Original Article
The Effect of Epoetin Beta (Recombinant Human Erythropoietin) on the Need for Transfusion in Very-Low-Birth-Weight Infants
N Engl J Med 1994; 330:1173-1178April 28, 1994
- Abstract
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Media in This Article
Figure 1
Number of Transfusions per Infant during the Study Period in the Control Group and the Epoetin Group.Figure 2
Kaplan-Meier Curves for the Rate of Successful Treatment and the Rate of Freedom from Transfusion in the Treatment Groups during the Study Period.Article Activity
- Article
The anemia of prematurity is commonly associated with low reticulocyte counts and deficient erythropoietin production1,2. In addition, diagnostic tests cause blood loss,3 which may add up to an infant's total blood volume within 28 days4. Since anemia may decrease the amount of available oxygen to a critical level,5 preterm infants receive frequent transfusions according to the amount of blood drawn,4,6 but the objective benefit of this practice is uncertain7.
In vitro studies have indicated that recombinant human erythropoietin stimulates erythroid progenitors from preterm infants in a normal dose-response relation8,9. Pilot studies in small numbers of preterm infants suggested that low doses of this agent have some effect,10-12 but this finding was not confirmed in subsequent controlled trials6,13.
We undertook the present study to determine whether recombinant human erythropoietin, given as epoetin beta in a dose of 750 IU per kilogram of body weight per week, would prevent anemia and reduce the need for transfusion in infants with very low birth weights.
Methods
A randomized blinded trial was performed at 12 centers in six European countries, with the consent of appropriate ethics committees and the infants' parents. Eligible infants were randomly assigned to a control group or an epoetin-treated group on the third day of life, by means of numbered, sealed envelopes. Block randomization was performed at each center.
Primary End Point
Treatment was defined as successful if an infant had no need of transfusions and had a venous-blood hematocrit that never fell below 32 percent during the study period.
Calculation of Sample Size
To detect an increase in the success rate from 50 percent, as expected in controls,13 to 75 percent, with a power of 90 percent at a two-tailed level of significance of 5 percent, 85 infants would be required for each treatment group. The estimated rate of withdrawal during the study was 29 percent13. Consequently, 240 infants had to be enrolled.
Blinding
Most participating doctors were reluctant to administer repeated subcutaneous injections of a placebo to low-birth-weight infants. Therefore, two teams were formed at each center: treating physicians determined whether infants could be enrolled or withdrawn from the study, decided whether they should receive transfusions, and monitored them without knowing their treatment group; “dosing investigators” performed the randomization and administered the epoetin beta but were not involved in the infants' care. When treatment was to be given, a dosing investigator carrying a “black box” containing appropriate equipment visited each infant, administered the study medication, and placed adhesive strips on both thighs (of both epoetin recipients and controls), which remained there until the next visit. During this procedure, staff and parents had to leave. A treating physician or a dosing investigator assigned to an infant had to serve in that capacity as long as the infant was studied.
Criteria for Entry and Withdrawal
All infants with birth weights of 750 to 1499 g were considered for randomization. Infants with any of the following predefined criteria were excluded before randomization: hemolytic disease (11 infants), exchange transfusion (6), a venous-blood hematocrit above 59 percent (24), a leukocyte count above 60,000 per cubic millimeter (0), a platelet count above 750,000 per cubic millimeter (0), renal failure (10), systolic blood pressure above 90 mm Hg (1), cyanotic heart disease or a major congenital malformation requiring surgery (15), participation in another therapeutic trial (9), anticipated discharge before day 42 (113), a gestational age of more than 34 full weeks (10), or a lack of parental consent (155).
The criteria for withdrawal from the study after randomization included any of those listed above and the following: ventilation or a continuous positive airway pressure with a fraction of inspired oxygen above 0.40 after day 6, a severe reaction at the injection site, receipt of medication that might have bone marrow toxicity, a vertically transmitted infection, major surgery, discharge before 42 days, or withdrawal of parental consent.
Patients
From September 1991 to December 1992, 598 infants were admitted, of whom 354 were excluded from the study as described above. Three of the 244 infants who underwent randomization were also excluded: all data on 2 infants were lost, and treatment (epoetin) was inadvertently omitted in 1 infant, whose records were not completed. The remaining 241 infants were evaluated in an intention-to-treat analysis. Sixty-one infants had birth weights of 750 to 999 g, 86 weighed 1000 to 1249 g, and 94 weighed 1250 to 1499 g. One hundred thirty-six infants were born before 30 weeks of gestation.
After randomization, 61 infants were withdrawn for the reasons listed above. Three infants completed the study but underwent ventilation longer than the protocol allowed. Thus, 177 infants completed the study according to the protocol.
Administration of Epoetin Beta
Infants assigned to the epoetin group received 250 IU of epoetin beta per kilogram, injected subcutaneously into a thigh on Mondays, Wednesdays, and Fridays and begun as soon as possible after randomization (day 3 to 5). Treatment continued until day 40 to 42, for a total of 17 doses. Lyophilized epoetin beta (Boehringer-Mannheim, Mannheim, Germany) stored in vials containing 1000 IU was dissolved with sterile water so that the injected volume ranged from 0.25 to 0.55 ml.
Recommended Iron Treatment
Oral iron supplementation (2 mg per day) was started on day 14 in all infants. If the serum ferritin level fell below 100 ng per milliliter or signs of iron deficiency appeared (or both events occurred), the dose of iron was increased. Vitamin E supplementation was not part of the protocol.
