Published online November 1, 2006
PEDIATRICS Vol. 118 No. 5 November 2006, pp. 2004-2013 (doi:10.1542/peds.2006-1113)
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ARTICLE

Effects of a Combined Therapy of Erythropoietin, Iron, Folate, and Vitamin B12 on the Transfusion Requirements of Extremely Low Birth Weight Infants

Nadja Haiden, MDa, Jens Schwindt, MDa, Francesco Cardona, MDa, Angelika Berger, MDa, Katrin Klebermass, MDa, Martin Wald, MDa, Christina Kohlhauser-Vollmuth, MDa, Bernd Jilma, MDb and Arnold Pollak, MDa

a Division of Neonatology and Intensive Care, Department of Pediatrics
b Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Erythropoietin is frequently administered to premature infants to stimulate erythropoiesis. The primary goal of erythropoietin therapy is to reduce transfusions, but the efficacy of erythropoietin has not been convincingly demonstrated in this regard. The aim of this trial was to investigate whether combined administration of vitamin B12, folic acid, iron, and erythropoietin could decrease transfusion requirements in extremely low birth weight infants.

PATIENTS AND METHODS. In a randomized, controlled trial, extremely low birth weight infants with a birth weight ≤800g and a gestational age ≤32 weeks were randomly assigned to a group receiving combination treatment or a control arm.

RESULTS. The treatment increased levels of folate in red blood cells, vitamin B12, ferritin, transferrin receptor levels in plasma, and reticulocyte counts. The proportion of infants requiring no transfusions was lower in the treatment group (38%) as compared with controls (5%). The treatment group and the need for mechanical ventilation were independent predictors of the number of transfusions in multiple regression analysis. Cox regression analysis indicated that combined therapy resulted in a 79% risk reduction for any transfusion.

CONCLUSION. Combined treatment with erythropoietin, intravenous iron, folate, and vitamin B12 during the first weeks reduces the need for transfusion in extremely low birth weight infants.

Key Words: folate • vitamin B12 • erythropoietin • iron • ELBW infant • transfusions

Abbreviations: RBC—red blood cell • GA—gestational age • ELBW—extremely low birth weight • TFR—transferrin receptor • CI—confidence interval • IRF—immature reticulocyte fraction • MCV—mean corpuscular volume • ROP—retinopathy of prematurity

The majority of premature infants, especially very low birth weight (birth weight <1500 g) infants, receive ≥1 red blood cell transfusion for anemia of prematurity during their first months of life.1In this patient group, anemia is most commonly the combined result of substantial iatrogenic blood loss, poor iron stores, and the inability of red blood cell (RBC) production to keep pace with somatic growth.2 Therapy with recombinant erythropoietin3–11 seems to be effective in the treatment of anemia of prematurity, as evidenced by increased reticulocytosis and increased hematocrit.12–14 However, the optimal therapeutic strategy with regard to dosage, duration, and mode of application of erythropoietin and iron to stimulate erythropoiesis most efficiently remains controversial. Furthermore, the results are, in part, conflicting with regard to reduction of blood transfusions.15 Varying degrees of success are attributed to variables like birth weight, gestational age (GA), dosage of erythropoietin and iron, and the initiation and duration of therapy. Especially in the subgroup of critically ill extremely low birth weight ([ELBW] birth weight <1000 g) infants, considerable iatrogenic blood loss during the first weeks of life limits a significant impact on transfusion requirements.16,17

