The effect of recombinant human erythropoietin on circulating hematopoietic progenitor cells in anemic premature infants. Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity. Recombinant human erythropoietin therapy in low-birthweight preterm infants: a prospective controlled study. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Use of erythropoietin and its effects on blood lactate and 2, 3-diphosphoglycerate in premature neonates. [Evaluation of treatment results for anemia of prematurity treated with various doses of human recombinant erythropoietin]. An approach to using recombinant erythropoietin for neuroprotection in very preterm infants. [Early erythropoietin use for the prevention of anemia in infant premature]. In which neonates does early recombinant human erythropoietin treatment prevent anemia of prematurity? Results of a randomized, controlled study. Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. Recombinant erythropoietin and blood transfusion in selected preterm infants. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Efficacy and safety of recombinant human erythropoietin to prevent the anaemias of prematurity. European Randomized Multicenter Trial. [Efficacy of early erythropoietin use in critically ill, very-low-birthweight premature newborn infants: controlled clinical trial]. The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. European Multicentre Erythropoietin Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Preventive effect of different dosage of recombinant human erythropoietin on anemia of premature infants. [Early use of recombinant human erythropoietin promotes neurobehavioral development in preterm infants]. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? Effects of early human recombinant erythropoietin therapy on the transfusion in healthy preterm infants. A comparison of high versus low dose recombinant human erythropoietin versus blood transfusion in the management of anaemia of prematurity in a developing country. Effect of recombinant human erythropoietin on transfusion needs in preterm infants.
In vitro and animal studies suggest that high concentrations of recombinant human erythropoietin (rHuEPO) might divert multipotent progenitors into erythroid maturation at the expense of granulocyte production. We determined whether changes of number and lineage commitment of peripheral blood progenitor cells occur in premature infants during therapy with rHuEPO. Thirty preterm infants were randomly assigned either to receive 300 IU of eopoetin alpha s.c. per kilogram body weight three times a week for four weeks or to a control group. At study entry and after two weeks of treatment the numbers of circulating BFU-E, granulocyte-macrophage colony-forming units (CFU-GM) and granulocyte-erythrocyte-macrophage-megakaryocyte CFU (CFU-GEMM) were analyzed by semisolid culture technique, CD34+ cells and early myeloid CD34+CD45RA- progenitors by flow cytometry. As compared with the control group, rHuEPO treatment did not exert any significant modulatory effect on numbers of CFU-GM, nor was there a significant change in numbers of BFU-E, CFU-GEMM, total-CFU, percentage of CD34+ or CD34+CD45RA- cells. Mean neutrophil count was not significantly reduced at any period during the study. Compared with the control group, the infants receiving rHuEPO had higher hematocrit values (p = 0.003) and absolute reticulocyte counts (p < 0.001). The median cumulative volume of blood transfused per kilogram per day was 0.86 ml (first quartile 0.5 ml; third quartile 1.1 ml) in the control group and 0 ml (first quartile 0 ml; third quartile 0.47 ml) in the rHuEPO group (p = 0.038). We conclude using a relatively high dose of rHuEPO in premature infants, no significant in vivo effect on circulating peripheral blood progenitor or neutrophil count could be detected. Erythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function. This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight < or =800 g and a gestational age < or =32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment. With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count. We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life. Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls. This study aimed to detect the effectiveness of recombinant human erythropoietin therapy in preventing premature anemia in low-birthweight preterm infants.
                A total of 292 premature infants who were born earlier than 33 gestational weeks and smaller than 1500 g birthweight were enrolled into the study. In addition to their conventional supportive therapy (medications), recombinant human erythropoietin 200 U/kg twice a week, subcutaneously, was given to randomly selected 142 premature infants for 6 weeks. The blood count variables and need for transfusions were compared with the remaining 150 premature infants during 6 months follow up.
