PEDIATRICS Vol. 110 No. 6 December 2002, pp. 1253-1255
Erythropoietin and Preemies
To the Editor.—Ohls et al1 should be congratulated on successfully completing a difficult clinical trial. The results lead one to reflect on the role, if any, of erythropoietin (Epo) in reducing transfusions in preterm infants. Before we abandon it as a therapy, however, there are at least 2 points that deserve consideration. First, there are no accepted standards to determine phlebotomy losses, yet these, like transfusion guidelines, have a major impact on determining transfusion requirements. For example, a recent Epo study2 at Middlemore Hospital (Auckland, New Zealand) enrolled 23 infants <1000 g with a similar mean birth weight (779 ± 112 g) and gestation (26 ± 1 weeks) to those in the multicenter study. The mean total blood loss of these infants during their entire hospital stay was only 21.7 ± 7.8 mL compared with 84 ± 55 mL in the Epo group during treatment in the study of Ohls et al (P < .001). Although it appears that with current phlebotomy losses early use of Epo is unsuccessful in decreasing transfusion requirements, stimulation of erythropoiesis may overcome lower blood losses than those reported in the multicenter study. Second, it is the "early" use of Epo in that the multicenter study has shown to be ineffective in reducing transfusions. The study showed a reduction of transfusions to <1000 g beginning after about 4 weeks of age and reaching statistical significance between weeks 7 and 10. Although the actual number of transfusions is not stated, it appears from Fig 1 that about one third of the total were given after week 4. In 2 other recent studies presented at the European Society for Paediatric Research,2,3 there were statistically significant reductions in blood transfusions after 2 to 4 weeks of age in <1000-g infants. We should target our therapeutic and research efforts to <1000-g infants after the initial 2 to 4 weeks of life.
Michael P. Meyer, MBChB, MRCP,MD
Neonatal Unit
Middlemore Hospital
Auckland, New Zealand
REFERENCES
- Ohls R, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial.
Pediatrics.2001; 108
:934
–942
[Abstract/Free Full Text] - Meyer MP, Rous J, Carsons M. Recombinant erythropoietin and blood transfusion in selected preterm infants. Proceedings of the European Society for Paediatric Research, Helsinki (Abstract 36), August 2001
- Maier RF, Obladen M, Muller-Hansen I, et al. Recombinant erythropoietin (rhEPO) is effective in extremely low birth weight (ELBW) infants. Proceedings of the European Society for Paediatric Research, Rhodes (Abstract P12), September 2000
Erythropoietin and Preemies
To the Editor.—We were interested to read the paper by Ohls et al on the early use of erythropoietin (Epo) in infants weighing <1250 g at birth.1 Contrary to the authors’ assertion, however, this was not the first "large, multicenter, placebo-controlled study" of its kind. In May 2000, Pediatrics published the results of our randomized, placebo-controlled, multicenter trial of early versus late Epo administration in 114 severely ill preterm infants2; these results had been previously presented at the APS-SPR meeting in 1998.3 The characteristics of the patients and the dose of Epo administered were very similar to those of Ohls et al. Our study merited an editorial by Zipursky4 and a comment by Ohls in her September 2000 review of the use of Epo in neonates.5 Thus, it is all the more puzzling that a) our study was omitted by the authors, and b) it is erroneously stated that their study was the first of its kind.
We suggest that a comparison between these 2 large trials would have enriched the discussion. In fact, their most important conclusions are the confirmation of our results: reticulocyte counts and hematocrit values were higher in the Epo-treated group than in the placebo group, but, despite such an evidence of increased erythropoiesis, the early administration of Epo did not decrease the need for transfusions.1,2
We have some additional questions: the decision to reduce the iron dose when the serum ferritin exceeded 400 ng/mL appears arbitrary, particularly as ferritin is frequently elevated in acute disease and may not accurately reflect the body’s iron stores.6 Ohls et al also report that no patient had platelet counts of <200 x 109/L although we are unaware of other reports of thrombocytopenia as a side effect of Epo administration. On the contrary, we reported that thrombocytosis occurred at some point during treatment with Epo in 31% of our patients,2 and increased platelet counts have been found by others.7,8 In addition, Ohls et al do not discuss the contradictory results that they found in 2 previous smaller randomized trials9,10 in which the early administration of Epo significantly decreased the transfusion requirements in infants weighing less than 1250 g.
