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Erythropoietin (EPO) treatment for anemia of prematurity is still controversial. Large multicentric trials demonstrate that administration of EPO+Fe cannot prevent early transfusions, particularly in very low birth weight newborns and in infants with severe neonatal diseases, but may have some beneficial effect to prevent late transfusions. Current treatment of anemia of prematurity should be multifactorial trying to minimize all causes that reduce erthrocytic mass (phlebotomies, use of noninvasive procedures) and promoting all factors that increase it (placental transfusion, adequate nutrition support). To evaluate the real impact of EPO treatment it is mandatory to follow similar transfusion protocols for preterm infants in all the studies. The aim of EPO+Fe administration should be to avoid new late transfusions in very low birth weight preterm infants or to prevent the first transfusion after the second week of life in less immature premature with the objective of reducing the number of donors rather than the number of transfusions. We have limited the use of EPO+Fe to infants <30 weeks gestational age and birth weight ≤1250 g as well as to infants weighing 1250–1500 g with initial severe disease. The comparison of outcomes before (28 months period with EPO+Fe treatment to all premature ≤32 weeks gestational age) and after 20 months of implementation of the new protocol showed a significant decrease in EPO+Fe treatment candidates (40.3% vs. 85.9%, P<0.001) without changes in the percentage of transfusions in both periods. Therefore if EPO treatment is to be given it should be limited to preterm infants with a birth weight <1000 g or those of 1000–1250 g associated with risk factors for blood transfusion. It should be started at 3–7 days of life at doses of 250 U/kg subcutaneously, three times a week, for 4–6 weeks depending on gestational age with oral iron 2–12 mg/kg/day to keep ferritin levels greater than 100 ng/mL.
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