                Serum erythropoietin levels were 11.3 +/- 6.1 mU/mL and 38.3 +/- 19.1 mU/mL in the erythropoietin group before and at the fourth week of the study, respectively (P < 0.001). Reticulocyte counts of the group treated with erythropoietin were 146 x 10(6) +/- 28 x 10(6)/mL and 122 x 10(6) +/- 27 x 10(6)/mL at the fourth and seventh week of the study, respectively, and these values were significantly higher when compared with the control group (P < 0.001 and P < 0.001). At the same period, hematocrit values were also found to be higher in the treatment group than the control group (P < 0.001). Serum ferritin levels were lower in the treatment group compared with the control group at the fourth week of the study. No side-effects related to erythropoietin usage were encountered. The need for packed cell transfusions were 47% in the group treated with erythropoietin and 62.6% in the control group. A statistically significant difference was found for transfusion needs between the control and treatment groups (P < 0.001).
                Recombinant erythropoietin is effective therapy for maintaining stable hematocrit levels in low-birthweight preterm infants and prevents the need for blood transfusions. Infants of </=1250 g birth weight receive multiple erythrocyte transfusions during their hospitalization. We hypothesized that early erythropoietin (Epo) and iron therapy would 1) decrease the number of transfusions received (infants 401-1000 g birth weight; trial 1) and 2) decrease the percentage of infants who received any transfusions (1001-1250 g birth weight; trial 2).
                A total of 172 infants in trial 1 and 118 infants in trial 2 were randomized to treatment (Epo, 400 U/kg 3 times weekly) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Complete blood and reticulocyte counts were measured weekly, and ferritin concentrations were measured monthly. Transfusions were administered according to protocol. Phlebotomy losses and transfusion data were recorded.
                Treated and placebo/control infants in trial 1 received a similar number of transfusions (4.3 +/- 3.6 vs 5.2 +/- 4.2, respectively). A similar percentage of treated and control infants in trial 2 received at least 1 transfusion (37% vs 46%). Reticulocyte counts were higher in treated infants during each week of the study in both trials. Hematocrits were higher among treated infants from week 2 on in both trials. Ferritin concentrations were higher in placebo/controls than in treated infants at weeks 4 and 8 in trial 1 and at week 4 in trial 2. No adverse effects of Epo or supplemental iron occurred.
                The combination of early Epo and iron as administered in this study stimulated erythropoiesis in infants who were </=1250 g at birth. However, the lack of impact on transfusion requirements fails to support routine use of early Epo.neonate, intravenous iron, donor exposure. The aim of this study was to investigate the effect of recombinant human erythropoietin (rHu-EPO) on oxygen affinity and adequate oxygen delivery to the tissues of stable premature infants. 36 very-low-birth-weight infants were randomly assigned to either receive rHu-EPO (200 units/kg every other day) or not, and both groups were supplemented with iron, folic acid and vitamin E. Arterial blood gases, oxygen saturation, complete blood counts, fetal haemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and blood lactate were analysed weekly, from the 1st week till discharge. Patients in the two groups were comparable. There was a trend in increasing lactate values towards the 4th to 5th weeks of life, which did not reach statistical significance. There was no correlation between lactate values and the studied variables (pH, BE, oxygen saturation). In 35 transfusions, pre- and 24 h post-transfusion blood lactate status was studied. In 23 of them, a decrease in post-transfusion lactate was noticed, whilst an increased post-transfusion level was shown in 10 cases and no change in 2 cases. The mean pre-transfusion lactate value was significantly higher than the post-transfusion one (24.04 +/- 11.9 mg/dl before and 16.27 +/- 8.5 mg/dl after transfusion; p = 0.0025). In both groups there was a steady rise in 2,3-DPG concentration over the period of study, and the 2,3-DPG values at the end of our study were significantly increased in the rHu-EPO group (rHu-EPO 5.98 +/- 0.9, control 4.84 +/- 0.7; p = 0.04). In conclusion, the use of rHu-EPO did not affect blood lactate levels compared to the control group. Regarding oxygen affinity, it seems that rHu-EPO causes a shift of the oxy-haemoglobin dissociation curve to the right. This is a previously unreported effect of rHu-EPO and its clinical use may, thus, confer to preterm babies an added advantage. We evaluated the results of administering recombinant human erythropoietin (rHuEPO) and iron in 19 randomly selected premature infants, who had no infections, did receive oxygen support or aminophylline. rHuEPO was administered intravenously from days to 37 (biweekly) in a dose of 100 U/kg (group I) or 400 U/kg (group II). Also, infants in both groups were supplemented with 10 mg/kg/week of iron intravenously. Seven of 19 infants did not receive either rHuEPO or iron (group III). Infants of all groups had similar birth weights, gestational age and hematocrit, RBC count as well as total and fetal hemoglobin concentrations in blood obtained within the first hour of life. However, infants treated with 400 U/kg of rHuEPO required a significantly (p < 0.04) lower volume of packed erythrocytes in comparison to untreated infants, both between days 7 and 37 of life (18.6 ml vs 46.8 ml; p < 0.04) and between day 7 of life and the day of discharge (35.8 ml vs 94.2 ml; p < 0.04). No difference in neutrophil count, fetal hemoglobin concentration and no toxicity were observed in infants treated with rHuEPO in comparison to untreated prematures. Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome.