We believe this cannot be attributed simply to sample size because the result was positive and not negative. Some discussion of these issues would be of interest to the reader.
Hugo Donato, MD
Pablo Rendo, MD
Bio Sidus, Inc
Bueno Aires, Argentina
Luis Prudent, MD
Hospitals Suizo Argentina and Otamendi
Néstor Vain, MD
Hospitals Trinidad
REFERENCES
- Ohls RK, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics.2001; 108 :934 –940
- Donato H, Vain N, Rendo P, et al. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: Results of a randomized, placebo-controlled, multicenter trial.
Pediatrics.2000; 105
:1066
–1072
[Abstract/Free Full Text] - Donato H, Vivas N, Vain N, et al. Early vs late recombinant human erythropoietin (rHuEpo) in anemia of prematurity. Results of a randomized, placebo-controlled, multicentric trial. Pediatr Res.1998; 43 :234A (abstract 1383)
- Zipursky A. Erythropoietin therapy for premature infants: cost without benefit? Pediatr Res.2000; 48 :136[Web of Science][Medline]
- Ohls RK. The use of erythropoietin in neonates. Clin Perinatol.2000; 27 :681 –694[CrossRef][Web of Science][Medline]
- Andrews NC, Bridges RK. Disorders of iron metabolism and sideroblastic anemia. In: Nathan DG, Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood, I. Philadelphia, PA: WB Saunders Co; 1998;440
- Halperin DS, Felix M, Wacker P, Lacourt G, Babel JF, 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][Medline]
- 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
[Abstract/Free Full Text] - Ohls RK, Osborne KA, Christensen RD. 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. J Pediatr.1995; 126 :421 –426[CrossRef][Web of Science][Medline]
- Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr.1997; 131 :661 –665[CrossRef][Web of Science][Medline]
In Reply.—
We appreciate Dr Meyer’s thoughts regarding our study and welcome his knowledgeable comments. We agree with his first point, that the phlebotomy losses in our population of infants weighing <1000 g significantly impacted the success of erythropoietin in decreasing their overall transfusion requirements. In addition to the study referenced by Dr Meyer, other investigators have shown significant correlation between phlebotomy losses and transfusion requirements.1,2 The administration of Epo to preterm infants certainly stimulates erythropoiesis, as has been shown in every clinical study in which appropriate doses of Epo were used. The gain of red cells through the use of Epo matched against the loss of red cells through phlebotomy ultimately becomes a "blood flux" phenomenon. Under conditions of maximal stimulation of erythropoiesis by Epo, the focus must shift to limiting phlebotomy losses. We concur with Dr Meyer that, although not specifically evaluated in our study, erythropoiesis can probably be stimulated to a degree that can match or overcome minimal to moderate blood loss. However, our trial confirmed the importance of conservative transfusion guidelines in effectively and safely limiting transfusions without demonstrating any additional benefit from early Epo and iron therapy.
We also welcome the questions and comments from Drs Donato, Vain, Prudent, and Rendo, whose study was inadvertently left out of our references. We sincerely apologize for this oversight. Although there are similarities between our study designs and conclusions, our study design maintained Epo treatment and placebo/control groups throughout the duration of the trial,3 while their study design compared early versus late Epo therapy.4 The enrollment of our last infant weighing <1000 g occurred in March 1998.
The decision to reduce iron supplementation based on ferritin concentrations was based on our wish to avoid iron overload and potential oxidative damage.5 We were unable to distinguish elevated ferritin values attributable to acute disease from those attributable to iron overload; therefore, we chose to respond to values above 400 ng/mL by moderately decreasing iron supplementation. Importantly, no infants in the treated or placebo groups experienced adverse effects from parenteral or enteral iron.
We understand that thrombocytopenia is not generally associated with Epo administration. The lower platelet counts seen in some of our patients were likely attributable to complications of their extreme prematurity, not to Epo administration.