Besides erythropoietin, several other factors have an impact on the prevention of anemia of prematurity. A sufficient supply of protein, calories, folic acid, and vitamin B12 plays a decisive role in erythropoiesis of premature infants.18–20 In situations of increased erythropoiesis, such as erythropoietin therapy, preterm infants with lower folate stores can become folate deficient10,21 and may require supplementation. There is evidence that the combined supplementation of folic acid and vitamin B12 supplementation has an impact on RBC production in premature infants.22 An additional supply of folic acid (100 µg/kg per day) and vitamin B12 (100 µg/kg per month), exceeding the basic requirements of premature infants, stimulated erythropoiesis as evidenced by a significantly lesser decline in hemoglobin compared with untreated controls.22 However, the infants in this study did not receive erythropoietin therapy. Based on these considerations, our group recently examined the additional benefit of adding vitamin B12 and high-dose folate to erythropoietin and iron in premature infants with a birth weight between 800 and 1300 g. This resulted in greater efficacy of stimulating erythropoiesis, but the data may have partly been driven by insignificant differences at baseline.23 Therefore, we hypothesized that the combination of vitamin B12 and high-dose folate with erythropoietin and iron may decrease the number of infants who require any transfusion as compared with control conditions. Thus, the aim of this randomized, controlled clinical trial was to investigate the impact of this combined therapy on the transfusion requirements in ELBW infants.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design and Population
The study design was a randomized, controlled trial with 2 treatment arms. Premature infants with a birth weight between 450 and 800 g and a GA ≤32 weeks admitted to the NICUs of the Department of Pediatrics, Medical University of Vienna, were eligible for inclusion in the study. Exclusion criteria were hemolytic disease, maternal causes of neonatal thrombocytopenia, major hemorrhage (defined as intraventricular hemorrhage III° or IV°24 diagnosed by cerebral ultrasound before study entry or gastrointestinal or pulmonary hemorrhage associated with a hemoglobin drop of >2 g/dL in 24 hours), twin-to-twin transfusion syndrome, major congenital malformations, and known gastrointestinal abnormalities.

Infants were assigned randomly to combined erythropoietin therapy or to a control group. Random assignment was done using sealed opaque envelopes. The study was approved by the University of Vienna Ethics Committee. Written consent was given by the parents after full explanation of the procedure.

Study Protocol
Group treatments are delineated in Table 1 (erythropoietin: Erypo, Janssen-Cilag Pharma, Vienna, Austria; iron dextran: INFeD, Schein Pharmaceutical Inc, Florham Park, NJ; iron polymaltose complex: Maltofer, Vifor International, St Gallen, Switzerland; folic acid: Folsan, Solvay Pharma, Klosterneuburg, Austria; and vitamin B12: Vitamin B12 Lannacher, Lannacher Heilmittel, Lannach, Austria).10,16,22,25 With the exception of folate, all of the study medications were administered from the second day of life up to 40 weeks' GA corrected for prematurity or until discharge, whichever came first. Folate is only available as an oral preparation and was started on day 15 of life or when the infant tolerated 60 mL/kg of enteral feeding, whichever came first. Iron dextran and vitamin B12 were added to the parenteral nutrition. Once the infant was on full enteral feedings, iron was given enterally and vitamin B12 was administered as subcutaneous injection. Recommendations for daily parenteral intake are 56 µg/kg for folic acid and 0.3 µg/kg for vitamin B12,18 respectively. Infants received this basic supply via an intravenous vitamin supplementation solution (Soluvit; Fresenius AB, Stockholm, Sweden; containing 40 µg/mL of folic acid and 0.5 µg/mL of vitamin B12) added to the parenteral nutrition.


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  		TABLE 1 Therapy Protocol

 
Because erythropoietin has been shown to be safe at lower doses, there has been a tendency recently to increase the dose of erythropoietin to increase efficacy.16 We, therefore, decided to administer a consistently higher dose (intravenously and subcutaneously) during the whole study period. Initial doses were based on birth weight and were adjusted to the current weight twice a week. Criteria for withholding the erythropoietin and iron included neutropenia (neutrophil count <500/µL), and severe sepsis (defined as culture-proven sepsis requiring catecholamine or ventilatory support). The study drug was restarted when neutrophil counts increased over 500/µL. In case of severe sepsis, erythropoietin therapy was interrupted for 3 days and then restarted. Parenteral iron was not administered while erythropoietin was held. The primary rationale for withholding study medication was to pause iron in culture-proven sepsis. Iron has been reported to be a growth factor for a number of bacteria and might worsen the patient's condition during sepsis.26,27 During the study, a strict transfusion protocol as published by Shannon et al3 was abided (Table 2). If the transfusion criteria were fulfilled, a daily maximum of 15 mL/kg of packed RBC (irradiated, washed, and filtered) was transfused until the infant's hematocrit raised ≥40%. Transfusions were applied only once in 24 hours; packed RBCs were transfused over 3 to 4 hours (rate: <10 mL/kg per hour). On the next day, hematocrit was reevaluated. If hematocrit did not exceed 40%, another transfusion was administered to the patient and documented as a second transfusion. The exact volume of blood transfused, number of donors, and increase in hematocrit and hemoglobin were recorded on the case report form.