                This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth.
                The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count.
                No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age. Anemia is common among very low birth weight newborns and requires frequent blood transfusions. Erythropoietin was been reported to be useful in the prevention of this anemia.
                To assess the benefits of early (before the third week of life) Human recombinant Erythropoietin (r-EPO) administration to reduce the requirement of blood transfusions in very low birth weight newborns.
                Sixty newborns under 1500 g of birthweight were randomly assigned to receive r-EPO (n = 29) or placebo (n = 31) three times per week, during four weeks. Packed red cell volume and reticulocyte counts were measured weekly. Serum erythropoietin was measured prior to eighth dose. Transfusion requirements were recorded.
                r-EPO reduced transfusions from 1.41 +/- 1.1 to 0.69 +/- 1 transfusions/newborns (p < 0.001). At the fourth week of treatment, reticulocyte count was 14.8 +/- 7 and 6.4 +/- 4.9% in the active treatment group and placebo group respectively (p < 0.001).
                r-EPO reduces the requirement of transfusions in low birth weight infants. To assess whether erythropoietin (EPO) treatment is safe and reduces the need for transfusion, we randomized 44 preterm infants to an EPO group and a comparable control (CON) group. EPO 150 U/kg was given s.c. twice weekly for 6 wk from the 1st wk of life. Hematologic parameters, transfusion requirements, and growth were followed during therapy and for 6 mo thereafter. To better assess in which neonates EPO treatment was effective, we classified retrospectively the EPO and CON groups into uncomplicated neonates (EPO A: n = 9, birth weight = 1247 +/- 126 g, gestational age = 29.8 +/- 1.5 wk; CON A: n = 7, birth weight = 1217 +/- 145 g, gestational age = 29.9 +/- 1.5 wk) and neonates requiring artificial ventilation (EPO B: n = 16, birth weight = 1169 +/- 249 g, gestational age = 28.1 +/- 2 wk; CON B: n = 12, birth weight = 1173 +/- 215 g, gestational age = 28.3 +/- 2 wk). There were significant differences in reticulocytes between both uncomplicated and ventilated neonates in the EPO group compared with respective control groups. However, the need for transfusion was significantly less in the uncomplicated EPO group (EPO A: 0.44 +/- 0.73 versus CON A: 1.28 +/- 0.75, p < 0.05) but not in the neonates on ventilation (EPO B: 8.25 +/- 5 versus CON B: 7.75 +/- 3.7). In conclusion, early EPO administration reduces the need for transfusion in uncomplicated premature neonates.(ABSTRACT TRUNCATED AT 250 WORDS) Treatment with recombinant human erythropoietin (rHuEPO) stimulates erythropoiesis and reduces the need for transfusions in hospitalized preterm infants. The aim of our study was to follow very low birth weight infants after the initial 6 weeks of rHuEPO treatment.