We do not believe the results of the NICHD Neonatal Research Network study contradict previously published studies.6,7 Those studies differed from the network study in that: 1) patients were treated daily with Epo or placebo for only 2 weeks, and 2) criteria for administering transfusions were significantly different. Moreover, as a large, multicenter management trial in which treatment was initiated within 96 hours of birth and continued until discharge or 35 completed weeks’ postmenstrual age, we believe the network’s results are more applicable than small trials at 1 or 3 centers.6,7 In the single-center study published in 1995,6 infants were larger (1229 g, 30 weeks) and less ill than those in the network study. In the 3-center study published in 1997,7 infants were smaller (660 g and 24–25 weeks), had significantly greater phlebotomy losses that approximated 1.5–2 times their entire blood volume, and received 4.7 (Epo) versus 7.5 (placebo) transfusions per patient over a 3-week period.7 In contrast, although phlebotomy losses seen in Trial 1 of the NICHD study approximated one blood volume, the number of transfusions received was 4.3 (Epo) versus 5.2 (placebo/control) transfusions per patient over a 10-week period.3 Thus, early Epo and iron therapy was not significantly better than conservative transfusion guidelines in reducing the need for transfusions.
It is interesting to note that in studies evaluating the early use of Epo,3,4,6–9 there is a similar "response lag" that occurs 5 to 7 days after the initiation of treatment. This does not appear to occur in preterm infants receiving Epo to treat the anemia of prematurity,10,11 and requires additional investigation to determine if there is a "period of resistance" shortly after birth during which any dose of Epo would be ineffective.
In many infants phlebotomy losses can be decreased with concerted effort. However, there will remain a population of extremely ill infants in whom this will not be the case. Some investigators believe a combination of erythrocyte transfusions and Epo will serve to maintain an adequate circulating erythrocyte volume, but a reasonable algorithm has yet to be developed to facilitate such management. On the basis of our results, we concluded that the routine use of early Epo and iron therapy in very low birth weight infants would not substantially reduce the need for transfusions and was not warranted. Future research may determine if therapy with Epo will prove efficacious in certain neonatal populations.
Robin K. Ohls, MD
Department of Pediatrics
Children’s Hospital of New Mexico
University of New Mexico
Albuquerque, NM, 87131-5311
Richard A. Ehrenkranz, MD
Department of Pediatrics
Yale University School of Medicine
New Haven, CT
REFERENCES
- Shannon KM. Recombinant human erythropoietin in neonatal anemia. Clin Perinatol.1995; 22 :627[Web of Science][Medline]
- Kling PJ, Sullivan TM, Leftwich ME, Roe DJ. Score for neonatal acute physiology and phlebotomy blood loss predict erythrocyte transfusions in premature infants.
Arch Pediatr Adolesc Med.1997; 151
:27
–31
[Abstract/Free Full Text] - Ohls RK, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized controlled trial. Pediatrics.2001; 108 :934 –942
- Donato H, Vain N, Rendo P, et al. Effect of early versus late recombinant human erythropoietin on transfusion requirements in premature infants: results of randomized, placebo-controlled, multicenter trial. Pediatrics.2000; 105 :1066 –1072
- Pollak A, Hayde M, Hayn M, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants.
Pediatrics.2001; 107
:78
–85
[Abstract/Free Full Text] - Ohls RK, Osborne KA, Christensen RD. 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. J Pediatr.1995; 126 :421 –426
- Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants
750 grams: a randomized, double-blind, placebo-controlled study.
J Pediatr.1997; 131
:661
–665
- Maier RF, Obladen M, Scigalla P, et al. 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
–1178
[Abstract/Free Full Text] - Soubasi V, Kremenopoulos G, Diamandi E, Tsantali C, Tsakiris D. In which neonates does early recombinant human erythropoietin treatment prevent anemia of prematurity? Results of a randomized, controlled study. Pediatr Res.1993; 34 :675 –679[Web of Science][Medline]
- Meyer MP, Meyer JH, Commerford A, et al. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics.1994; 93:9 :18 –23
- Shannon KM, Keith JF, Mentzer WC, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.
Pediatrics.1995; 95
:1
–8
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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