Brain Imaging and Developmental Follow up of Infants Treated With Erythropoietin
Condition: Prematurity
MeSH terms: Premature Birth
Study type: Observational

Summary: 
      Approximately 60,000 premature infants are born each year who weigh less than 1,500
      grams,many of whom sustain brain damage because of their prematurity. This study is designed
      to evaluate the long-term developmental effects of one promising neuroprotective
      treatment,erythropoietin (Epo), when given in the neonatal period. Using detailed
      neurodevelopmental testing and state-of-the-art brain imaging, we hope to determine whether
      this is an effective treatment to prevent brain injury associated with prematurity, and to
      lay the groundwork for further studies to improve the developmental outcome of infants
      delivered prematurely.
    

Detailed description: 
      Over twelve percent of infants born less than 1,500 grams (VLBW) sustain brain injury with
      subsequent developmental delay. Although various neuroprotective strategies have been
      evaluated, none have been successful. One promising intervention is the use of recombinant
      erythropoietin (Epo, also known as an erythropoiesis stimulating agent, or ESA). In addition
      to stimulating red cell production, Epo has been shown to be protective in the developing
      brain in animal models. We have preliminary data suggesting its efficacy when used in VLBW
      infants, who are at risk of requiring transfusions, and who are also at risk for brain
      hemorrhage, hypoxicischemic brain injury, and developmental delay. We are currently
      performing a multicentered study evaluating hematopoietic and short term developmental
      effects of ESAs in preterm infants randomized to receive Epo, Darbepoetin alfa (a longer
      acting ESA), or placebo/ control for the first 10 weeks of age (NCT00334737). The first
      enrolled infants will reach 42-48 months in January, 2010. While that study evaluates the
      safety and general short-term developmental effects of ESAs, there is an unprecedented
      opportunity to study long term effects of ESA in significant detail, including evaluating the
      long term developmental effects and the underlying mechanism of neurologic improvement with
      state of the art neuroimaging. This proposal seeks to evaluate longitudinal, long-term
      developmental effects and underlying neurologic mechanisms of ESAs administered to VLBW
      infants in the first 10 weeks of life. Our specific hypotheses are:

      1) ESAs administered to preterm infants during the neonatal period improve long-term
      neurodevelopmental outcome, 2) ESAs affect regional brain structure, neurochemistry and
      neurologic organization as reflected in magnetic resonance (MR) imaging, and 3) the blood
      level of ESA correlates with MR imaging and neurodevelopmental outcome. To test these
      hypotheses, neurodevelopmental outcome will be assessed through a comprehensive
      neurodevelopmental assessment at two time points: 42-48 months, and 66-72 months (WPSSI III,
      Early Child Assessment, Executive Categorization Battery). Brain imaging will be performed
      concurrent with developmental assessments and includes measures of volume (high resolution
      volumetric analysis), neurochemistry (magnetic resonance spectroscopy) and regional cerebral
      blood flow (arterial spin labeling). This study is highly clinically relevant due to the
      long-term developmental and imaging follow up studies that are part of the design,
      significantly increasing our ability to determine if developmental, functional and anatomical
      differences exist in infants randomized to ESAs, a relatively new interventional strategy
      used in preterm infants. This proposal addresses our long-term goal of developing effective
      treatment strategies for disorders associated with prematurity through an improved
      understanding of brain-behavioral relationships.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        All infants previously enrolled in NCT00334737, a randomized masked study of darbepoetin
        administration in preterm infants, are eligible for the study. In addition we will enroll
        term infants matched for age, gender and ethnicity to the preterm group to serve as healthy
        controls.
      
Keywords: brain; development; erythropoietin; neuroprotection; MRI