                We randomly assigned 97 very low birth weight infants with a gestational age of 31 weeks or less and birth weight of 1500 gm or less to receive rHuEPO, 300 units/kg per week (erythropoietin (EPO) 300, n = 33), rHuEPO, 750 units/kg per week (EPO 750; n = 28), or no treatment (control, n = 36). The rHuEPO was administered from the first week of life for 6 weeks. After EPO therapy was discontinued, 75 neonates were followed weekly until discharge and at 3, 6, and 12 months of age.
                Mean numbers (+/- SD) of packed erythrocyte transfusions per patient from the time rHuEPO therapy was discontinued until discharge were 0.38 +/- 0.64 (EPO 300), 0.23 +/- 0.52 (EPO 750), 0.9 +/- 1.1 (control) (p < 0.05 in both EPO groups vs control). Mean reticulocyte counts at the sixth week were 6% +/- 2.2% (EPO 300), 6.9% +/- 2.2% (EPO 750), and 3.1% +/- 2.6% (control) in the three groups (p < 0.01 in both EPO groups vs control), and at the eighth week were 4.7% +/- 2.8% (EPO 300), 5.4% +/- 2.7% (EPO 750), and 2.6% +/- 2.2% (control) (p < 0.01 in both EPO groups vs control). Serum ferritin levels were significantly higher at the sixth week, and the percentage of hemoglobin F was significantly lower at 6, 8, and 10 weeks in the control group versus EPO groups. At 3, 6, and 12 months of age, there were no differences in reticulocytes, ferritin, HbF, and growth among groups.
                Preterm infants who received rHuEPO had a normal pattern of erythropoiesis after the drug was discontinued. These data provide strong evidence that the anemia of prematurity is the result of a transient developmental abnormality in EPO production. To comprehensively identify preterm infants likely to require blood transfusion and to investigate the effectiveness of recombinant erythropoietin in this high risk subgroup.
                Double blind randomised controlled trial.
                Neonatal Intensive Care Unit, Middlemore Hospital, Auckland, New Zealand.
                Preterm infants < 33 weeks gestation and < 1700 g birth weight meeting specific criteria indicating a high possibility of requiring blood transfusion.
                Predictors of blood transfusion were determined by analysis of preterm infants admitted to a neonatal intensive care unit over a two year period. Using the criteria developed, high risk infants entered the study and received erythropoietin or sham treatment until 34 weeks completed gestation. The sample size was calculated to detect a reduction of one blood transfusion per infant (significance level 5%, power 80%).
                The selection criteria had a positive predictive value for transfusion of 91% and a negative predictive value of 94%. Mean birth weights and gestational ages were similar in the two groups. Absolute reticulocyte counts and haemoglobin values were higher in the group receiving erythropoietin. There was no significant difference in the number of blood transfusions received in the treatment and control groups. However, comparing transfusions given to < 1000 g infants after 30 days of age, there were significantly fewer transfusions in the erythropoietin group (mean (SD) 0.5 (0.7) in those receiving erythropoietin and 1.6 (1.1) in the controls). No adverse effects were noted.
                The selection criteria for the study were highly predictive of subsequent transfusion. In the group receiving erythropoietin, a reduction in transfusion requirements was apparent only in the < 1000 g birthweight group after 1 month of age. Clinical trials of erythropoietin (EPO) administration to preterm infants have not focused on infants weighing 750 gm or less, the population most likely to receive multiple transfusions because of large phlebotomy losses. It is unknown whether preterm infants weighing 750 gm or less will respond to EPO by accelerating erythropoiesis, or whether EPO administered to this population will decrease blood transfusions.
                We randomly assigned 28 extremely low birth weight preterm infants (mean +/- SEM: 24.7 +/- 0.3 weeks' gestation, 662 +/- 14 gm birth weight), in the first 72 hours of life, to receive either EPO (200 U/kg/day) or placebo for 14 days and administered transfusions only according to protocol over a 21-day study period. All infants received 1 mg/kg/day iron dextran in their total parenteral nutrition solution during the 14-day treatment period.
