PEDIATRICS Vol. 118 No. 3 September 2006, pp. e635-e640 (doi:10.1542/peds.2005-3186)
ARTICLE |
Erythropoietin Concentrations and Neurodevelopmental Outcome in Preterm Infants
a Department of Pediatrics, University of Arizona, Tucson, Arizona
b Department of Pediatrics and Pathology, University of New Mexico, Albuquerque, New Mexico
| ABSTRACT |
|---|
|
|
|---|
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: NICHDNational Institute of Child Health and Human Development PMApostmenstrual age ELBWextremely low birth weight ROPretinopathy of prematurity MDIMental Development Index PDIPsychomotor Development Index CSFcerebrospinal 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.510 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 |
|---|
|
|
|---|
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 (401750 and 7511000 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
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 |
|---|
|
|
|---|
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.
|
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).
|
|
|
| DISCUSSION |
|---|
|
|
|---|
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.1921 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.510,2224 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.510,25,26 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.3133 However, none of the randomized, masked, placebo-controlled studies reported an increased incidence of this neonatal morbidity, even in the smallest infants studied.1,3437 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 |
|---|
|
|
|---|
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 |
|---|
|
|
|---|
- 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
[Abstract/Free Full Text] - Soubasi V, Kremenopoulos G, Diamanti E, Tsantali C, Sarafidis K, Tsakiris D. Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. J Pediatr. 1995;127 :291 297[CrossRef][Web of Science][Medline]
- Newton NR, Leonard CH, Piecuch RE, Phibbs RH. Neurodevelopmental outcome of prematurely born children treated with recombinant human erythropoietin in infancy. J Perinatol. 1999;19 :403 406[CrossRef][Medline]
- Ohls RK, Ehrenkranz RA, Das A, et al. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron.
Pediatrics. 2004;114
:1287
1291
[Abstract/Free Full Text] - Siren A-L, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.
Proc Natl Acad Sci U S A. 2001;98
:4044
4049
[Abstract/Free Full Text] - Grasso G, Buemi M, Alafaci C, et al. Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage.
Proc Natl Acad Sci U S A. 2002;99
:5627
5631
[Abstract/Free Full Text] - Wen TC, Sadamoto Y, Tanaka J, et al. Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J Neurosci Res. 2002;67 :795 803[CrossRef][Web of Science][Medline]
- Solaroglu I, Solaroglu A, Kaptanoglu E, et al. Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst. 2003;19 :19 22[Web of Science][Medline]
- Chong ZZ, Kang J-Q, Maiese K. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br J Pharmacol. 2003;138 :1107 1118[CrossRef][Web of Science][Medline]
- Demers EJ, McPherson RJ, Juul SE. Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia. Pediatr Res. 2005;58 :297 301[CrossRef][Web of Science][Medline]
- Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276 :357 368[Web of Science][Medline]
- The Committee for the Classification of Retinopathy of Prematurity. An international classification for retinopathy of prematurity.
Arch Ophthalmol. 1984;102
:1130
1134
[Abstract/Free Full Text] - 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 1500 grams. J Pediatr. 1978;92 :529 534[CrossRef][Web of Science][Medline]
- Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33 :179 201[Web of Science][Medline]
- Hamill PV, Drizd TA, Johnson TA, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles.
Am J Clin Nutr. 1979;32
:607
629
[Abstract/Free Full Text] - 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][Medline]
- Shannon KM, Mentzer WC, Abels RI, Freeman P, Newton N. 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][Medline]
- Gumy-Pause F, Ozsahin H, Mermillod B, Cingria L, Berner M, Wacker P. Stepping up versus standard doses of erythropoietin in preterm infants, a randomized controlled trial. J Pediatr Hematol Oncol. 2005;22 :667 678[CrossRef]
- Croce MA, Tolley EA, Claridge JA, Fabian TC. Transfusions result in pulmonary morbidity and death after a moderate degree of injury. J Trauma. 2005;59 :19 23[Web of Science][Medline]
- Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group.
N Engl J Med. 1999;340
:409
417
[Abstract/Free Full Text] - Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients.
JAMA. 2002;288
:1499
1507
[Abstract/Free Full Text] - Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int. 1995;47 :740 745[Web of Science][Medline]
- Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells.
J Neurosci. 2001;21
:9733
9743
[Abstract/Free Full Text] - Dame C, Bartmann P, Wolber E, Fahnenstich H, Hofmann D, Fandrey J. Erythropoietin gene expression in different areas of the developing human central nervous system. Dev Brain Res. 2000;125 :69 74[Medline]
- Juul SE. Erythropoietin in the central nervous system and its use to prevent hypoxic-ischemic brain damage. Acta Paediatr Suppl. 2002;438 :36 42
- Sola A, Wen TC, Hamrick SE, Ferriero DM. Potential for protection and repair following injury to the developing brain: a role for erythropoietin? Pediatr Res. 2005;57 :110R 117R[CrossRef][Web of Science][Medline]
- Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8 :495 505[Web of Science][Medline]
- Juul SE, Stallings SA, Christensen RD. Erythropoietin in the cerebrospinal fluid of neonates who sustained CNS injury. Pediatr Res. 1999;46 :543 547[Web of Science][Medline]
- Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.
N Engl J Med. 2005;353
:782
792
[Abstract/Free Full Text] - Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury.
Proc Natl Acad Sci U S A. 2002;99
:10659
10664
[Abstract/Free Full Text] - Liu A, Dunbar J, Neimeyer M, et al. Recombinant human erythropoietin treatment and incidence of retinopathy of prematurity. Pediatr Res. 2004;55 :531A
- Brown MS, Baron AE, France EK, Hamman RF. Association between higher cumulative doses of recombinant erythropoietin and risk for retinopathy of prematurity. J AAPOS. 2006; 10: 143149[CrossRef][Medline]
- Shah NC, Kim MR, Jadav P, Cohen LM, Jean Baptiste D, Weedon J. Effect of recombinant human erythropoietin (rhEPO) on the development of retinopathy of prematurity. Pediatr Res. 2005;57 :546
- 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] - 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
[Abstract/Free Full Text] - Maier RF, Obladen M, Muller-Hansen I, et al. Early treatment with erythropoietin ß 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]
- 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[CrossRef][Web of Science][Medline] - Patel S, Rowe M, Ohls RK. Erythropoietin protein expression in the developing human eye. Pediatr Res. 2006; 59: 3593.432
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
This article has been cited by other articles:
![]() |
V. Degos, G. Loron, J. Mantz, and P. Gressens Neuroprotective Strategies for the Neonatal Brain Anesth. Analg., June 1, 2008; 106(6): 1670 - 1680. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Okumura, H. Kidokoro, T. Kato, T. Kubota, F. Hayakawa, K. Kuno, and K. Watanabe A Pilot Study on Cord Blood Levels of Erythropoietin and Its Relationship to Periventricular Leukomalacia in Preterm Infants J Child Neurol, February 1, 2008; 23(2): 231 - 234. [Abstract] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||







