The Effects of Erythropoietin (EPO) on the Transfusion Requirements of Very Low Birth Weight Infants (EPO)

The Effects of Erythropoietin (EPO) on the Transfusion Requirements of Preterm Infants 401-1250 Grams: Two Multi-Center, Randomized, Double-Masked, Placebo Controlled Studies

This study tested the safety and efficacy of transfusing erythropoietin (Epo) and iron in infants of <1,250g birth weight. For infants 401-1,000g birth weight, we tested whether early erythropoietin (Epo) and iron therapy would decrease the number of transfusions received. For infants 1,001-1,250g birth weight, we tested whether early erythropoietin (Epo) and iron therapy would decrease the percentage of infants who received any transfusions.

Study Overview

• Status: Completed
• Conditions: Anemia, Neonatal; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Drug: Erythropoietin; Other: Sham Comparator

Detailed Description

Critically ill preterm infants experience in the first 1-2 weeks after birth daily blood losses that may equal 5-10% of their total blood volume. Such losses and associated anemia typically result in multiple erythrocyte transfusions. This iatrogenic anemia commonly is followed by the anemia of prematurity, prompting additional transfusions.

This study tested the safety and efficacy of transfusing erythropoietin (Epo) and iron in infants of <1,250g birth weight. For infants 401-1,000g birth weight (Trial 1), we tested whether early erythropoietin (Epo) and iron therapy would decrease the number of transfusions received. For infants 1,001-1,250g birth weight (Trial 2), we tested whether early erythropoietin (Epo) and iron therapy would decrease the percentage of infants who received any transfusions.

Therapy was initiated by day of life 4 and continued through the 35th postmenstrual week. Infants were randomized to receive either Epo and iron therapy or a sham procedure. Treated infants received 400 U/kg Epo 3 times weekly and a weekly intravenous infusion of 5 mg/kg iron dextran until they had an enteral intake of 60 mL/kg/d. Infants in the placebo/control group received sham subcutaneous injections when intravenous access was not available. Complete blood and reticulocyte counts were measured weekly, and ferritin concentrations were measured monthly.

Transfusions were administered according to protocol. Infants did not receive a transfusion solely to replace blood lost through phlebotomy. Infants who met transfusion criteria received a transfusion of 15 mL/kg packed red blood cells (PRBC) for a hematocrit of >25% or 20 mL/kg PRBC for a hematocrit of <=25%. Blood losses and transfusion data were recorded.

Trial 2 was terminated after enrollment of 118 infants after the Data and Safety Monitoring Committee reviewed the final results of Trial 1 and preliminary results of Trial 2. On the basis of these data, the Committee concluded that it was statistically unlikely that Trial 2 would demonstrate a significant decrease in the percentage of infants who would receive a transfusion during the study.

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20052
      • George Washington University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02138
      • Harvard University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 months (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants with a birth weight of 4010-1250g, <32 weeks' gestation, and 24-96 hours old at the time of study entry
• Likely to survive >72 hours
• Informed consent from a parent or guardian.

Exclusion Criteria:

• 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)
• Absolute neutrophil count (ANC) of <=500/micro-L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Trial 1 Experimental; Infants 401-1,000g birthweight	Drug: Erythropoietin; Infants received 400 U/kg Erythropoietin (Epo) 3 times weekly and a weekly intravenous infusion of 5 mg/kg iron dextran until they had an enteral intake of 60 mL/kg/d.; Other Names: Human recombinant erythropoietin
SHAM_COMPARATOR: Trial 1: Sham Comparator; Infants 401-1,000g birthweight	Other: Sham Comparator; Infants in the placebo/control group received sham subcutaneous injections when intravenous access was not available.
EXPERIMENTAL: Trial 2: Experimental; Infants 1,001-1,250g birth weight	Drug: Erythropoietin; Infants received 400 U/kg Erythropoietin (Epo) 3 times weekly and a weekly intravenous infusion of 5 mg/kg iron dextran until they had an enteral intake of 60 mL/kg/d.; Other Names: Human recombinant erythropoietin
SHAM_COMPARATOR: Trial 2: Sham Comparator; Infants 1,001-1,250g birth weight	Other: Sham Comparator; Infants in the placebo/control group received sham subcutaneous injections when intravenous access was not available.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Erythrocyte transfusions in infants 401-1,000g birthweight	Hospital discharge or 35 weeks postmenstrual age
Blood transfusions	Hospital discharge or 35 weeks postmenstrual age

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Ann R. Stark, MD, Brigham and Women's Hospital; Study Director: Robin K. Ohls, MD, University of New Mexico

Publications and helpful links

General Publications

• Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, Stark AR, Shankaran S, Donovan EF, Close NC, Das A. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics. 2001 Oct;108(4):934-42. doi: 10.1542/peds.108.4.934.
• Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, Delaney-Black V, Papile LA, Simon NP, Steichen JJ, Lee KG; National Institute of Child Health and Human Development Neonatal Research Network. 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 Nov;114(5):1287-91. doi: 10.1542/peds.2003-1129-L.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: August 1, 1997
• Primary Completion (ACTUAL): August 1, 1998
• Study Completion (ACTUAL): August 1, 2000

Study Registration Dates

• First Submitted: September 15, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (ESTIMATE): September 16, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 26, 2017
• Last Update Submitted That Met QC Criteria: September 22, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Prematurity; Phlebotomy; Blood loss; NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW); Erythrocyte transfusions; Erythropoietin (Epo)
• Additional Relevant MeSH Terms: Hematologic Diseases; Infant, Newborn, Diseases; Body Weight; Anemia; Birth Weight; Anemia, Neonatal; Hematinics; Epoetin Alfa
• Other Study ID Numbers: NICHD-NRN-0017; U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD021415 (U.S. NIH Grant/Contract); U10HD027881 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); M01RR006022 (U.S. NIH Grant/Contract); M01RR000750 (U.S. NIH Grant/Contract); M01RR000997 (U.S. NIH Grant/Contract); U10HD034167 (U.S. NIH Grant/Contract); M01RR000039 (U.S. NIH Grant/Contract); M01RR001032 (U.S. NIH Grant/Contract); M01RR002172 (U.S. NIH Grant/Contract); M01RR002635 (U.S. NIH Grant/Contract)