Published online August 14, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e635-e640 (doi:10.1542/peds.2005-3186)
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ARTICLE

Erythropoietin Concentrations and Neurodevelopmental Outcome in Preterm Infants

Ryann Bierer, MDa, M. Connie Peceny, BSb, Carol H. Hartenberger, MPHb and Robin K. Ohls, MDb

a Department of Pediatrics, University of Arizona, Tucson, Arizona
b Department of Pediatrics and Pathology, University of New Mexico, Albuquerque, New Mexico


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations >1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants.

METHODS. Preterm infants who weighed ≤1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes.

RESULTS. Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 ± 1464 mU/mL; placebo/control: 26 ± 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores <70. Erythropoietin recipients had Mental Development Index scores of 96 ± 11, and placebo/control infants had Mental Development Index scores of 78 ± 7. Psychomotor Development Index scores were similar between groups (87 ± 13 vs 80 ± 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations ≥500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations <500 mU/mL.

CONCLUSIONS. Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome.

Key Words: erythropoietin • premature infants • neurologic outcome

Abbreviations: NICHD—National Institute of Child Health and Human Development • PMA—postmenstrual age • ELBW—extremely low birth weight • ROP—retinopathy of prematurity • MDI—Mental Development Index • PDI—Psychomotor Development Index • CSF—cerebrospinal fluid

Erythropoietin administration to preterm infants has decreased transfusions to varying degrees in clinical studies. We previously reported the results of a randomized, double-masked, placebo-controlled trial of early erythropoietin and iron treatment in infants who weighed ≤1250 g at birth.1 Infants were randomly assigned in that study to treatment (erythropoietin 400 U/kg 3 times weekly, given intravenously over 1 hour or subcutaneously) or placebo/control. Therapy was initiated by 96 hours of age and was continued through 35 weeks' postmenstrual age (PMA). All infants received supplemental parenteral and enteral iron.

The combination of early erythropoietin and iron therapy stimulated erythropoiesis, statistically decreased transfusion requirements, and was not associated with an increased incidence of neonatal morbidities or adverse events.1 Studies that evaluated neonatal outcomes after erythropoietin therapy reported no significant differences between treatment groups,2,3 and an 18- to 22-month follow-up of infants who weighed ≤1000 g and were enrolled in the National Institute of Child Health and Human Development (NICHD) erythropoietin study reported similar results.4 The treatment of preterm infants with erythropoietin is considered part of clinical care in many units throughout the United States and Europe.

In addition to its hematopoietic effects, erythropoietin has neuroprotective properties.5–10 Recent animal studies have shown beneficial neurologic effects of erythropoietin, including decreased hypoxic-ischemic brain injury, decreased infarction volume, decreased hemorrhagic volume, reduced vasoconstriction, decreased neuronal apoptosis, and decreased neurologic deterioration. The purpose of this study was to compare measures of neurodevelopmental and anthropometric outcomes at 18 to 22 months' corrected age with serum erythropoietin concentrations. We studied extremely low birth weight (ELBW) infants at the University of New Mexico using a similar, previously published erythropoietin study protocol.1 We hypothesized that elevated serum erythropoietin concentrations would correlate with improved neurodevelopmental outcomes.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Infants were eligible when they weighed ≥401 g and ≤1000 g at birth, were ≤32 weeks' gestation, were between 24 and 96 hours of age at the time of study entry, were likely to survive >72 hours (as determined by the attending neonatologist), and had informed consent from a parent or guardian. Patients were ineligible when they had any of the following: a major congenital anomaly, a positive direct antiglobulin test, evidence of coagulopathy, clinical seizures, systolic blood pressure >100 mm Hg (in the absence of pressor support), or an absolute neutrophil count ≤500/µL. Randomization was stratified by birth weight (401–750 and 751–1000 g) using a permuted block method. All caregivers and investigators (except the research nurses) were masked to the treatment assignment.

Discharge data were collected on all surviving study participants. Information on neonatal morbidities was collected and included incidence of bronchopulmonary dysplasia (oxygen administration at 36 weeks' PMA11), retinopathy of prematurity (ROP; stage 3 or higher12), patent ductus arteriosus, intraventricular hemorrhage (grade 3 or higher13), and necrotizing enterocolitis (Bell's stage II or higher14).