Transfusions
Guidelines for transfusion were derived from the experience of the participating doctors. Infants who were receiving ventilation or who were less than two weeks old and had signs of anemia were given transfusions if their hematocrit fell below 40 percent, their hemoglobin concentration fell below 14 g per deciliter (8.7 mmol per liter), or blood samples totaling at least 9 ml per kilogram had been obtained from them since their previous transfusion. Spontaneously breathing infants more than two weeks old whose fraction of inspired oxygen was less than 0.40 were given transfusions if they had signs of anemia and their hematocrit fell below 32 percent and their hemoglobin concentration below 11 g per deciliter (6.8 mmol per liter); if they had no signs of anemia, the corresponding cutoff values were 27 percent and 9 g per deciliter (5.6 mmol per liter). The team of treating physicians decided the timing and volume of transfusions within these guidelines.
Monitoring and Blood Sampling
Delayed cord clamping was recommended14. The heart and respiratory rates, blood pressure, blood gas values, and renal and liver function were monitored (data not shown). Blood sampling was carried out on day 3, day 12 to 14, day 24 to 26, and day 40 to 42 as part of routine care. The volume of the blood samples was recorded. Cranial ultrasound scans were obtained at least on day 3 and from day 12 to day 14. Intraventricular hemorrhage was graded according to the classification of Papile et al.15. Ophthalmoscopic examination for retinopathy of prematurity16,17 was performed at least once up to four weeks after the estimated date of delivery.
Hematologic Measurements
The hematocrit was measured in venous blood and blood units after centrifugation. The volume of transfused red cells was determined from the volume of blood transfused and the blood-unit hematocrit. The leukocyte, erythrocyte, and platelet counts and the hemoglobin concentration were determined with automated blood counters. The neutrophil count was calculated from the number of leukocytes and the percentage of neutrophils in a blood smear. The reticulocyte count was “normalized” (corrected) to a hematocrit of 45 percent by multiplying the count by the actual hematocrit and dividing by 45.
Statistical Analysis
Kaplan-Meier estimations, which allow patients with censored data to be included in an analysis in an appropriate manner, were used to express the success rate and the rate of freedom from the need for transfusions in each treatment group. Log-rank tests were used to analyze the distributions of failure-free time and transfusion-free time since the start of treatment. Cox's proportional-hazards analysis was used to adjust the time-dependent treatment effects for prognostic factors found to be significant. Spearman's correlation coefficient was calculated for the volume of red cells transfused and blood sampled. The Mann-Whitney U test was carried out to compare the number of transfusions per infant, the cumulative volume of blood transfused, the cumulative blood loss, the absolute change between base-line and final values, and body weight between the two groups. Cox's proportional-hazards model was also used to analyze specific adverse events, taking into account censoring and predictors unrelated to treatment.
All P values are two-tailed. A P value below 0.05 was considered to indicate statistical significance. Analyses were carried out with the Statistical Analysis System (SAS Institute, Cary, N.C.).
Results
Table 1Table 1
Characteristics of the Treatment Groups at Entry (Third Day of Life). shows the characteristics of both treatment groups at entry. There were no significant differences between the groups.Blood Loss
The median cumulative blood loss due to diagnostic tests was 0.74 ml per kilogram per day in the control group (first quartile, 0.51 ml; third quartile, 1.24 ml) and 0.83 ml in the epoetin group (0.57 ml and 1.45 ml, respectively) (P = 0.104). These losses were inversely related to birth weight: 0.59 ml per kilogram per day among infants weighing 1250 to 1499 g (first quartile, 0.43 ml; third quartile, 0.77 ml), 0.83 ml among those weighing 1000 to 1249 g (0.60 ml and 1.42 ml), and 1.27 ml among those weighing 750 to 999 g (0.95 ml and 1.70 ml). The median blood loss was 0.78 ml in boys and 0.75 ml in girls (P = 0.651).
At study entry, grade I or II intraventricular hemorrhage was found in 8 infants in the control group and 10 in the epoetin group, and grade III hemorrhage in 1 infant in the epoetin group.
Success Rate and Need for Transfusions
Seventeen infants in the control group and 28 in the epoetin group needed transfusions before they entered the study (P = 0.071). There was no significant difference between the groups in the need for transfusion and the success rates during the first two weeks of the study period (Figure 1Figure 1
Number of Transfusions per Infant during the Study Period in the Control Group and the Epoetin Group. and Figure 2Figure 2Kaplan-Meier Curves for the Rate of Successful Treatment and the Rate of Freedom from Transfusion in the Treatment Groups during the Study Period. and Table 2Table 2
Need for Transfusions and Success Rate in the Treatment Groups.). Thereafter, the epoetin group had a reduced need for transfusion and a higher success rate (P<0.001 for each comparison). The most important predictors of the success of the treatment were birth weight and the base-line hematocrit (P<0.001 for each comparison). Moreover, boys responded better to epoetin beta than girls.During the first two weeks, the median hematocrit before transfusion was 38 percent in both the control and epoetin groups. From the third to the sixth week, the median hematocrit before transfusion was 28 percent in the control group and 35 percent in the epoetin group.