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  		TABLE 2 Indications for Packed RBC Transfusions3

 
Blood Sampling and Laboratory Methods
Baseline values of all of the parameters were obtained from cord blood. In both groups, full blood counts and differential, as well as reticulocyte, counts were measured weekly in samples obtained from venipunctures (usually from a hand or foot vein) or from a central venous line. Levels of folic acid in RBC, vitamin B12, ferritin, transferrin receptor, and iron were measured at baseline and after 4, 8, and 12 weeks. The volume of withdrawn blood was measured by using volume-calibrated tubes. Complete blood cell counts with differentials and reticulocyte counts were performed using an automatic blood cell counter (Cell Dyn 4000; Abbott, Vienna, Austria). Ferritin was measured by nephelometry (Beckmann Image; Instrumentation Laboratory, Vienna, Austria), transferrin receptor (TFR) with an enzyme linked immunoassay method (R&D Systems, Oxon, United Kingdom), iron with a 2-point measurement procedure (Vitros 950, Orthodiagnostic; Assista Laborelektrik, Vienna, Austria), vitamin B12 by micro part enzyme intrinsic factor system (IMX; Abbott, Vienna, Austria), and RBC folic acid with an iron capture assay (IMX). Determinations of serum orthothyrosine were performed by reverse-phase high-performance liquid chromatography (Agilent/Hewlett Packard series 1100, Böblingen, Germany).

Statistical Analysis
We hypothesized that the combination of vitamin B12 and high-dose folate with erythropoietin and iron may decrease the number of infants who require any transfusion as compared with control conditions (primary end point). From chart reviews of previous infants at our department, we estimated that in this specific population the proportion of patients requiring transfusions could approach ~90%. We calculated that a total sample size of 40 patients would be necessary to detect a 33% reduction in the number of infants requiring any transfusion with a power of 80% and a significance level of 0.05.

Results are expressed as the median with the range in the text and tables, with upper and lower quartiles in the figures. Comparisons of the cumulative number of transfusions over time between the treatment groups were made by repeated-measurement analysis of variance. Given the nonnormal distribution of the data, all of the posthoc comparisons were performed using nonparametric tests. Differences between groups were tested with the Mann-Whitney U test. Differences before and after treatment were tested for significance using the Wilcoxon test. The {chi}2 test was used to test for differences in dichotomous variables (including the proportion of infants requiring no transfusion). The Friedman analysis of variance was applied for repeated measurements for posthoc comparisons. A P < .05 was considered statistically significant. Calculations were done with STATISTICA software (StatSoft Inc, Tulsa, OK) or SPSS 12.0 (SPSS Inc, Chicago, IL) for Cox regression analysis.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
During the 2-year study period (October 2000 to November 2002), 47 infants were eligible for enrollment in the study. Four infants were excluded because of parental refusal (n = 2) or intraventricular hemorrhage IV° (n = 2), respectively. Three infants died before random assignment. Therefore, the final cohort included 40 infants. Twenty-one and 19 infants were randomly assigned to the intervention group and control group, respectively. The only criterion for dropout after random assignment was death.

Demographic data and clinical characteristics including outcome of both groups are given in Tables 3 and 4. No differences were noted for GA, gender, birth weight, duration of study period, hospital stay, weight at discharge, or complications of prematurity between the groups. However, 17 treated infants (81%) and 9 control infants (47%) needed respiratory support (P = .026) and required mechanical ventilation for a median of 4 days (mean: 12 days; range: 0–52 days) in the erythropoietin group versus a median 0 days (mean: 5 days; range: 0–27 days) in the control group (P = .07).