                During the 21-day study period, a lower number and volume of transfusions were received by the EPO recipients (4.7 +/- 0.7 transfusions per patient and 70 +/- 11 ml/kg per patient) than by the placebo recipients (7.5 +/- 1.1 transfusions per patient and 112 +/- 17 ml/kg per patient; p < 0.05, EPO vs placebo), whereas hematocrits remained similar in the two groups. Reticulocyte counts were similar in both groups on day 1 but were greater in the EPO recipients on day 14 (EPO day 1, 351 +/- 53; EPO day 14, 359 +/- 40 x 10(3)/microl; placebo day 1, 334 +/- 64; placebo day 14, 120 +/- 10 x 10(3)/microl; p < 0.01, EPO vs placebo). Serum ferritin concentrations were similar in both groups at the beginning of the study but were greater in the placebo recipients by day 14 (EPO, 262 +/- 44 microg/L; placebo, 593 +/- 92 microg/L; p < 0.01). No adverse effects of EPO or iron were noted.
                The combination of EPO and parenteral iron stimulates erythropoiesis in preterm infants weighing 750 gm or less and results in fewer transfusions during their first 3 weeks of life. We hypothesized that using a higher dose of erythropoietin (Epo) and starting treatment on the first day of life would reduce the transfusion requirements of ventilator-dependent and non-ventilator-dependent very low birth weight (VLBW) infants. Moreover, we hypothesized that this treatment would be cost-effective.
                We randomly assigned 20 ill newborn VLBW infants to receive either Epo (200 units/kg per day) or placebo during their first 2 weeks of life. The caregivers were unaware of the treatment assignments, and erythrocyte transfusions were administered according to hematocrit and signs of anemia.
                On day 1, reticulocyte counts and hematocrits were similar in the two groups. During the subsequent 2 weeks, reticulocyte counts of the placebo recipients fell significantly below those of the Epo recipients, but hematocrits in the two groups did not differ. More transfusions were received by the placebo recipients (mean = 1.4 per patient) than by the Epo recipients (mean = 0.2 per patient; p < 0.01). No adverse effects of Epo were noted, and the costs in the placebo group exceeded those in the Epo group.
                We conclude that administration of Epo to VLBW infants during the first 2 weeks of life results in fewer transfusions and is cost-effective. To determine whether prophylactic treatment with recombinant human erythropoietin (rHuEPO) and iron would reduce the need for blood transfusions, we randomly assigned 22 premature infants with gestational ages less than or equal to 32 weeks and birth weights less than or equal to 1.75 kg to receive rHuEPO, 400 IU/kg three times a week, plus iron, 20 mg/wk intravenously, from the second day of life (11 infants), or no rHuEPO and no iron (11 infants). The two groups had similar birth weights and clinical variables. The treated infants required fewer blood transfusions (0.8 +/- 1.5 vs 3.1 +/- 2.1; p = 0.01) and less volume of packed erythrocytes (14.2 +/- 25.9 vs 48.4 +/- 34.0 ml/kg; p = 0.02). The amounts of blood sampled were not different (19.5 +/- 21.1 vs 27.8 +/- 19.1 ml/kg; p = 0.35). Reticulocyte and hematocrit values were higher in the treated group (4.46% +/- 0.8% vs 1.49% +/- 1.1% (p = 0.0001) and 48.1% +/- 7.3% vs 43.8% +/- 4.7% (p = 0.004), respectively). No side effects of either rHuEPO or intravenously administered iron were noted. These data indicate that rHuEPO, in combination with iron supplementation, is effective in reducing the need for blood transfusions in the premature infant. More information is needed on dosage, timing, and iron and vitamin supplementation. To determine whether iron supplementation would enhance erythropoiesis in preterm infants treated with high doses of human recombinant erythropoietin (r-HuEPO).
                Sixty three preterm infants were randomly allocated at birth to one of three groups to receive: r-HuEPO alone, 1200 IU/kg/week (EPO); or r-HuEPO and iron, 1200 IU/kg/week of r-HuEPO plus 20 mg/kg/week of intravenous iron (EPO + iron); or to serve as controls. All three groups received blood transfusions according to uniform guidelines.
