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Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children and adolescents

English title Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children and adolescents
Applicant Hagmann Cornelia Franziska
Number 169733
Funding scheme Project funding (Div. I-III)
Research institution Kinderspital Zürich Universitäts-Kinderklinik
Institution of higher education University of Zurich - ZH
Main discipline Paediatrics
Start/End 01.02.2017 - 31.01.2021
Approved amount 464'481.00
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Keywords (5)

Executive function; Connectomics; Erythropoetin; Preterm children; Neuroprotection

Lay Summary (German)

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children and adolescentsLangfristige neuroprotektive Effekte des Erythropoietin auf exekutive Funktionen bei frühgeborenen Kindern und JugendlichenFrühgeborene Kinder haben ein erhöhtes Risiko für kognitive Beeinträchtigung, im speziellen den exekutiven Funktionen. Langfristiger Effekt von bei der Geburt verabreichten Erythropoetin soll am Kinderspital Zürich untersucht werden in diesem Projekt.
Lay summary

Inhalt und Ziele des Forschungsprojektes

Frühgeborene Kinder haben ein erhöhtes Risiko für motorische und kognitive Beeinträchtigungen infolge von perinatalen Hirnläsionen; etwa 10% der überlebenden Kinder entwickeln zerebrale Parese, und etwa 50% entwickeln kognitive Probleme und Verhaltensauffälligkeiten. Zwischen 2005 und 2012 wurde in der Schweiz die erste randomisierte neuroprotektive Studie durchgeführt, bei welcher Frühgeborenen nach der Geburt innerhalb den ersten 3 Tagen Erythropoetin oder Placebo erhielten.

Dieses Projekt untersucht die Langzeitwirkung des früh applizierten Erythropoetin auf die exekutiven Funktionen und auf die Hirnentwicklung im Alter von 7-12 Jahren. Die exekutiven Funktionen werden mittel Computer- und Papier-basierten Tests untersucht, die schulischen Leistungen werden erfasst und sowie Details zu der Lebensqualität.  Eine Magnetresonanzuntersuchung wird durchgeführt, um die globale funktionelle Konnektivität darzustellen. Beide Therapiegruppen (Epo/Plazebo) werden miteinander verglichen, um einen Langzeiteffekt des früh applizierten Erythropoetin festzustellen.


Wissenschaftliche und gesellschaftlicher Kontext des Forschung Projektes

Dies ist ein prospektives Follow-up Projekt der randomisierten Erythropoetin Studie “Does erythropoietin (Epo) improve outcome in preterm infants” (NCT00413946). 450 Kinder wurden damals rekrutiert, 365 Kinder können in dieser Follow-up Studie angefragt werden.  Verbesserte Exekutive Funktionen werden nicht nur den Schulerfolg erhöhen sondern auch die Lebensqualität nicht nur der Kinder aber auch derer Familie.

Falls aufgezeigt werden kann, dass die frühe Gabe von Erythropoetin die exekutiven Funktionen im Schulalter verbessert, kann diese neuroprotektive Gabe eingeführt werden und die kognitive Funktionen vieler Frühgeborener Kinder verbessert werden.


Key words

Neuroprotection, executive functions, brain development, preterm birth

Direct link to Lay Summary Last update: 24.01.2017

Responsible applicant and co-applicants


Associated projects

Number Title Start Funding scheme
172914 Executive function and brain maturation in children with severe congenital heart disease: A window of opportunity for intervention 01.09.2018 Project funding (Div. I-III)


Background: Premature infants are particular vulnerable to brain injury. As a consequence of perinatal acquired brain injury, five to 10% of the survivors develop cerebral palsy, and 40-50% develop cognitive and behavioural deficits; and higher-order cognitive function impairment such as executive function deficits are very frequent in this population. These impairments may influence the academic success and the quality of life of the children born preterm and their families. Hence, brain injury and its consequences in preterm infants is a serious issue that needs to be addressed, as it remains a substantial economic and public health burden. To date, no postnatal neuroprotective agent has been implemented into clinical care of preterm infants. The worldwide first randomised neuroprotective interventional trial entitled “Does erythropoietin (Epo) improve outcome in preterm infants” was initiated in Switzerland with Zurich being the lead hospital and included 450 very preterm infants. Imaging at term-equivalent age showed less white matter injury in those infants exposed to prophylactic high dose recombinant human erythropoietin compared to those treated with placebo. However, despite these promising imaging findings, neurodevelopmental outcome at two years showed no beneficial effect of early Epo on cognitive and motor outcome. One possible explanation could be that assessment of more complex cognitive functions such as executive functions is only possible at later age. Hypothesis: We therefore hypothesise that due to improved white matter development and less white injuries seen on imaging, children and adolescents born preterm which were treated with high-dose Epo will have better higher-order cognitive functions such as executive functions at 8-11 years of age than those treated with placebo. Aims: (i) to assess the long-term effects on early Epo on higher-order cognitive functions such as executive functions at 8 to 11 year of age; (ii) to compare global connectivity using magnetic resonance imaging between the two treatment groups and to correlate global connectivity measures with executive functions and (iii) to correlate longitudinal brain growth with executive functions Methods: Children born preterm and enrolled in the trial entitled “Does erythropoietin (Epo) improve outcome in preterm infants” (NCT00413946) will be recruited at the age of 8-11 years (n=366). A variety of performance-based and rating scale measures will be applied to test the three core executive functions: Working memory, Inhibition and Cognitive flexibility. Planning abilities and verbal fluency will be assessed as well. Motor and verbal processing speed will be assessed within the different executive function tests. The test battery includes both computerized and paper-pencil tasks. The Behaviour Rating Inventory of Executive Function for parents will be used to investigate whether executive function deficits translate into daily life of their child. The parents will also be asked to report on the school performance of their children and basic academic skills such as reading, writing and mathematical skills will be assessed. For general behaviour assessment, the strength and difficulties questionnaire will be applied. T1 and T2 weighted 3D images, diffusion weighted imaging and multicomponent relaxometry (McDESPOT) will be acquired to examine structural and functional connectivity, global network connectivity and myelination. Expected value of the project: If we can show that children and adolescents born preterm treated with early erythropoietin have better executive functions and hence better school skills than those treated with placebo, we can start to implement this neuroprotective and safe strategy into clinical practice, and hence improve long-term higher-order cognitive functions. Better executive functions will lead to an improvement in academic success and in the quality of life of children and adolescents born preterm and of their families. This will have a great impact not only on the involved children and their families but also on the public health and school systems.