Changes in Hematologic Values
The changes in the hematocrit and reticulocyte count during the study are shown in Figure 3Figure 3
Median Corrected Reticulocyte Counts and Hematocrits in the Treatment Groups during the Study Period.. The two treatment groups did not differ significantly at the end of the study in their leukocyte, neutrophil, and platelet counts or total plasma protein levels (data not shown).Withdrawals and Adverse Events
There was no significant difference between the two groups in the number of infants withdrawn (Table 3Table 3
Reasons for Withdrawal after Randomization.). Of the 61 infants withdrawn, 15 had birth weights of 750 to 999 g, 25 weighed 1000 to 1249 g, and 21 weighed 1250 to 1499 g; 37 of these infants were born before 30 weeks of gestation, and 35 were boys. The infants withdrawn were similar in weight and gestational age to those who continued in the study.Adverse events are listed in Table 4Table 4
Adverse Events Reported.. The rate of septicemia, meningitis, and septic arthritis was higher in the epoetin group, but the rate of these infections was influenced more by gestational age (P = 0.030) than by treatment with epoetin beta (P = 0.189). Induration of the injection site was reported in two infants.Iron Supplementation
The median cumulative dose of iron was 37 mg per kilogram in the control group (first quartile, 24 mg; third quartile, 54 mg) and 45 mg in the epoetin group (28 mg and 54 mg, respectively) (P = 0.219). The median serum ferritin concentration decreased during the study period by 16.5 ng per milliliter in the control group (first quartile, decrease of 97.0 ng; third quartile, increase of 45.3 ng) and by 73.0 ng per milliliter in the epoetin group (first quartile, decrease of 133.5 ng; third quartile, decrease of 22.5 ng) (P<0.001). No hemolysis due to iron supplementation was noted.
Weight Gain
Infants in the epoetin group gained weight more slowly than those in the control group (median gain, 520 vs. 571 g; P = 0.02 [first and third quartiles, 300 and 635 g vs. 361 and 750 g]).
Cost Effectiveness
The Zurich center calculated the cost effectiveness of treatment per infant. One vial containing 1000 IU of epoetin beta cost $25 (in U.S. dollars), one unit of red cells $80, transfusion equipment $35, treatment of hepatitis C (estimated incidence, 0.6 percent) $840, and treatment of infection with human immunodeficiency virus (estimated incidence, 0.005 percent) $7. With a mean of 1.25 transfusions per control infant and 0.87 transfusion per epoetin-treated infant, the calculated cost of treatment was $1,203 for a control infant and $1,262 for an epoetin-treated infant. However, the costs and rates of complications of transfusion vary from center to center and from country to country.
Discussion
Several studies of the treatment of small numbers of preterm infants with recombinant human erythropoietin have been published,6,10-12,18-20 usually reporting promising results. These papers have been difficult to compare because of differences in study design, criteria for entry, timing and dose of drug administration, and nutritional supplementation. Some studies were uncontrolled10-12.
We studied only infants with birth weights of less than 1500 g and gestational ages of less than 34 weeks so that we could exclude infants who were relatively mature but small for their gestational age, in whom the anemia of prematurity is not a major problem. We tried to prevent this anemia by beginning treatment early, as did Carnielli et al.18. Our approach therefore differed from that of Ohls and Christensen,19 who gave late treatment (from day 22 to day 70) for symptomatic anemia (hematocrit, ≤ 30 percent), and that of Shannon et al.,6,20 who gave early-to-intermediate treatment (from day 4 to day 35) for anemia (hematocrit, ≤ 35 or 37 percent) to infants weighing less than 1250 g.
To exclude patients with severe iatrogenic anemia, we withdrew infants who required prolonged ventilation. This may explain why the need for transfusion in our control group was lower than the need reported by Strauss7 and Brown et al.21.
We have shown that epoetin beta reduces the need for transfusion in very-low-birth-weight infants, even though the infants treated with this agent received transfusions when their hematocrits were higher than those of the controls, and despite blood loss due to diagnostic tests. Boys whose birth weight was 1200 g or more and whose base-line hematocrit was 48 percent or higher benefited most from epoetin beta.
With the doses of epoetin beta and iron used in this study, we could not reduce the need for transfusion during the first two weeks of life. This result may have been due to clamping of the umbilical cord too early, high levels of blood loss, a delayed start of iron supplementation, or a delayed effect of epoetin beta. We therefore favor starting treatment with this drug early.
Although not statistically significant, the higher rate of transfusions in the epoetin group before entry may have biased the success rate. Epoetin beta may have averted only one donor exposure per infant, and its cost may not seem to favor prophylaxis with this agent. On the other hand, the hematocrits of the infants given the drug tended to be maintained nearer “normal” than those of the controls.
The decrease in serum ferritin levels in the epoetin group reflects active erythropoiesis. Although serum ferritin values do not provide complete information about iron storage, they were available at all participating centers. Our iron supplements might have been inadequate for optimal erythropoiesis. In pilot studies, Shannon et al. increased the daily intake of oral iron from 3 to 6 mg per kilogram6,20. Carnielli et al.18 administered 20 mg of iron per kilogram per week intravenously without complications.
Epoetin beta may affect other hematopoietic cells: at high concentrations, it has been found to decrease the formation of neutrophils from progenitors in vitro; however, no changes in blood neutrophils, monocytes, or lymphocytes were observed in weanling rats after injections of 2000 IU per kilogram22. In patients with the anemia of chronic renal failure, Dessypris et al.23 found that recombinant erythropoietin stimulated progenitors of erythrocytes, granulocytes, and platelets. All well-controlled studies conducted to date6,13,18,20 in preterm infants have found that this drug does not affect granulopoiesis. In the present study, we found no effects on platelets or granulocytes that could be attributed to the epoetin beta. Although not statistically significant, the higher incidence of septicemia in the epoetin group may be a cause for concern. Treatment with epoetin beta required 17 subcutaneous injections per infant, and it also depleted iron stores. Either factor might have increased the risks of infection, especially in very premature infants.