                Infants in the EPO + iron group needed fewer transfusions than controls--mean (95% CI) 1.0 (0.28-1.18) vs 2.9 (1.84-3.88) and received lower volumes of blood--mean (95% CI) 16.7 (4.9-28.6) vs 44.4 (29.0-59.7) ml/kg. The EPO group also needed lower volumes of blood than the controls--mean (95% CI) 20.1 (6.2-34.2) vs 44.4 (29.0-59.7) ml/kg, but the same number of transfusions, 1.3 (0.54-2.06) vs 2.9 (1.84-3.88). Reticulocyte and haematocrit values from postnatal weeks 5 to 8 were higher in the EPO + iron than in the EPO group, and both groups had higher values than the controls. Mean (SEM) plasma ferritin was lower in the EPO group-65 (55) micrograms/l than in the EPO + iron group 780 (182) micrograms/l, and 561 (228) micrograms/l in the control infants.
                Early administration of high doses of r-HuEPO with iron supplements significantly reduced the need for blood transfusion. Intravenous iron (20 mg/kg/week in conjunction with r-HuEPO yielded a higher reticulocyte count and haematocrit concentration after the forth week of life than r-HuEPO alone. Infants treated with r-HuEPO alone showed signs of reduced iron stores. nan To determine the efficacy of erythropoietin in very low birth weight (VLBW) newborns less than 72 h of age.
                We randomly assigned 40 critically ill newborn VLBW infants to receive either recombinant human erythropoietin (EPO) 150 units/kg per day (21 patients) or placebo (19 patients) during their first six weeks of life. The observers were unaware of the treatment assignments. Frequency of erythrocyte transfusion, adverse effects and haematologic measures were evaluated and compared.
                Before treatment gestational age, weight, haemoglobin, and pathology were similar in both groups. During the subsequent 6 weeks, haemoglobin and haematocrit of the placebo group fell significantly below those of the EPO recipients. More transfusions were received by the placebo recipients (7/21) than by the EPO recipients (2/21; p = 0.04). No adverse effects of EPO were observed.
                We recommend the administration of recombinant human erythropoietin since the first 72 h of age, because of the high frequency of anaemia, the efficacy of EPO and lack of side effects. Anemia of prematurity is characterized by low reticulocyte counts and inadequate erythropoietin response, for which many very-low-birth-weight infants receive multiple blood transfusions. We investigated whether early treatment of such infants with recombinant human erythropoietin would reduce their need for transfusions.
                We performed a controlled, blinded trial in 241 infants with very low birth weights at 12 centers in six European countries. When three days old, the infants were randomly assigned either to the epoetin group or to the control group. Those in the epoetin group received 250 IU of epoetin beta per kilogram of body weight subcutaneously three times a week from day 3 to day 42 (for a total of 17 doses); those in the control group did not receive this drug. Infants in both groups received oral iron (2 mg per day) from day 14 onward.
                The control infants needed a mean of 1.25 transfusions each, as compared with 0.87 transfusion for epoetin-treated infants (P = 0.013). The median cumulative volume of blood transfused per kilogram per day was 0.41 ml in the control group (first quartile, 0 ml; third quartile, 0.8 ml) and 0.09 ml in the epoetin group (first quartile, 0 ml; third quartile, 0.8 ml) (P = 0.044). The rate of success, defined as an absence of need for transfusions and a hematocrit that never fell below 32 percent, was 4.1 percent in the control group and 27.5 percent in the epoetin group (P = 0.008). Epoetin was most beneficial in boys with birth weights of 1200 g or more and a base-line hematocrit of 48 percent or more. No toxic effects were observed in the epoetin group; as compared with the control group, the epoetin group had an increased incidence of septicemia (14 vs. 7 episodes, P not significant) and reduced weight gain (520 vs. 571 g, P = 0.02).
                Infants with very low birth weights have less need of transfusions if given epoetin beta during the first six weeks of life (250 IU per kilogram three times a week). We recommend early epoetin treatment for all such infants, but further studies of nutrition and iron supplementation during treatment are needed. To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment.