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  		TABLE 3 Patient Demographics

 

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  		TABLE 4 Clinical Outcomes of the Study Population

 
Transfusion Requirements
The proportion of infants requiring transfusions was significantly lower in the treatment group (62%) as compared with the control group (95%; P = .013). A Kaplan-Meier plot depicts the transfusion-free survival among patients (Fig 1). Except for 3 delays in transfusions, no violations of the transfusion protocol occurred. The need of ventilatory support (P < .001; ß = .81) and treatment group (P = .01; ß = –.28) were independent predictors of the number of transfusions and blood volume administered in multiple regression analysis (treatment group: P = .007; ß = –.34; need of ventilatory support: P < .001; ß = .72). The average (median) number of transfusions was 2.0 in the erythropoietin and 4.5 in the control group (Fig 2; P = .22). Furthermore, the cumulative median volume of transfused blood averaged 28 mL in the erythropoietin group versus 75 mL in the control group (P = .65; Table 5). In both cases, this was not significant, because of 3 outliers in the erythropoietin group (Fig 2) with very long duration of ventilation (37, 45, and 52 days) and associated high transfusion requirements in the erythropoietin group. To further estimate the impact of ventilation on measured outcome parameters, we performed a Cox regression analysis. This analysis showed that every day of ventilation was associated with a 12% (% 95 confidence interval [CI]: 7%–16%) increase in the risk for transfusion (P < .001). Furthermore, erythropoietin treatment resulted in a 79% (% 95 CI: 35%–87%) risk reduction for any transfusion (P = .003).


Figure 1
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  		FIGURE 1 Transfusion-free survival. Effects of erythropoietin therapy in combination with vitamin B12 and folate for treatment of anemia of prematurity on time of administration of the first transfusion in ELBW infants. Infants of the control group are indicated by - - -, infants of the erythropoietin group by —, and censored infants by +.

 

Figure 2
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  		FIGURE 2 Number of transfusions per individual. Effects of erythropoietin therapy in combination with vitamin B12 and folate for treatment of anemia of prematurity on transfusion requirements in ELBW infants. Horizontal lines indicate the median number of transfusions The proportion of infants requiring no transfusion was significantly higher in the treatment arm (38%) versus controls (5%; P = .013; {chi}2 test).

 

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  		TABLE 5 Transfusions and Phlebotomy Losses During the Study

 
RBC Parameters and Reticulocytes
Erythropoietin increased reticulocyte counts on average threefold to fivefold above the control group (Fig 3B). Erythropoietin also increased the immature reticulocyte fraction (IRF; high- and medium-fluorescence reticulocytes), particularly during weeks 1 to 5 (Fig 3D). Hemoglobin decreased somewhat from baseline levels in both groups and remained below baseline during the study (data not shown). Hematocrit values also decreased from baseline levels in both groups but were significantly lower in the control group during the last 2 weeks of the study period (Fig 3A). Mean corpuscular volume (MCV) dropped from baseline in both groups, which is described as a physiologic decrease,28 but was significantly lower in the control group between study weeks 4 to 12 (Fig 3C).


Figure 3
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  		FIGURE 3 Changes in hematologic parameters during the study period. Pharmacodynamic effects of erythropoietin herapy in combination with vitamin B12 and folate ({diamondsuit}) as compared with controls ({triangleup}) in ELBW infants. Hematocrit values (A) were significantly lower in the control group during the last 2 weeks. The counts for reticulocytes (B) and IRF (D) were significantly higher in the treatment group versus controls (P < .05). MCV (C) also decreased from baseline but was higher at week 4 to 12 in the treatment group (P < .05). a Statistically significant at P < .05.

 
Folate and Vitamin B12
Folate was introduced on day 17 of life (range: 12–42 days) in the control group, and infants received supplementation for 39 days (range: 15–111 days). In the erythropoietin group, folate supplementation started on day 15 of life (range: 13–58 days) and was administered for 44 days (range: 9–110 days). Folate in RBC decreased significantly from baseline in the control group but increased slightly in the erythropoietin group. This yielded a twofold difference between study groups during weeks 4 and 8 (Table 6). Serum vitamin B12 tended to be higher in the erythropoietin group during the whole study period but reached significance only after 12 weeks (P = .04; Table 6).


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  		TABLE 6 Changes in Folic Acid in RBC, Vitamin B12, and Iron Status

 
Iron Status
TFR concentrations increased in the erythropoietin group and decreased in the control group attaining statistical significance during the whole study period (weeks 4, 8, and 12). However, randomization unfortunately yielded significant baseline differences between groups: the control group had a slightly lower mean TFR concentration at baseline. To consider the difference between starting values, we have calculated differences between baseline and 4, 8, and 12 weeks within the groups and compared these between the groups. Because these relative changes were significant, the results seem not to be driven by the baseline differences. There were no differences in serum levels of iron or transferrin saturation. Ferritin concentrations were similar at study entry in the 2 groups but increased significantly more over baseline in the erythropoietin group as compared with controls (Table 6).

