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Original Investigation |

Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age

Russia Ha-Vinh Leuchter, MD1; Laura Gui, PhD1; Antoine Poncet, MSc2; Cornelia Hagmann, MD, PhD3; Gregory Anton Lodygensky, MD1; Ernst Martin, MD4; Brigitte Koller, MD3; Alexandra Darqué, MSc1; Hans Ulrich Bucher, MD3; Petra Susan Hüppi, MD1
[+] Author Affiliations
1Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland
2Clinical Research Center and Division of Clinical Epidemiology, Department of Health and Community Medicine, University of Geneva and University Hospital of Geneva, Geneva, Switzerland
3Division of Neonatology, University Hospital, Zurich, Switzerland
4MR-Center, University Children’s Hospital Zurich, Zurich, Switzerland
JAMA. 2014;312(8):817-824. doi:10.1001/jama.2014.9645.
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Importance  Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies.

Objective  To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age.

Design, Setting, and Participants  A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age.

Interventions  Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.

Main Outcomes and Measures  The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome.

Results  At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89).

Conclusions and Relevance  In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT00413946

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Figure 1.
Participant Flow in the Study of Erythropoietin in Preterm Infants

MRI indicates magnetic resonance imaging.

aInformation about screening prior to randomization is not available.

bFollowing randomization, which occurred before 3 hours of life, exclusion criteria or nonadherence to inclusion criteria (due to errors in reporting of gestational age) were discovered in some infants; thus, they were excluded after randomization. Inclusion criteria: gestational age at birth between 26 weeks and 31 weeks, 6 days of gestation. Exclusion criteria: presence of a genetically defined syndrome, severe congenital malformation adversely affecting life expectancy, or abnormality known to affect neurodevelopment.

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Figure 2.
Examples of T2-Weighted Brain MRI Images for Different WMI Scores

Coronal slices of T2-weighted magnetic resonance imaging (MRI) of 4 different infants and their associated white matter injury (WMI) scores. Gestational age at birth: A, 28 weeks and 4 days; B, 31 weeks and 4 days; C, 30 weeks and 3 days; D, 28 weeks and 6 days.

aGestational age at time of MRI.

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Figure 3.
Empirical Cumulative Distributions of White Matter Injury (WMI) and Gray Matter Injury (GMI) Scores

Plots show the percentage of infants in each group with scores less than or equal to the values shown on the x-axis. The empirical cumulative distribution function is the cumulative distribution function associated with the empirical measure of the sample. For example, the WMI score graph may be interpreted as follows: 40% of the infants in the placebo group had a WMI score of 5, 64% had a WMI score of 6 or less, 80% had a WMI score of 7 or less, etc. In comparison, 78% of infants in the recombinant human erythropoietin group had a WMI score of 6 or less. Theoretical ranges of the WMI and GMI scores are from 5 to 15 and from 3 to 9, respectively.

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