The infants we treated with epoetin beta gained less weight than the controls, like the infants studied by Shannon et al.20. Bechensteen et al.24 found similar growth rates among infants given recombinant erythropoietin and control infants, all of whom were fed extra protein. It is likely that the stimulation of erythropoiesis increases protein and caloric needs.
Recently, Emmerson et al.25 reported two cases of sudden infant death syndrome after treatment with recombinant human erythropoietin. In our trial, three infants died of this disorder: one infant had been treated with epoetin beta and completed the study, one had been assigned to this treatment but was withdrawn after receiving one dose because of prolonged ventilation, and one was a control. Neither the first trial of recombinant human erythropoietin for anemia of prematurity13 nor the present results suggest that the incidence of sudden infant death syndrome increases after this treatment.
Epoetin prevents the anemia of prematurity and effectively and safely reduces the need for transfusion. We regard the administration of epoetin beta as one tactic in a logical therapeutic strategy for managing anemia in very-low-birth-weight infants. This strategy should also include attempts to optimize these infants' blood count through placental transfusion at birth, minimize their blood losses due to diagnostic testing, and improve their nutrition to promote growth and hematopoiesis.
Supported by a grant (Sonderforschungsbereich 174/A9) from Deutsche Forschungsgemeinschaft and by Boehringer-Mannheim.
Source Information
From Universitatsklinikum Rudolf Virchow (R.F.M., M.O.) and Universitatsklinikum Steglitz (H.T.V.), Freie Universitat Berlin, Berlin, Germany; Boehringer-Mannheim, Mannheim, Germany (P.S.); Universitat Heidelberg, Heidelberg, Germany (O.L.); Universitat Zurich, Zurich, Switzerland (G.D.); Olgahospital, Stuttgart, Germany (G.H.); Royal Maternity Hospital, Belfast, United Kingdom (H.L.H.); Centre Hospitalier Universitaire Cochin Port-Royal, Paris (G.M.); Universitat Munster, Munster, Germany (G.J.); Universite Catholique de Louvain, Brussels, Belgium (G.V.); University Hospital Nijmegen, Nijmegen, the Netherlands (B.A.S.); Charite, Humboldt Universitat, Berlin (E.L.G.); Queen Mother's Hospital, University of Glasgow, Glasgow, United Kingdom (B.M.H.); and the Department of Hematology, University of Wales, Cardiff, United Kingdom (C.A.J.W.).
Address reprint requests to Dr. Obladen at the Department of Neonatology, Universitatsklinikum Rudolf Virchow, Freie Universitat Berlin, Heubnerweg 6, D-14059 Berlin, Germany.
The institutions and other coworkers of the European Multicentre Erythropoietin Study Group are listed in the Appendix.
Appendix
The following institutions and workers are members of the European Multicentre Erythropoietin Study Group.
Participating Centers (listed in order of the number of infants enrolled): Klinikum Rudolf Virchow, Freie Universitat Berlin, Berlin -- K. Abraham, C. Buhrer, and C. Domeyer; Universitat Heidelberg, Heidelberg -- J. Poschl; Universitat Zurich, Zurich -- P. Baeckert, A.M. Bucher, and H.U. Bucher; Olgahospital Stuttgart, Stuttgart -- M. Wagner, M. Kroll, and H. Gulde; Royal Maternity Hospital, Belfast -- M.G. O'Connor, F.A. Casey, and B.G. McClure; Universitatsklinikum Steglitz, Freie Universitat Berlin, Berlin -- M. Bartsch; Centre Hospitalier Universitaire Cochin Port-Royal, Paris -- C. Clamadieu, M. Monset-Couchard, and P. Mussat; Universitat Munster, Munster -- H. Rabe, E. Michel, and S. Lindner; Universite Catholique de Louvain, Brussels -- C. Debauche, D. Moulin, and S. Clement; University Hospital Nijmegen, Nijmegen -- L.A.A. Kollee; Charite, Humboldt Universitat, Berlin -- H. Weigel and S. Ledwon; and Queen Mother's Hospital, University of Glasgow, Glasgow -- G. Stewart.
Steering Committee: M. Obladen and R.F. Maier (Klinikum Rudolf Virchow, Freie Universitat Berlin, Berlin) and P. Scigalla (Boehringer-Mannheim, Mannheim, Germany).
Consultant in Hematology: C.A.J. Wardrop (University of Wales, Cardiff).
Consultant in Statistics: D. Messinger (Boehringer-Mannheim, Mannheim, Germany).
Data Management and Evaluation: W. Wierich, J. Bruning, and R. Vonk (AFB Comstat, Berlin).