Tolerability and Oxidant Injury
No adverse effects were attributed to study medication. Administration of erythropoietin and vitamin B12 was switched from the intravenous to subcutaneous route after 6 weeks (median: 43 days; range: 19–304 days). Serum orthothyrosine levels remained unchanged throughout the study. No essential difference for this oxidant injury parameter was noted between the 2 groups during the study period (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The aim of the study was to investigate the impact of a combined therapy with erythropoietin, intravenous and oral iron, vitamin B12, and high-dose folate on erythropoiesis and transfusion requirements in ELBW infants. RBC folate, vitamin B12 levels (Table 6), iron stores (ferritin), and reticulocyte counts (Fig 3) increased significantly compared with the control group. Importantly, the new therapeutic approach reduced the number of infants requiring transfusions by one third.

Erythropoiesis and Blood Loss
Combined erythropoietin therapy induced erythropoiesis as evidenced by reticulocytosis, including IRF (Fig 3), which is a strong indicator for increased erythropoietic activity.29 However, the primary goal of erythropoietin therapy in premature infants is to reduce transfusions. So far, randomized, controlled trials yielded mixed results in this regard. The best effects were observed in relatively mature, stable, and spontaneously breathing infants. Anemia of prematurity seems to have 2 periods of different origin, with an early state mainly caused by iatrogenic blood loss and a late state caused by inadequate erythropoietin production.7 Thus, the estimation of the erythropoietin efficacy is complex and difficult, especially in ELBW infants belonging to the group of the sickest infants. Despite randomization, our groups unfortunately were not ideally balanced with regard to clinical outcome variables. The proportion of infants who needed respiratory support in the erythropoietin group was twofold higher than in control subjects (P = .026; Table 4). Because the transfusion protocol is strongly dependent on respiratory support, mechanical ventilation was an independent predictor of the number of transfusions and blood volume administered. Multivariate analysis indicated that every day of ventilation increased the risk for any transfusion by 12%.

The impact of mechanical ventilation on higher transfusion requirements in premature infants has been demonstrated previously3 and is known to be a risk factor for multiple transfusions. The percentage of infants receiving mechanical ventilation seemed to be slightly lower than in comparable large international erythropoietin trials: 81% for the erythropoietin group in the present study versus 95%16 reported previously. Furthermore, erythropoietin therapy is usually reported to decrease the risk of mechanical ventilation.6,7 This indicates that the imbalance in mechanical ventilation between the groups unlikely represents an adverse effect of erythropoietin but is conceivably because of chance.

Multivariate analysis indicates that our combined erythropoietin strategy resulted in a 79% (95% CI: 35%–87%) risk reduction for any transfusion (P = .003). The total iatrogenic blood loss was ~60% less than that in a previous erythropoietin trial.16 The authors reported that erythropoietin did not lower transfusion requirements and did not recommend routine use of erythropoietin in this group of patients. Discrepancies in outcome may be explained by the fact that infants in the present study had less iatrogenic blood loss and more restrictive RBC transfusion guidelines as compared with the previous trial.

Folate, Vitamin B12, and MCV
RBC folate increased by 50% over baseline in the treatment group, which was equivalent to a twofold increase relative to placebo. This is consistent with previously published data30 and could be because of an elevated absorption of folate by erythrocytes under erythropoietin therapy. Additional administration of vitamin B12 resulted in a moderate increase in serum vitamin B12, which was only significant versus placebo after 12 weeks. MCV declined quicker in the control group, which is consistent with our recent findings in more mature infants.23 Hence, we cannot exclude that supplementation of folic acid and vitamin B12 in the applied doses may still be insufficient during erythropoietin-enhanced erythropoiesis in premature infants.

