Correspondence
Recombinant Erythropoietin in Very-Low-Birth-Weight Infants
N Engl J Med 1994; 331:676-678September 8, 1994
- Article
To the Editor:
The report by Maier et al. (April 28 issue)1 on the effect of epoetin beta (recombinant human erythropoietin) in very-low-birth-weight infants provides important new data on the efficacy and safety of the agent in this age group. However, the results of Maier et al. raise several questions. First, what does their success rate tell us about anemia in these infants? The anemia of prematurity reaches a nadir by 6 to 10 weeks of age,2 a period barely covered by data on the first 45 days of life. As presented, the data could indicate that the need for transfusion to treat early anemia was decreased, not that anemia of prematurity was prevented. This may explain why the success rate did not differ significantly between the control group and the epoetin group among babies with birth weights ≤ 1199 g, those most likely to need transfusion for anemia of prematurity2.
Second, what were the criteria for the selection of the dose, and what is the evidence that the dose used by Maier et al. is indeed the dose to be recommended? In early studies by Halperin et al.3 and by us,4 escalation of the dose did not establish a dose-response relation. A later study suggested a dose dependency5.
Third, was the withdrawal rate of about 25 percent comparable in the two groups? In interpreting the Kaplan-Meier curves, it would have been helpful to know the numbers of patients at risk in each 10-day period.
5 ReferencesDaniel Beck, M.D.
Andre Calame, M.D.
Eric Masserey, M.D.
University Hospital, CH-1011 Lausanne, Switzerland1
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
Full Text | Web of Science | Medline2
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 | Medline3
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 | Medline4
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 | Medline5
Messer J ,Haddad J ,Donato L ,Astruc D ,Matis J . Early treatment of premature infants with recombinant human erythropoietin. Pediatrics 1993;92:519-523
Web of Science | Medline
To the Editor:
With regard to the report by Maier et al.,1 we do not agree with the exclusion from the study of the “sick” infants on day 6 of life. We think that these infants are the most likely to receive numerous blood transfusions and that they may benefit the most from treatment with erythropoietin. Furthermore, it is not clear to us what happened to those infants. Was the study stopped on day 7? Was erythropoietin therapy discontinued? Had these patients been excluded, as is described under the criteria for entry and withdrawal, data related to them should not have appeared in Table 2, where the outcomes of all babies entering the study are reported1. Had the sick infants who met the criteria for withdrawal on day 6 continued to receive erythropoietin, data on their transfusion status should have been presented in a separate table.
We have shown2 that high doses of erythropoietin (1200 IU per kilogram of body weight per week), together with iron supplementation, were well tolerated and significantly reduced the need for blood transfusion in premature infants born before 32 weeks' gestation and with birth weights of less than 1.75 kg. The rationale for the high doses was later supported by pharmacologic studies in sheep3.
The results of the European Multicentre Erythropoietin Study Group1 appear to be quite disappointing (the number of transfusions was reduced by only 0.38 per patient), and the dose of the drug was 750 IU per kilogram per week -- much lower than in our study2. We would have expected to read in the Discussion section about the possible dependence of the less satisfactory results of Maier et al. on the insufficient dosage of erythropoietin rather than about their dependence on the role of iron supplementation.
3 ReferencesVirgilio P. Carnielli, M.D., Ph.D.
Rosalia Da Riol, M.D.
Giovanni Montini, M.D.
University of Padua, 35128 Padua, Italy1
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
Full Text | Web of Science | Medline2
Carnielli VP ,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 | Medline3
Widness JA ,Veng-Pedersen P ,Modi NB ,Schmidt RL ,Chestnut DH . Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep. J Pharmacol Exp Ther 1992;261:977-984
Web of Science | Medline
To the Editor:
The article by Maier et al.1 and the accompanying editorial by Strauss2 underscore the finding that erythropoietin is not effective in small, sick infants1,3,4 In almost all studies of preterm infants, however, erythropoietin has been administered subcutaneously. Perhaps this route of administration was not optimal, because of the erratic absorption of erythropoietin from subcutaneous sites in sick preterm infants. One study of the pharmacokinetics of erythropoietin in preterm infants5 showed that the bioavailability of subcutaneous doses ranged from 10.8 percent to 70.9 percent, and there was much greater variability in volume of distribution and clearance after subcutaneous administration of erythropoietin than after intravenous administration. Therefore, future studies of the efficacy of erythropoietin in small, sick preterm infants should measure the serum concentration of erythropoietin.