Treated infants received 400 U/kg erythropoietin 3 times per week.1 Initial doses were based on birth weight and adjusted weekly on the basis of current weight. Erythropoietin or placebo was administered by the research nurse as a 1-hour intravenous infusion or subcutaneously when intravenous access was not available. Infants in the placebo/control group received sham subcutaneous injections when intravenous access was not available. An adhesive bandage covered the true and sham injection sites. The study drug was brought to the bedside in a closed container, and injections were shielded from the caregivers by screens. Treatment continued until discharge, transfer, death, or 35 completed weeks' PMA. Infants received parenteral or enteral iron supplementation per the previously published erythropoietin study protocol.1

Transfusions were administered in accordance with a conservative transfusion protocol.1 Daily phlebotomy losses and transfusion information were recorded from birth to study completion.

Serum was obtained for measurement of erythropoietin concentrations at study entry and every 2 weeks thereafter until study completion. Infants who received intravenous study drug had blood sampled at the completion of the 1-hour infusion. Infants who received subcutaneous study drug or sham dosing had blood sampled 6 to 8 hours after administration. Samples were frozen at –80°C and batched for measurement of erythropoietin concentrations by commercial enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN).

Assessments at 18 to 22 months were performed by certified examiners who were masked to the infants' treatment group. Evaluations included a standardized neurologic examination, anthropometric measurements,15 the Bayley Scales of Infant Development-IIR, structured parent interviews about medical and social history, and functional performance.

Hearing information was obtained from parental report supplemented with the results of audiologic evaluations when available. Deafness was defined as hearing disability that required amplification. Vision status and information from any postdischarge ophthalmologic examinations were obtained from the parent and supplemented by information from the medical chart. A standard eye examination was performed to evaluate tracking, nystagmus, and roving eye movements. Blindness was defined as no functional vision in both eyes. The overall outcome of survival with neurodevelopmental impairment was defined as survival to 18 to 22 months' corrected age with 1 or more of the following: Mental Development Index (MDI) < 70, Psychomotor Development Index (PDI) <70, moderate or severe cerebral palsy, blindness in both eyes, or deafness.

Comparisons were made between the erythropoietin and placebo/control groups using {chi}2 or Fisher's exact tests for categorical variables and t tests for continuous variables. Spearman's correlation was performed comparing the log of erythropoietin concentrations with neurodevelopmental scores. No power analysis was performed for this pilot study. Statistical significance was defined as P < .05. Institutional review board approval and informed consent were obtained for all infants who were enrolled in the study at the University of New Mexico.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Sixteen ELBW infants (7 erythropoietin treated and 9 placebo/control) were enrolled at the University of New Mexico between August 1997 and March 2000. One infant in the placebo/control group died at 2 weeks of age and did not have erythropoietin concentrations measured or morbidities included in the results. One infant in the erythropoietin group died at 6 months and was not included in the follow-up. Two infants in the placebo/control group died at 3 months and were not included in the follow-up. Of those who survived and in whom erythropoietin concentrations were determined by enzyme-linked immunosorbent assay, 6 of the erythropoietin-treated and 6 of the placebo/control infants were evaluated at 18 to 22 months' corrected age and were included in analysis.

Infants in the erythropoietin group had significantly higher erythropoietin concentrations and received fewer transfusions than those in the placebo/control group (Table 1). Peak erythropoietin concentrations generally occurred between the third and fifth week of study. None of the infants in either group received transfusions after discharge from the hospital. There were no differences in outcome characteristics between treatment groups at the time of discharge (Table 1). Infants who were evaluated at 18 to 22 months were similar in size and gestation and had similar neonatal morbidities, including ROP stage 3 or higher and intraventricular hemorrhage grade 3 or higher.


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  		TABLE 1 Characteristics of the Infants

 
Infants had similar anthropometric measurements at follow-up (Table 2) and were similar in their neurodevelopmental impairments at 18 to 22 months (Table 3). Two of 6 infants in the placebo/control group had MDI scores <70, whereas none of the 6 infants in the erythropoietin group had an MDI score <70. Infants with erythropoietin concentrations ≥500 mU/mL had MDI scores higher than those of infants with erythropoietin concentrations <500 mU/mL (100 ± 15 vs 77 ± 16; P < .05; Figure 1). PDI scores were not statistically different between these 2 groups (89 ± 19 vs 76 ± 18; P = .21; Figure 1).


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  		TABLE 2 Growth at 18 to 22 Month's Follow-up

 

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  		TABLE 3 Neurodevelopmental Outcomes at 18 to 22 Months' Corrected Age

 

Figure 1
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  		FIGURE 1 Box plot of MDI scores (A) and PDI scores (B) for infants with erythropoietin concentrations <500 or ≥500 mU/mL. Mean ± SD values are depicted in each box. Infants with erythropoietin concentrations ≥500 mU/mL had higher MDI scores. a P < .05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The administration of human recombinant erythropoietin to preterm infants first was reported in 1990, when Halperin et al16 published their pilot study that evaluated the use of erythropoietin to treat anemia of prematurity. Since then, doses that have been evaluated in clinical studies that involved preterm infants ranged from 100 U/kg twice per week17 to 5000 U/kg per week.18 Adverse effects of treatment at all doses tested have been minimal, and the decreased number of transfusions reported is thought to be beneficial. The treatment of preterm infants with erythropoietin is considered part of clinical care in many units throughout the United States and Europe, and outcomes continue to be studied.