Iron Status
The combination of TFR, serum ferritin, and reticulocyte count seems to be predictive of an erythropoietic response to increased erythropoietin dosage or increased iron requirements.31 The zinc protoporphyrin/heme ratio32,33 is a new promising additional indicator of iron status but was not available for this study. However, the various tests that measure iron status should be interpreted with caution during the first months of life, because they do not necessarily reflect the actual status of the infant's iron stores.34 In premature infants, plasma levels of ferritin (a marker for iron storage capacity) decrease with increasing postnatal age.35 However, former studies investigating anemia of prematurity showed that ferritin levels decrease during erythropoietin therapy despite iron supplementation.36 Our finding that ferritin levels increased during erythropoietin therapy differs from these data published previously. Differences in dosing regimens of erythropoietin and iron and different routes of administration of iron may account for this result (2100 IU/kg per week of erythropoietin and 1.5 mg/kg per day of intravenous iron + 9 mg/kg per day of oral iron in the present study vs 900 IU/kg per week of erythropoietin and 6 mg/kg per day of oral iron previously36). It is conceivable that our iron supplementation filled iron stores more effectively, as indicated by plasma ferritin levels. However, orthothyrosine serum levels did not change throughout the study period. This indicates that major oxidant injury by transient iron overload is unlikely.

TFR levels indicate erythroid TFR expression or iron status when stores are depleted.37,38 An early rise in TFR has been shown to predict the erythropoietic response to erythropoietin.39,40 Although there was an imbalance in baseline TFR in the present study, the concentration of TFR also increased slightly in the erythropoietin group, whereas it decreased significantly in the control group, indicating that TFR plasma levels are influenced by erythropoiesis and not just by nutritional iron status in this specific group of patients.

Clinical Outcome
In the present study, infants in the erythropoietin group had more ventilator days yet no difference in BPD. There is evidence from animal41 as well as human data42 that erythropoietin therapy might reduce the risk of developing BPD. The mechanisms are supposed to be correction of anemia by erythropoietin on the one hand and direct effects on the lung structure on the other hand: erythropoietin therapy is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis.42 This might be an explanation for a lower incidence of BPD in our erythropoietin group, although a higher number of infants were ventilated and had more days on ventilator as compared with controls. Although we found no difference in retinopathy of prematurity (ROP), recent published data address the risk of an association between cumulative erythropoietin exposure and an increased risk for ROP.43 The mechanisms are not fully understood but might be because of the angiogenetic activity of erythropoietin independent of vascular endothelial growth factor, which is the primary mediator for retinal angiogenesis. Similar observations have been made in adults suffering from diabetic retinopathy,44 indicating that erythropoietin is a potent angiogenic factor, and high doses have to be used with caution. Furthermore, we found higher although insignificant imbalance in necrotizing enterocolitis incidence among our patients. Conversely, to the present data, a retrospective study in 483 premature infants showed that the incidence of necrotizing enterocolitis is lower in erythropoietin-treated infants than in control subjects.45 However, our study is underpowered in this respect.

Limitations
Although the new approach of combined erythropoietin therapy is encouraging, transfusion and treatment practices of ELBW infants may differ between centers; for example, we did not routinely use arterial lines in ventilated patients and monitored ventilation with transcutaneous partial pressure of carbon dioxide. Furthermore, we used microblood gas analysis requiring only 60 µL of blood for a blood gas analysis (including sodium, potassium, glucose, bilirubin, and lactate). This could be an explanation for the lack of difference in phlebotomy loss between groups despite the differences in ventilatory support. Thus, our data may not be automatically extrapolated to other centers. However, the current study provides valuable information to confirm the safety and efficacy of this combined treatment approach in further studies.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Combined treatment with erythropoietin, intravenous iron, high-dosed folate, and vitamin B12 markedly enhanced erythropoiesis in ELBW infants compared with controls. The number of infants requiring any transfusion was one-third lower in the treatment arm. Mechanical ventilation was confirmed to be an independent predictor of the number of transfusions and of the blood volume transfused in ELBW infants.


   FOOTNOTES
 
Accepted Jul 13, 2006.

Address correspondence to Nadja Haiden, MD, Department of Pediatrics, Division of Neonatology and Intensive Care, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail: nadja.haiden{at}meduniwien.ac.at

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Ohls RK. Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity. Paediatr Drugs. 2002;4 :111 –121[Medline]
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  7. Maier RF, Obladen M, Muller-Hansen I, et al. European Multicenter Erythropoietin Beta Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. J Pediatr. 2002;141 :8 –15[CrossRef][Web of Science][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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