Erythropoietin and prematurity – where do we stand?

Abstract

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 <or=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 <or=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.

Comparison between one and three doses a week of recombinant erythropoietin in very low birth weight infants

“…1,2 However, the fundamental clinical objective of using rEPO in very low birth weight (VLBW) infants has been to slow down the decline in hemoglobin parameters during the first weeks of life and to reduce the transfusion requirement, which is very high for these infants. [3][4][5][6][7] Since the first pilot trial, published by Halperin et al in 1990, 8 rEPO use has spread and many studies have evaluated it as safe and effective. [9][10][11][12] In terms of efficacy, rEPO stimulates erythropoiesis in VLBW infants and diminishes the number of transfusions per infant as well as the cumulative volume transfused and the exposure to multiple donors.…”

“…Control of phlebotomies and the use of strict transfusion criteria by themselves lower the transfusion requirement. 6,7 Regarding safety, long-term adverse effects are still unknown, 6 but in the short term, rEPO does not increase neonatal morbidity (sepsis, necrotizing enterocolitis, intraventricular hemorrhage, chronic lung disease, death before discharge, hypertension). [10][11][12] Nevertheless, because of its demonstrated angiogenic activity, 13 several trials have associated the use of rEPO with retinopathy of prematurity (ROP).…”

Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin

“…However, others reported that the effect of EPO treatment was insufficient in reducing RBC transfusions to be of clinical significance in the treatment of anemia of prematurity (5,25,38). These differences may be due to inconsistent transfusion guidelines, treatment protocols, and/or interpatient variability in EPO responsiveness (9). Also, since none of the study designs considered the complex pharmacokinetics/pharmacodynamic (PK/PD) of EPO, this likely resulted in empirical EPO doses and dosing schedules that were suboptimal.…”

1 RBC Concentrates

“…Combined treatment with erythropoietin, oral iron substitution, vitamin B12 and folic acid [18,19] starting in the first week of life can decrease the need for transfusion in preterm infants [8,42].…”