- References
References
1
Brown MS ,Garcia JF ,Phibbs RH ,Dallman PR . Decreased response of plasma immunoreactive erythropoietin to “available oxygen” in anemia of prematurity. J Pediatr 1984;105:793-798
CrossRef | Web of Science | Medline2
Stockman JA III ,Graeber JE ,Clark DA ,McClellan K ,Garcia JF ,Kavey REW . Anemia of prematurity: determinants of the erythropoietin response. J Pediatr 1984;105:786-792
CrossRef | Web of Science | Medline3
Shannon KM . Anemia of prematurity: progress and prospects. Am J Pediatr Hematol Oncol 1990;12:14-20
CrossRef | Medline4
Obladen M ,Sachsenweger M ,Stahnke M . Blood sampling in very low birth weight infants receiving different levels of intensive care. Eur J Pediatr 1988;147:399-404
CrossRef | Web of Science | Medline5
Wardrop CAJ ,Holland BM ,Veale KEA ,Jones JG ,Gray OP . Nonphysiological anaemia of prematurity. Arch Dis Child 1978;53:855-860
CrossRef | Web of Science | Medline6
Shannon KM ,Mentzer WC ,Abels RI , et al. Recombinant human erythropoietin in the anemia of prematurity: results of a placebo-controlled pilot study. J Pediatr 1991;118:949-955
CrossRef | Web of Science | Medline7
Strauss RG . Transfusion therapy in neonates. Am J Dis Child 1991;145:904-911
Web of Science | Medline8
Shannon KM ,Naylor GS ,Torkildson JC , et al. Circulating erythroid progenitors in the anemia of prematurity. N Engl J Med 1987;317:728-733
Full Text | Web of Science | Medline9
Rhondeau SM ,Christensen RD ,Ross MP ,Rothstein G ,Simmons MA . Responsiveness to recombinant human erythropoietin of marrow erythroid progenitors from infants with the “anemia of prematurity.” J Pediatr 1988;112:935-940
CrossRef | Web of Science | Medline10
Beck D ,Masserey E ,Meyer M ,Calame A . Weekly intravenous administration of recombinant human erythropoietin in infants with the anaemia of prematurity. Eur J Pediatr 1991;150:767-772
CrossRef | Web of Science | Medline11
Halperin DS ,Wacker P ,Lacourt G , et al. Effects of recombinant human erythropoietin in infants with the anemia of prematurity: a pilot study. J Pediatr 1990;116:779-786
CrossRef | Web of Science | Medline12
Halperin DS ,Felix M ,Wacker P ,Lacourt G ,Babel J-F ,Wyss M . Recombinant human erythropoietin in the treatment of infants with anaemia of prematurity. Eur J Pediatr 1992;151:661-667
CrossRef | Web of Science | Medline13
Obladen M ,Maier R ,Segerer H , et al. Efficacy and safety of recombinant human erythropoietin to prevent the anaemias of prematurity: European Randomized Multicenter Trial. Contrib Nephrol 1991;88:314-326
Web of Science | Medline14
Kinmond S ,Aitchison TC ,Holland BM ,Jones JG ,Turner TL ,Wardrop CA . Umbilical cord clamping and preterm infants: a randomised trial. BMJ 1993;306:172-175
CrossRef | Web of Science | Medline15
Papile LA ,Burstein J ,Burstein R ,Koffler H . Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529-534
CrossRef | Web of Science | Medline16
An international classification of retinopathy of prematurity
Web of Science | Medline17
The International Committee for the Classification of the Late Stages of Retinopathy of Prematurity 18
Carnielli V ,Montini G ,Da Riol R ,Dall'Amico R ,Cantarutti F . Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. J Pediatr 1992;121:98-102
CrossRef | Web of Science | Medline19
Ohls RK ,Christensen RD . Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. J Pediatr 1991;119:781-788
CrossRef | Web of Science | Medline20
Shannon KM ,Mentzer WC ,Abels RI , et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. J Pediatr 1992;120:586-592
CrossRef | Web of Science | Medline21
Brown MS ,Berman ER ,Luckey D . Prediction of the need for transfusion during anemia of prematurity. J Pediatr 1990;116:773-778
CrossRef | Web of Science | Medline22
Koenig JM ,Christensen RD . Effect of erythropoietin on granulocytopoiesis: in vitro and in vivo studies in weanling rats. Pediatr Res 1990;27:583-587
CrossRef | Web of Science | Medline23
Dessypris EN ,Graber SE ,Krantz SB ,Stone WJ . Effects of recombinant erythropoietin on the concentration and cycling status of human marrow hematopoietic progenitor cells in vivo. Blood 1988;72:2060-2062
Web of Science | Medline24
Bechensteen AG ,Haga P ,Halvorsen S , et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child 1993;69:19-23
CrossRef | Web of Science | Medline25
Emmerson AJB ,Coles HJ ,Stern CMM ,Pearson TC . Double blind trial of recombinant human erythropoietin in preterm infants. Arch Dis Child 1993;68:291-296
