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Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study
  1. Flavia Maria Wehrle1,2,3,
  2. Ulrike Held4,
  3. Ruth Tuura O’Gorman2,5,
  4. Vera Disselhoff1,2,
  5. Barbara Schnider1,2,
  6. Jean-Claude Fauchère6,
  7. Petra Hüppi7,
  8. Beatrice Latal2,3,
  9. Cornelia Franziska Hagmann1,2
  1. 1 Department of Neonatology and Pediatric Intensive Care, University Children’s Hospital Zurich, Zurich, Switzerland
  2. 2 Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
  3. 3 Child Development Center, University Children’s Hospital Zurich, Zurich, Switzerland
  4. 4 Department Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
  5. 5 MR Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland
  6. 6 Department of Neonatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
  7. 7 Division of Child Development and Growth, Department of Paediatrics, Geneva University, Geneva, Switzerland
  1. Correspondence to Dr Cornelia Franziska Hagmann; cornelia.hagmann{at}


Introduction Premature infants are particularly vulnerable to brain injuries with associated cognitive and behavioural deficits. The worldwide first randomised interventional multicentre trial investigating the neuroprotective effects of erythropoietin (entitled ‘Does erythropoietin improve outcome in very preterm infants?’ (NCT00413946)) included 450 very preterm infants in Switzerland. MRI at term equivalent age showed less white matter (WM) injury in the erythropoietin group compared with the placebo group. Despite these promising imaging findings, neurodevelopmental outcome at 2 years showed no beneficial effect of early erythropoietin. One explanation could be that the assessment of more complex cognitive functions such as executive functions (EFs) is only possible at a later age. We hypothesise that due to improved WM development and fewer WM injuries, children born preterm treated with early erythropoietin will have better EF abilities at 7–12 years than those treated with placebo.

Methods and analysis 365 children who were included into the primary analysis of the original trial (NCT00413946) will be eligible in this prospective follow-up study at the age of 7–12 years. 185 children born at term will be control children. Primary outcome measures are EF abilities and processing speed, while secondary outcomes are academic performance, IQ, fine motor abilities and global brain connectivity. A comprehensive test battery will be applied to assess EFs. MRI will be performed to assess global brain connectivity. Cognitive scores and MRI measures will be compared between both groups using the Wilcoxon test. Propensity score matching will be used to balance gender, age, socioeconomic status and other potentially unbalanced variables between the children born preterm and the healthy control children.

Ethics and dissemination The cantonal ethical committee granted ethical approval for this study (KEK 2017-00521). Written consent will be obtained from the parents. Findings from this study will be disseminated via international and national conference presentations and publications in peer-reviewed journals.

  • neuroprotection
  • preterm birth
  • executive function
  • neuroimaging

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  • Contributors CFH, FW, RTOG, UH and BL were involved in the study design. FW, BS, VD and CFH were responsible for conceiving ethical approval. CFH, FW, RTOG and UH wrote the first draft of the manuscript. CFH, FW, RTOG, UH, BL, PH, J-CF, VD and BS commented and critically reviewed drafts of the paper.

  • Funding This project is supported by the Swiss National Science Foundation (grant number 320030_169733), the Gottfried and Julia Bangerter-Rhyner Foundation, the Hartmann Müller Foundation and the Uniscientia Foundation.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval The cantonal ethical committee of Zurich, Switzerland, granted ethical approval for this study in May 2017 (KEK 2017-00521).

  • Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.

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