (although a study by Elimian et al did not find this to be true ). More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. These losses are often 5-10% of the total blood volume.
Taken together, the premature infant is at risk for the development of AOP because of limited RBC synthesis during rapid growth, a diminished RBC life span, and an increased loss of RBCs.
The risk of anemia of prematurity (AOP) is inversely related to gestational maturity and birthweight. As many as half of infants of less than 32 weeks gestation develop AOP. AOP is not typically a significant issue for infants born beyond 32 weeks' gestation.
Race and sex have no influence on the incidence of AOP.
Testosterone is believed to be at least partially responsible for a slightly higher hemoglobin level in male infants at birth, but this effect is of no significance with regard to risk of AOP. The nadir of the hemoglobin level is typically observed 4-10 weeks after birth in the tiniest infants, with concentrations of 8-10 g/dL if birthweight was 1200-1400 grams, or 6-9 g/dL at birth weights of less than 1200 grams.
Spontaneous recovery of mild anemia of prematurity (AOP) may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.
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