CrossRef | Web of Science | Medline
- Citing Articles (71)
Citing Articles
1
M Á Vázquez López, M Á Llamas, R Galera, A R Sanchez, F Lendinez, M Gonzalez-Ripoll, J Díez, A Bonillo. (2011) Comparison between one and three doses a week of recombinant erythropoietin in very low birth weight infants. Journal of Perinatology 31:2, 118-124
CrossRef2
F. Dick-Amon-Tanoh, B. E. Lasme-Guillao, R. Nguessan, R. Konan Ble, A. E. Akaffou, M. Cardenat. (2011) Anemie du Premature et Pratiques Transfusionnelles au Centre Hospitalo-Universitaire de Yopougon à Abidjan, Cote d'Ivoire. Clinics in Mother and Child Health 8, 1-5
CrossRef3
Maria Roberta Cilio, Donna M. Ferriero. (2010) Synergistic neuroprotective therapies with hypothermia. Seminars in Fetal and Neonatal Medicine 15:5, 293-298
CrossRef4
Arne Ohlsson, Sanjay M Aher. (2010) Cochrane review: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Evidence-Based Child Health: A Cochrane Review Journal 5:1, 151-238
CrossRef5
C. Arberet, P. Bétrémieux, T. Gaillot. (2009) Quelle place reste-t-il pour l’érythropoïétine en néonatalogie ?. Revue de médecine périnatale 1:3, 146-154
CrossRef6
Isabelle Von Kohorn, Richard A. Ehrenkranz. (2009) Anemia in the Preterm Infant: Erythropoietin Versus Erythrocyte Transfusion—It's not that Simple. Clinics in Perinatology 36:1, 111-123
CrossRef7
Srividya Neelakantan, John A. Widness, Robert L. Schmidt, Peter Veng-Pedersen. (2009) Erythropoietin pharmacokinetic/pharmacodynamic analysis suggests higher doses in treating neonatal anemia. Pediatrics International 51:1, 25-32
CrossRef8
Seyedeh Fatemeh Khatami, Gholamali Mamouri, Mohamad Torkaman. (2008) Effects of early human recombinant erythropoietin therapy on the transfusion in healthy preterm infants. The Indian Journal of Pediatrics 75:12, 1227-1230
CrossRef9
L. Pelken, R.F. Maier. (2008) Risikofaktoren und Prävention der Retinopathia praematurorum. Der Ophthalmologe 105:12, 1108-1114
CrossRef10
Jacqueline K Schneider, Debra K Gardner, Leandro Cordero. (2008) Use of Recombinant Human Erythropoietin and Risk of Severe Retinopathy in Extremely Low-Birth-Weight Infants. Pharmacotherapy 28:11, 1335-1340
CrossRef11
Pramod Mainie. (2008) Is there a role for erythropoietin in neonatal medicine?. Early Human Development 84:8, 525-532
CrossRef12
Kevin K. Suk, Jennifer A. Dunbar, Anthony Liu, Noha S. Daher, Cheri K. Leng, Jason K. Leng, Pauline Lim, Samantha Weller, Elba Fayard. (2008) Human recombinant erythropoietin and the incidence of retinopathy of prematurity: A multiple regression model. Journal of American Association for Pediatric Ophthalmology and Strabismus 12:3, 233-238
CrossRef13
A Ohlsson, SM Aher. (2007) Cochrane review: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Evidence-Based Child Health: A Cochrane Review Journal 2:1, 336-394
CrossRef14
Martina Klipp, Anne-Ulrike Holzwarth, Johannes M Poeschl, Mathias Nelle, Otwin Linderkamp. (2007) Effects of erythropoietin on erythrocyte deformability in non-transfused preterm infants. Acta Paediatrica 96:2, 253-256
CrossRef15
SHIGEHARU HOSONO, HIDEO MUGISHIMA, MASAMI SHIMADA, MICHIYOSHI MINATO, TOMO OKADA, SHIGERU TAKAHASHI, KENSUKE HARADA. (2006) Prediction of transfusions in extremely low-birthweight infants in the erythropoietin era. Pediatrics International 48:6, 572-576
CrossRef16
Jorge Fabres, Gay Wehrli, Marisa B. Marques, Vivien Phillips, Reed A. Dimmitt, Andrew O. Westfall, Robert L. Schelonka. (2006) Estimating blood needs for very-low-birth-weight infants. Transfusion 46:11, 1915-1920
CrossRef17
Howard J. Birenbaum, Maria A. Pane, Sabah M. Helou, Karen P. Starr. (2006) Comparison of a Restricted Transfusion Schedule with Erythropoietin Therapy versus a Restricted Transfusion Schedule Alone in Very Low Birth Weight Premature Infants. Southern Medical Journal 99:10, 1059-1062
CrossRef18
Arne Ohlsson, Sanjay M Aher, Arne Ohlsson. 2006. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. .
CrossRef19
Arne Ohlsson, Sachin S Shah, Arne Ohlsson. 2006. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. .
CrossRef20
Xavier Carbonell-Estrany, Josep Figueras-Aloy, Enriqueta Alvarez. (2005) Erythropoietin and prematurity – where do we stand?. Journal of Perinatal Medicine 33:4, 277-286
CrossRef21
Hugo Donato. (2005) Erythropoietin: an update on the therapeutic use in newborn infants and children. Expert Opinion on Pharmacotherapy 6:5, 723-734
CrossRef22
William C. Mentzer, Bertil E. Glader. 2005. Erythrocyte Disorders in Infancy. , 1180-1214.
