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Recombinant human erythropoietin therapy in low-birthweight preterm infants: A prospective controlle

Abstract

Recombinant human erythropoietin therapy in low-birthweight preterm infants: A prospective controlle

Publication: Pediatr Int 2005;47:67-71.
Friday, February 11th, 2005
Author: Arif B, Ferhan K.

Article
Arif B, Ferhan K. Recombinant human erythropoietin therapy in low-birthweight preterm infants: A prospective controlled study. Pediatr Int 2005;47:67-71.

Design
Single-center, prospective, randomized, single-blind trial. Number of patients: 292. Study period: 1993-2002. Setting: Neonatal Intensive Care Unit of Gulhane Military Medical Academy Haydarpasa Training Hospital, Istanbul, Turkey.

Overview

Background
Following birth, both term and preterm infants experience a decline in their hemoglobin (Hb) concentrations and in their plasma erythropoietin (EPO) levels. In preterm infants, the expected decline in Hb concentration is more prolonged and frequently results in profound anemia requiring red blood cell (RBC) transfusions. Studies evaluating recombinant human erythropoietin (rHuEPO) as a potential alternative to RBC transfusion in the treatment of the anemia of prematurity have yielded mixed results. In this single-center, prospective, randomized, single-blind trial, the authors assessed the efficacy of rHuEPO in improving anemia and reducing the need for RBC transfusions in premature infants.

Methods
Premature infants who were followed between 1993 and 2002 at the Neonatal Intensive Care Unit of Gulhane Military Medical Academy Haydarpasa Training Hospital, Istanbul, Turkey, were enrolled in the study. Inclusion criteria were as follows: gestation age < 33 weeks, birthweight < 1500 g, no blood sampling > 10 mL within the first 7 days after birth, no previous blood transfusion, no intraventricular hemorrhage more severe than Grade 1, and no history of hematological disease.

Patients were randomized to the treatment group or the control group through the use of a computer-assisted randomization scheme. In the treatment group, rHuEPO 200 U/kg was administered subcutaneously from the seventh day of life and continued twice weekly for 6 weeks. In both groups, infants received vitamin E (5 units/day) and oral iron (3-5 mg/kg/day) from the first week of the study.

Outcome measures were the proportion of patients requiring RBC transfusions and laboratory variables including total blood count, reticulocyte count, serum ferritin, and serum erythropoietin. Infants with Hb concentration < 7 g/dL and reticulocyte count < 108/mL or with Hb concentration < 8 g/dL and bradycardia, tachypnea or apnea, or who were not able to gain weight despite adequate calorie intake, were selected as candidates for blood transfusion.

Results
A total of 292 patients were included in the study, 142 in the treatment group and 150 in the control group. Baseline characteristics were similar in among groups, except for significantly greater white blood cell counts and absolute neutrophil counts in the treatment group (p < 0.001). In both groups, infant had the same amount of blood samples taken.

In the fourth week of therapy mean erythropoietin level was 38.3 ± 19.1 mU/mL in the treatment group versus 15.9 ± 13.4 mU/mL in the control group (p < 0.001). While the baseline serum ferritin concentrations in the rHuEPO and the control groups were comparable (303.5 ± 51.1 µg/L vs. 291.8 ± 64.3 µg/L, respectively; p = 0.065), in the third week it was 137.2 ± 47.4 µg/L in the treatment group, significantly lower than in the control group where it was 186.0 ± 14.1 µg/L (p < 0.001).

In the fourth week of treatment, mean reticulocyte count was 146 x 106 ± 28 x 106/mL and 60 x 106 ± 13 x 106/mL in rHuEPO-treated and control patients, respectively (p < 0.001). Mean hematocrit value was 31.9 ± 3.6% and 27.8 ± 3.4%, respectively, in the seventh week of the treatment (p < 0.001), and there was no significant difference between the groups after 10 weeks. The proportion of patients who received blood transfusions was 62.6% in the control group, compared with 47% in the treatment group (p < 0.001). The authors observed no side effect related to rHuEPO therapy.

Conclusion
Twice-weekly subcutaneous administration of 200 U/kg rHuEPO was found to be safe and effective in improving anemia and decreasing transfusion needs in low-birthweight preterm infants.

Key Points
• After birth, preterm infants experience a prolonged decline in Hb concentration that frequently results in profound anemia requiring red blood cell (RBC) transfusions.
• Studies evaluating recombinant human erythropoietin (rHuEPO) as a potential alternative to RBC transfusion in the treatment of the anemia of prematurity have yielded mixed results.
• In this single-center, prospective, randomized, single-blind trial of 292 low-birthweight infants, twice-weekly subcutaneous administration of 200 U/kg rHuEPO from the first week of life significantly increased erythropoietin levels, reticulocyte counts, and hematocrit values, and decreased the proportion of patients requiring RBC transfusions from 62.6% to 47% (p < 0.001).
• The authors did not observe the side effects, such as hypertension, hyperkalemia, convulsion, or exanthema, reported by previous studies of rHuEPO in premature infants.
• Despite oral iron supplementation, serum ferritin concentration decreased in both treatment and control groups and became significantly lower in the infants treated with rHuEPO than the controls.

Limitations

• The authors provide no information on the subgroup of patients with birthweight < 1000 g, which was identified in previous studies as the group deserving more benefit from rHuEPO therapy.
• No information is given on the number of units transfused.
• Transferrin saturation was not measured, therefore it is not possible evaluate functional iron deficiency during erythropoiesis stimulation.


SABM Rating:***

In Brief
Although many studies have evaluated rHuEPO as a potential alternative to RBC transfusion in the treatment of the anemia of prematurity, there is currently no consensus among neonatologists over the use of rHuEPO in this setting, due to concerns about its safety and mixed results in terms of reducing allogeneic blood exposure. In this large single-center, prospective, randomized, single-blind trial that included 292 low-birthweight infants from 1993 to 2002 at the Neonatal Intensive Care Unit of Gulhane Military Medical Academy Haydarpasa Training Hospital, Istanbul, Turkey, the authors assessed the efficacy of rHuEPO in improving anemia and reducing the need for RBC transfusions. Twice-weekly subcutaneous administration of 200 U/kg rHuEPO from the first week of life significantly increased erythropoietin levels, reticulocyte counts, and hematocrit values, and decreased the proportion of patients requiring RBC transfusions from 62.6% to 47% (p < 0.001). No side effects associated with rHuEPO administration were reported. Along with other methods, such as restrictive transfusion triggers and minimization of blood samples, rHuEPO and iron therapy can help decrease allogeneic blood exposure in preterm infants at risk of anemia of prematurity. The significantly lower serum ferritin concentration in the rHuEPO treated neonates compared to the controls raises the question of appropriate iron supplementation and possible functional iron deficiency in stimulated erythropoiesis.

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