5 ReferencesJohn N. van den Anker, M.D.
Sophia Children's Hospital, 3015 GJ Rotterdam, the NetherlandsGiovanni Montini, M.D.
Virgilio P. Carnielli, M.D., Ph.D.
University of Padua, 35128 Padua, Italy1
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
Full Text | Web of Science | Medline2
Strauss RG . Erythropoietin and neonatal anemia. N Engl J Med 1994;330:1227-1228
Full Text | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
Messer J ,Haddad J ,Donato L ,Astruc D ,Matis J . Early treatment of premature infants with recombinant human erythropoietin. Pediatrics 1993;92:519-523
Web of Science | Medline5
Brown MS ,Jones MA ,Ohls RK ,Christensen RD . Single-dose pharmacokinetics of recombinant human erythropoietin in preterm infants after intravenous and subcutaneous administration. J Pediatr 1993;122:655-657
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: When we started our multicenter trial in 1991, only a few reports on the safety of epoetin therapy in preterm infants had been published. For safety reasons, we restricted the duration of treatment to 42 days, the period during which patients were likely to stay in the hospital. Also for safety, we discontinued therapy with epoetin beta in infants requiring prolonged artificial ventilation. The number of infants who did not complete the protocol, as well as the reasons for withdrawal, did not differ between the control and treatment groups, as indicated in Table 3 of the article1. The intention-to-treat analysis required the inclusion of all patients in the statistical evaluation.
The anemias of prematurity are multifactorial and include blood loss as well as failure of erythropoiesis. Blood loss that relates to the level of intensive care is maximal during the early weeks of life in the sickest babies and prompts most transfusions. Epoetin therapy could not reduce the frequency of these transfusions, although we started treatment when the infants were three days old. Later anemias were ameliorated by epoetin, as indicated by the presence of higher hematocrit levels despite a lower transfusion rate in the epoetin-treated infants. Perhaps allowing placental transfusion at birth would further obviate transfusions, by endowing the newborn with autologous blood containing hematopoietic stem cells2.
The dose of epoetin beta (750 IU per kilogram per week) was based on our dose-finding studies: 200 IU per kilogram per week was more effective than 100 IU, and 400 IU did not further stimulate erythropoiesis3,4. Epoetin dose dependency is influenced by nutrition (e.g., adequate amounts of iron and protein) and by inflammation that could inhibit erythropoiesis.
We chose the subcutaneous administration of epoetin because the infants were unlikely to have an intravenous route of access throughout the study period. In adults with the anemia of renal failure, subcutaneous rather than intravenous administration permitted the epoetin dose to be lowered5. More information on this issue in preterm infants is needed. We did not measure serum levels of erythropoietin because our aim was to reduce the need for transfusion by avoiding blood loss from diagnostic tests.
5 ReferencesRolf F. Maier, M.D.
Michael Obladen, M.D.
Freie Universitat Berlin, D-14059 Berlin, GermanyCharles A.J. Wardrop, F.R.C.P.E.
University of Wales, Cardiff CF4 4XN, United Kingdom1
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
Full Text | Web of Science | Medline2
Kinmond S ,Aitchison TC ,Holland BM ,Jones JG ,Turner TL ,Wardrop CAJ . Umbilical cord clamping and preterm infants: a randomised trial. BMJ 1993;306:172-175
CrossRef | Web of Science | Medline3
Obladen M, Maier RF, Grauel EL. Prevenir l'anemie du premature par l'administration de l'erythropoietine. In: Relier JP, ed. Progres en neonatologie. Vol. 13. Paris: Karger, 1993:34-42.
4
Stewart G ,Holland BM ,Turner TL ,Wardrop CAJ . Erythropoietin (rhEPO) in preterm infants: does it work? Br J Haematol 1991;77:Suppl 1:4-4 abstract.5
Ashai NI ,Paganini EP ,Wilson JM . Intravenous versus subcutaneous dosing of epoetin: a review of the literature. Am J Kidney Dis 1993;22:Suppl 1:23-31
Web of Science | Medline