                In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%.
                Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta.
                Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants. To assess the efficacy and the optimum dose of recombinant human erythropoietin (rhEpo) on the anemia of premature, 45 preterm infants with a gestational age of less than 35 weeks and birth weight of less 1,800 g were randomly assigned to treatment group 1 (n = 15, receiving subcutaneous rhEpo 150 U/kg.time), treatment group 2 (n = 15, receiving 250 U/kg.time), three times a week for 6 weeks, and control group (n = 15, no treatment was given). All preterm infants received supplements of vitamin E (20 IU) and iron (20 mg) each day. Our results showed that postnatal decline of hemoglobin (Hb) and hematocrit (Hct) were lessened in the treatment groups, particularly in the group 2 and the differences were very significant (P < 0.0001 for all). Treated infants had significantly higher reticulocyte counts (Ret) (P < 0.0001 for all), but there was no significant difference between the two treatment groups (P > 0.05). Serum iron dropped significantly in the treatment groups as compared with control group (P < 0.01 for all), but no dose-dependent relationship was observed in treated infants (P > 0.05). After treatment, serum levels of erythropoietin was higher in group 2 than those in group 1 and control group (P < 0.0001, P < 0.01 and P < 0.05, respectively). There was no significant difference between group 1 and control group (P > 0.05). No side effects related to rhEpo therapy were observed. Our study suggested that rhEpo therapy stimulates endogenous erythropoiesis and enhances Ret, Hct and level of Hb in a dose-dependent manner in premature infants. The therapy is more efficient when given in higher dosages. To evaluate the effect of the early use of recombinant human erythropoietin (rhu-EPO) on neurobehavioral development in preterm infants.
                Forty-four preterm infants (30 males and 14 females) were randomly divided into two groups: Rhu-EPO treatment and untreated control (n=22 each). From postnatal day 7, the Rhu-EPO treatment group received intravenous rhu-EPO (250 IU/kg3 times weekly) for 4 weeks. A Neonatal Behavioral Neurological Assessment (NBNA) was performed at 40 weeks of corrected gestational age. A Gesell Development Schedule was used to evaluate neurological development 6 and 12 months after birth.
                The NBNA score in the rhu-EPO treatment group (36.20+/-0.75) was significantly higher than that in the control group (34.40+/-1.05) at 40 weeks of corrected gestational age (P<0.05). The developmental quotient of fine motor in the rhu-EPO treatment group was significantly higher than that in the control group 6 months after birth (P<0.05). By 12 months after birth, the developmental quotient of gross motor, fine motor and language in the rhu-EPO treatment group was significantly higher than that in the control group (P<0.05).
                Early use of Rhu-EPO can promote neurobehavioral development in preterm infants. Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants.
                Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes.
                Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL.
                Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome. Comparing a group of infants treated with recombinant erythropoietin and iron supplementation to a group of control infants, no difference was observed concerning the transfusion need. The incidence of retinopathy of prematurity was significantly higher in the treated group. These data need to be confirmed in randomized controlled studies. Early recombinant erythropoietin therapy and iron therapy would decrease the need for red blood cells transfusions and prevents anemia of prematurity.
                Fifty-eight preterm infants in newborn services at Ghaem Medical Center randomly were assigned, among them 18 patients were excluded. A total of 40 preterm infants with gestational age 28-34 weeks, birth weight 1000-1750 g followed the study: 20 infants in treatment group and 20 infants in control group were randomized to treatment (rhu EPO, 500u per kg, per week, 2 times weekly, subcutaneous) and control (no treatment). Therapy was initiated 4 days after birth and continued throughout the 4 weeks. All infants on enteral feeds received supplements: iron 3 mg/kg/d, vitamins and folat. Complete blood cells and reticulocyte counts were measured weekly. Transfusions and phlebotomy data were recorded. Statistical significance was determined by chi-square test, student t test and Mann-Whitney. A P value of < 0.05 was considered statistically significant.