CrossRef23
Fabienne Gumy-Pause, Hulya Ozsahin, Bernadette Mermillod, Laurence Cingria, Michel Berner, Pierre Wacker. (2005) STEPPING UP VERSUS STANDARD DOSES OF ERYTHROPOIETIN IN PRETERM INFANTS: A Randomized Controlled Trial. Pediatric Hematology-Oncology 22:8, 667-678
CrossRef24
R Carr, N Modi. (2004) Haemopoietic growth factors for neonates: assessing risks and benefits. Acta Paediatrica 93, 15-19
CrossRef25
(2004) Transfusion guidelines for neonates and older children. British Journal of Haematology 124:4, 433-453
CrossRef26
Marya Strand, Alan H Jobe. (2003) The multiple negative randomized controlled trials in perinatology—why?. Seminars in Perinatology 27:4, 343-350
CrossRef27
Richard A. Ehrenkranz, Linda L. Wright. (2003) NICHD neonatal research network: contributions and future challenges. Seminars in Perinatology 27:4, 264-280
CrossRef28
Brian R. Jacobs, Kim Lyons, Richard J. Brilli. (2003) Erythropoietin therapy in children with bronchiolitis and anemia*. Pediatric Critical Care Medicine 4:1, 44-48
CrossRef29
Susan D. Roseff, Naomi L.C. Luban, Catherine S. Manno. (2002) Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 42:11, 1398-1413
CrossRef30
&NA;. (2002) Further study needed before human recombinant erythropoietin can be recommended for anaemia of prematurity. Drugs & Therapy Perspectives 18:10, 10-13
CrossRef31
Begüm Atasay, Ayla Günlemez, Nejat Akar, Saadet Arsan. (2002) Does early erythropoietin therapy decrease transfusions in anemia of prematurity ?. The Indian Journal of Pediatrics 69:5, 389-391
CrossRef32
David A. Paul, Kathleen H. Leef, Robert G. Locke, John L. Stefano. (2002) Transfusion Volume in Infants With Very Low Birth Weight: A Randomized Trial of 10 Versus 20 mL/kg. Journal of Pediatric Hematology/Oncology 24:1, 43-46
CrossRef33
Robin K. Ohls. (2002) Human Recombinant Erythropoietin in the Prevention and Treatment of Anemia of Prematurity. Pediatric Drugs 4:2, 111-121
CrossRef34
Xavier Carbonell-Estrany, Josep Figueras-Aloy. (2001) Anaemia of prematurity: treatment with erythropoietin. Early Human Development 65, S63-S67
CrossRef35
Donald M. Mock, Edward F. Bell, Gary L. Lankford, John A. Widness. (2001) Hematocrit Correlates Well with Circulating Red Blood Cell Volume in Very Low Birth Weight Infants. Pediatric Research 50:4, 525-531
CrossRef36
Marie Horan, Peter R Stutchfield. (2001) Severe congenital myotonic dystrophy and severe anaemia of prematurity in an infant of Jehovah's Witness parents. Developmental Medicine & Child Neurology 43:5, 346-349
CrossRef37
Eleftherios C. Vamvakas, Ronald G. Strauss. (2001) Meta-analysis of controlled clinical trials studying the efficacy of rHuEPO in reducing blood transfusions in the anemia of prematurity. Transfusion 41:3, 406-415
CrossRef38
Rolf F. Maier, R. F. Maier, M. Obladen. (2001) International Forum. Vox Sanguinis 80:2, 125-127
CrossRef39
DARLENE A. CALHOUN, MATHILDE LUN??E, YAN DU, SUSAN L. STABA, ROBERT D. CHRISTENSEN. (1999) Concentrations of Granulocyte Colony-Stimulating Factor in Human Milk after in Vitro Simulations of Digestion. Pediatric Research 46:6, 767
CrossRef40
Jean Messer, Benoît Escande, Jacqueline Matis. (1999) Erythropoietin and Iron in the Anemia of Prematurity. Transfusion Alternatives in Transfusion Medicine 1:3, 15-17
CrossRef41
John W. Adamson, Ivor Cavill, Steven Fishbane, Jeffrey Petersen, Jay B. Wish. (1999) A Consensus on Current Issues and Controversies in Iron Management of Patients with Chronic Renal Failure. Seminars in Dialysis 12:3, 182-194
CrossRef42
Robin K. Ohls. (1999) Erythropoietin to prevent and treat the anemia of prematurity. Current Opinion in Pediatrics 11:2, 108-114
CrossRef43
Chang Liwen, Liu Wanjun, Liao Caixu, Zhao Xici. (1998) Preventive effect of different dosage of recombinant human erythropoietin on anemia of premature infants. Journal of Tongji Medical University 18:4, 239-242
CrossRef44
Rolf F. Maier, Michael Obladen, Evelyn Kattner, Jürgen Natzschka, Jean Messer, Bianca M. Regazzoni, Christian P. Speer, Vineta Fellman, E.Ludwig Grauel, Peter Groneck, Martin Wagner, Guy Moriette, Bernard L. Salle, Gaston Verellen, Paul Scigalla. (1998) High- versus low-dose erythropoietin in extremely low birth weight infants. The Journal of Pediatrics 132:5, 866-870
CrossRef45
G. Latini, E. Rosati. (1998) Transient neutropenia may be a risk of treating preterm neonates with high doses of recombinant erythropoietin. European Journal of Pediatrics 157:5, 443-444
CrossRef46
Mark A. Helfaer, Benjamin S. Carson, Carol S. James, Judy Gates, David Della-Lana, Craig Vander Kolk. (1998) Increased hematocrit and decreased transfusion requirements in children given erythropoietin before undergoing craniofacial surgery. Journal of Neurosurgery 88:4, 704-708
CrossRef47