This report details results of ELBW infants who were enrolled in an erythropoietin study protocol and in whom erythropoietin concentrations were measured. ELBW Infants showed benefit when receiving erythropoietin, in that transfusions were significantly decreased (1.5 transfusions in erythropoietin recipients vs 4.3 transfusions in placebo/controls). These results differed from the NICHD erythropoietin study, in which ELBW erythropoietin recipients showed only mild benefit from erythropoietin (4.3 transfusions in erythropoietin recipients vs 5.2 transfusions in placebo/controls). It is not clear whether the decreased number of transfusions that were seen in our infants affected their developmental outcome. It is possible that decreasing the number of transfusions that ELBW infants receive improves their overall outcome. For example, in adult intensive care patients, a decreased number of transfusions correlates with improved outcome.19–21 Although the evaluation of transfusions in preterm infants has not been addressed specifically in this manner, a similar association might exist.

There are limited data regarding neurodevelopmental follow-up of infants who receive erythropoietin. The NICHD erythropoietin study followed 102 ELBW infants and showed no differences overall between treatment groups in neurodevelopmental and anthropometric parameters that were measured at 18 to 24 months.4 In an earlier study, Newton et al3 found no statistical difference in developmental outcomes between 20 erythropoietin-treated infants and 20 control infants. The results of these short-term follow-up studies are preliminary and warrant longer term evaluation.

Experimental studies outside the neonatal and hematopoietic arena have created a renewed interest in the use of erythropoietin in term and preterm infants. During the past decade, studies have demonstrated that, in addition to its hematopoietic functions, erythropoietin functions as an angiogenic, neurogenic, and neuroprotective agent by binding to its receptor in nonhematopoietic tissues and activating cellular mechanisms that include cell maturation, division, and inhibition of apoptosis.5–10,22–24 Studies that have evaluated erythropoietin in adult and neonatal animal models reported the prevention of hypoxic-ischemic brain injury, decreased neuronal apoptosis, decreased infarction volume, and improved functional outcomes.5–10,25,26 These studies evaluated doses of erythropoietin in the range of 1000 to 5000 U/kg, ~10 times the dose that generally is used to stimulate red cell production in infants. Clinical studies in adult stroke patients evaluated erythropoietin doses of 33000 U/day for 3 days, resulting in cerebrospinal fluid (CSF) erythropoietin concentrations 60- to 100-fold above baseline, and improved functional outcomes.27 Infants in our study had peak erythropoietin concentrations >2000 mU/mL that might have resulted in CSF concentrations within the "neuroprotective" range of 20 to 30 mU/mL28; however, CSF concentrations were not obtained in this study.

In addition to central nervous system effects, erythropoietin may play a role in the developing preterm eye. Recent reports in adult patients with diabetic retinopathy reveal a possible association between elevated vitreal erythropoietin concentrations and retinal vascular disease.29 A previous report suggested a protective effect of erythropoietin on the ischemic retina.30 Retrospective analyses report conflicting results regarding erythropoietin administration and the incidence of ROP.31–33 However, none of the randomized, masked, placebo-controlled studies reported an increased incidence of this neonatal morbidity, even in the smallest infants studied.1,34–37 Although it seems that erythropoietin mRNA and protein are present in the developing human vitreous,38 its function is unknown. Additional study is required to determine what, if any, association exists between erythropoietin administration and ROP.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This is the first study to report an association between serum erythropoietin concentrations and neurodevelopmental outcomes in preterm infants who receive erythropoietin. We cannot formulate conclusions from these preliminary observations on such a small number of infants. These observations merit additional evaluation into the possible benefit of erythropoietin as a neuroprotective agent in neonates. Long-term neurodevelopmental follow-up of infants who are involved in randomized studies of erythropoietin administration are warranted.


   ACKNOWLEDGMENTS
 
This study was supported by National Institutes of Health grants HD00988 and M01 RR 00997 and NICHD grant U10 HD27881.

We thank Clifford Qualls, PhD, for assistance in statistical analysis.


   FOOTNOTES
 
Accepted Mar 8, 2006.

Address correspondence to Robin K. Ohls, MD, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131. E-mail: rohls{at}unm.edu

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


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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