                The reticulocyte counts were higher in treated infants during the study (p: 0.009). Final hematocrits were higher in treated infants (p: 0.02).The volume of packed red blood cells transfusions mililiter per infant significantly reduced (p: 0.05), the average number of transfusion per infant was also lower for treated infant than control [2 (10 % )vs 8 (40%) respectively]. No adverse effects of EPO or supplemental iron occurred.
                The combination of early rhu EPO and iron as administered in the present study stimulated erythropoiesis and decreased red blood cells transfusion in premature infants who were 1000-1750 g at birth. The enrollments of the larger and healthier preterm infants, who are at lower risk for transfusion, are limitation of the present study. The purpose of this study was to evaluate the effectiveness of early treatment with erythropoietin (EPO) in two different treatment regimes (high vs. low dose) in comparison to the conventional treatment of packed red blood cell (PRBC) transfusions in the management of anaemia of prematurity in a country with limited resources. An open controlled trial was conducted on 93 preterm infants (7 days postnatal age, 900-1500 g birthweight). Patients were randomly assigned either to a low dose (250 IU/kg), a high dose (400 IU/kg), or a control group. EPO was administered subcutaneously three times a week and all infants received 6 mg/kg iron orally from study entry to endpoint of therapy. Haematological parameters were measured and compared. The success was defined as an absence of transfusions and a haematocrit that did not fall below 30 per cent during the time period that the infants were in the study. The three groups were statistically comparable at study entry with respect to gestational age, birthweight, Apgar scores, and haematological values. Over the period that the infants were in the study, 75 per cent of the low dose group and 71 per cent of the high dose group met the criteria for success compared with 40 per cent in the control group (p < 0.001). However, there was no significant difference in the number of transfusions when the low and high EPO dose groups (9.5 per cent) were combined and compared with the control group (26.7 per cent) p = 0.0587. It was concluded that in stable infants, 900-1500 g, where phlebotomy losses are minimized and stringent transfusion guidelines are adhered to, EPO does not significantly decrease the number of transfusions. A conservative approach in the management of anaemia of prematurity, is a viable alternative in areas with limited resources. To study the efficacy, safety and cost effectiveness of recombinant human erythropoietin (r-HuEPO) in reducing erythrocyte transfusion needs in very low birthweight (VLBW) infants.
                We conducted a non-blind randomized controlled trial and assigned 100 VLBW infants, less than 33 weeks gestation, to receive either r-HuEPO 750 U/kg per week subcutaneously from day 5 to day 40 or no erythropoietin (EPO). Infants received oral iron 3-6 mg/kg per day from day 10. Transfusion needs were analysed for all enrolled infants and in five weight subgroups: birthweight of less than 600 g, 600-799 g, 800-999 g, 1000-1199 g and infants more than 1200 g.
                VLBW infants on r-HuEPO attained higher reticulocyte counts and haematocrit than control infants but the mean number of transfusions and volume of erythrocyte transfused per infant were not statistically different. Of infants 800-999 g at birth, the mean number of transfusions per infant was 2.1 compared with 3.5 transfusions per control infant (P = 0.04). Volume of erythrocytes transfused was 34.9 +/- 32.1 mL/kg in r-HuEPO-treated infants and 56.6 +/- 25.8 mL/kg in control infants (P = 0.03). The cost per patient for transfusion and EPO was S$388 for r-HuEPO recipient and S$438 for control infant. Blood pressure, neutrophil count, platelet count and complications of prematurity were not significantly different in both groups of VLBW infants.
                r-HuEPO at 750 U/kg per week stimulates erythropoiesis in VLBW infants but significantly reduces the need for erythrocyte transfusion only in infants weighing 800-999 g at birth.
Early administration of EPO reduces the use of RBC transfusions and the volume of RBCs transfused. These small reductions are of limited clinical importance. Donor exposure is probably not avoided since most studies included infants who had received RBC transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage ≥ 3). Early EPO does not significantly decrease or increase any of the other important adverse outcomes. Ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Evidence is lacking for the possible neuro protective role of EPO in preterm infants. This topic will be reviewed in separate Cochrane reviews for preterm and term and late preterm infants.