Rolf F. Maier, Boris Metze, Michael Obladen. (1998) Low degree of regionalization and high transfusion rates in very low birthweight infants: A survey in Germany. Journal of Perinatal Medicine 26:1, 43-48
CrossRef48
Marcella Testa, Alessandra Reali, Maristella Copula, Bernadette Pinna, Francesca Birocchi, Cinzia Pisu, Francesco Chiappe. (1998) Role of Rhuepo on Blood Transfusions in Preterm Infants After the Fifteenth Day of Life. Pediatric Hematology-Oncology 15:5, 415-420
CrossRef49
C. Giannakopoulou, I. Bolonaki, E. Stiakaki, H. Dimitriou, H. Galanaki, E. Hatzidaki, M. Kalmanti. (1998) Erythropoietin (rHuEPO) Administration to Premature Infants for the Treatment of Their Anemia. Pediatric Hematology-Oncology 15:1, 37-43
CrossRef50
Jean-Claude Lavoie, Philippe Chessex. (1997) Bound Iron Admixture Prevents the Spontaneous Generation of Peroxides in Total Parenteral Nutrition Solutions. Journal of Pediatric Gastroenterology & Nutrition 25:3, 307-311
CrossRef51
Bernhard Meister, Heiner Maurer, Burkard Simma, Hannelore Kern, Hanno Ulmer, Anton Hittmair, Franz‐Martin Fink. (1997) The Effect of Recombinant Human Erythropoietin on Circulating Hematopoietic Progenitor Cells in Anemic Premature Infants. Stem Cells 15:5, 359-363
CrossRef52
Florence N. Hutchison, Walter J. Jones. (1997) A cost-effectiveness analysis of anemia screening before erythropoietin in patients with end-stage renal disease. American Journal of Kidney Diseases 29:5, 651-657
CrossRef53
JOHN A. WIDNESS, KENNETH A. LOMBARD, EKHARD E. ZIEGLER, ROBERT E. SERFASS, SUSAN J. CARLSON, KAREN J. JOHNSON, JUNE E. MILLER. (1997) Erythrocyte Incorporation and Absorption of 58Fe in Premature Infants Treated with Erythropoietin. Pediatric Research 41:3, 416-423
CrossRef54
John J. Doyle. (1997) The role of erythropoietin in the anemia of prematurity. Seminars in Perinatology 21:1, 20-27
CrossRef55
Fernando Valderrábano. (1996) Erythropoietin in chronic renal failure. Kidney International 50:4, 1373-1391
CrossRef56
J.S. Virot, G. Janin, J. Guillaumie, P. Michel, P. Dubot, D. Chevet, G. Rifle. (1996) Must erythropoietin be injected by the subcutaneous route for every hemodialyzed patient?. American Journal of Kidney Diseases 28:3, 400-408
CrossRef57
YAN LI, SANDRA E. JUUL, JOYCE A. MORRIS-WIMAN, DARLENE A. CALHOUN, ROBERT D. CHRISTENSEN. (1996) Erythropoietin Receptors Are Expressed in the Central Nervous System of Mid-Trimester Human Fetuses. Pediatric Research 40:3, 376-380
CrossRef58
FAYEZ M. BANY-MOHAMMED, STEFAN SLIVKA, MIKKO HALLMAN. (1996) Recombinant Human Erythropoietin: Possible Role as an Antioxidant in Premature Rabbits. Pediatric Research 40:3, 381-387
CrossRef59
Bart Chernow, Eric Jackson, JoAnn Miller, Jeff Wiese. (1996) Blood Conservation in Acute Care and Critical Care. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 7:2, 191-197
CrossRef60
J. C. Möller, U. Schwarz, T. F. Schaible, A. Artlich, F. K. Tegtmeyer, L. Gortner. (1996) Do cardiac output and serum lactate levels indicate blood transfusion requirements in anemia of prematurity?. Intensive Care Medicine 22:5, 472-476
CrossRef61
FAHRI OVALI, NEDIM SAMANCI, T??RKAN DA??O??LU. (1996) Management of Late Anemia in Rhesus Hemolytic Disease: Use of Recombinant Human Erythropoietin (A Pilot Study). Pediatric Research 39:5, 831-834
CrossRef62
D Bader, O Blondheim, R Jonas, O Admoni, M Abend-Winger, D Reich, A Lanir, A Tamir, I Eldar, D Attias. (1996) Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatrica 85:4, 496-501
CrossRef63
Hannah Tamary, Yehuda L. Danon. (1996) Recombinant Human Erythropoietin in Children with Cancer. Pediatric Hematology-Oncology 13:4, 305-308
CrossRef64
RONALD G. STRAUSS. (1996) NEONATAL ANEMIA: PATHOPHYSIOLOGY AND TREATMENT. Vox Sanguinis 70:S3, 57-61
CrossRef65
Heather Hume, Harry Bard. (1995) Small volume red blood cell transfusions for neonatal patients. Transfusion Medicine Reviews 9:3, 187-199
CrossRef66
A Røemnestad, PJ Moe, N Breivik. (1995) Enhancement of erythropoiesis by erythropoietin, bovine protein and energy fortified mother's milk during anaemia of prematurity. Acta Paediatrica 84:7, 809-811
CrossRef67
C. A. J. Wardrop, B. M. Holland. (1995) Recombinant haemopoietic growth factors in the newborn — will they be useful?. European Journal of Pediatrics 154:3, S13-S14
CrossRef68
Michael Obladen, Rolf F. Maier. (1995) Recombinant erythropoietin for prevention of anemia in preterm infants. Journal of Perinatal Medicine 23:1-2, 119-126
CrossRef69
LORNA WILLIAMSON. (1994) HOMOLOGOUS BLOOD TRANSFUSION: THE RISKS AND ALTERNATIVES. British Journal of Haematology 88:3, 451-458
CrossRef70
(1994) Recombinant Erythropoietin in Very-Low-Birth-Weight Infants. New England Journal of Medicine 331:10, 676-678
Full Text71
Strauss, Ronald G., . (1994) Erythropoietin and Neonatal Anemia. New England Journal of Medicine 330:17, 1227-1228
Full Text
- Letters
