Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study

Wehrle, Flavia M.; Held, Ulrike; O’Gorman, Ruth L.; Disselhoff, Vera; Schnider, Barbara; Fauchère, Jean‐Claude; Hüppi, Petra Susan; Latal, Beatrice; Hagmann, Cornelia

doi:10.1136/bmjopen-2018-022157

Cited by 18 publications

(17 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our pre-clinical results confirm these long-term effects with improved cognitive outcome even at adulthood. Taking these concerns into account, the Swiss study group has already planned a prospective follow-up study aiming to test executive function in their cohort at the age of 7–12 ( 48 , 51 ). In addition to dosage, timing of Epo applications might be a further explanation for inconsistent study results.…”

Section: Discussionmentioning

confidence: 99%

Repetitive Erythropoietin Treatment Improves Long-Term Neurocognitive Outcome by Attenuating Hyperoxia-Induced Hypomyelination in the Developing Brain

et al. 2020

View full text Add to dashboard Cite

Introduction: Preterm infants born before 28 weeks of gestation are at high risk of neurodevelopmental impairment in later life. Cerebral white and gray matter injury is associated with adverse outcomes. High oxygen levels, often unavoidable in neonatal intensive care, have been identified as one of the main contributing factors to preterm brain injury. Thus, preventive and therapeutic strategies against hyperoxia-induced brain injury are needed. Erythropoietin (Epo) is a promising and also neuroprotective candidate due to its clinical use in infants as erythropoiesis-stimulating agent. Objective: The objective of this study was to investigate the effects of repetitive Epo treatment on the cerebral white matter and long-term motor-cognitive outcome in a neonatal rodent model of hyperoxia-induced brain injury. Methods: Three-day old Wistar rats were exposed to hyperoxia (48 h, 80% oxygen). Four doses of Epo (5,000 IU/kg body weight per day) were applied intraperitoneally from P3-P6 with the first dose at the onset of hyperoxia. Oligodendrocyte maturation and myelination were evaluated via immunohistochemistry and Western blot on P11. Motor-cognitive deficits were assessed in a battery of complex behavior tests (Open Field, Novel Object Recognition, Barnes maze) in adolescent and fully adult animals. Following behavior tests animals underwent post-mortem diffusion tensor imaging to investigate long-lasting microstructural alterations of the white matter. Results: Repetitive treatment with Epo significantly improved myelination deficits following neonatal hyperoxia at P11. Behavioral testing revealed attenuated hyperoxia-induced cognitive deficits in Epo-treated adolescent and adult rats. Conclusion: A multiple Epo dosage regimen protects the developing brain against hyperoxia-induced brain injury by improving myelination and long-term cognitive outcome. Though current clinical studies on short-term outcome of Epo-treated prematurely born children contradict our findings, long-term effects up to adulthood are still lacking. Our data support the essential need for long-term follow-up of preterm infants in current clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Repetitive Erythropoietin Treatment Improves Long-Term Neurocognitive Outcome by Attenuating Hyperoxia-Induced Hypomyelination in the Developing Brain

et al. 2020

View full text Add to dashboard Cite

show abstract

“… 34 – 36 The long-term follow-up study (EpoKids) examines whether early administration of high-dose erythropoietin (Epo) in very preterm infants has beneficial effects on executive functions, processing speed and global brain connectivity at school-age. 37 Children were eligible for the EpoKids study if they were included in the 2-year follow-up ( n = 365) of the initial trial. 35 To date, children born between 2005 and 2009 have been approached for the Epokids study ( n = 180).…”

Section: Methodsmentioning

confidence: 99%

“…The neurodevelopmental tasks reported here have been described previously. 37 In short, IQ was estimated with an abbreviated version of the Wechsler Intelligence Scale for Children (WISC-IV, German version). 38 To assess processing speed, the symbol search and coding subtests of the WISC-IV 38 were applied.…”

Section: Methodsmentioning

confidence: 99%

Altered brain metabolism contributes to executive function deficits in school-aged children born very preterm

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Executive function deficits in children born very preterm (VPT) have been linked to anatomical abnormalities in white matter and subcortical brain structures. This study aimed to investigate how altered brain metabolism contributes to these deficits in VPT children at school-age. Methods Fifty-four VPT participants aged 8–13 years and 62 term-born peers were assessed with an executive function test battery. Brain metabolites were obtained in the frontal white matter and the basal ganglia/thalami, using proton magnetic resonance spectroscopy (MRS). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, glutamate + glutamine (Glx)/Cr, and myo-Inositol (mI)/Cr were compared between groups and associations with executive functions were explored using linear regression. Results In the frontal white matter, VPT showed lower Glx/Cr (mean difference: −5.91%, 95% CI [−10.50, −1.32]), higher Cho/Cr (7.39%, 95%-CI [2.68, 12.10]), and higher mI/Cr (5.41%, 95%-CI [0.18, 10.64]) while there were no differences in the basal ganglia/thalami. Lower executive functions were associated with lower frontal Glx/Cr ratios in both groups (β = 0.16, p = 0.05) and higher mI/Cr ratios in the VPT group only (interaction: β = −0.17, p = 0.02). Conclusion Long-term brain metabolite alterations in the frontal white matter may be related to executive function deficits in VPT children at school-age. Impact Very preterm birth is associated with long-term brain metabolite alterations in the frontal white matter. Such alterations may contribute to deficits in executive function abilities. Injury processes in the brain can persist for years after the initial insult. Our findings provide new insights beyond structural and functional imaging, which help to elucidate the processes involved in abnormal brain development following preterm birth. Ultimately, this may lead to earlier identification of children at risk for developing deficits and more effective interventions.

show abstract

“…The first of these, EpoKids, is an ongoing study that includes both school-aged VPT children and typically developing term-born peers. 16 Children were eligible for the current study if they had been assessed between July 2017 and mid-March 2020 (i.e., prior to the implementation of lockdown measures in Switzerland) and their parents had completed a set of questionnaires on child well-being and family functioning as part of the study (n = 221). The second study, Research and Child Health Outcome (ReachOut), followed children with CHD who underwent first cardiopulmonary surgery between 2004 and 2009 at below 6 years of age.…”

Section: Participants and Study Proceduresmentioning

confidence: 99%

Impact of the COVID‐19 pandemic on children with and without risk for neurodevelopmental impairments

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aim To examine how the ongoing COVID‐19 pandemic impacts child well‐being and family functioning, particularly among children at risk for neurodevelopmental impairments. Methods Families of 73 typically developing children, 54 children born very preterm (VPT) and 73 children with congenital heart disease (CHD) from two prospective cohort studies were assessed prior to (mean age: 10.4 [SD: 1.2] years) and during (mean age: 12.8 [SD: 2.0] years) the pandemic, more specifically, in April/May 2020. Child well‐being and family functioning were assessed with validated, parent‐reported questionnaires and tested with linear mixed models. Group comparison of child distress and parental concerns related to medical implications of COVID‐19 and homeschooling, assessed with 5‐point Likert scales, was done with Mann–Whitney U tests. Results Children's psychological well‐being and family functioning (both, p < 0.001) decreased significantly during the pandemic, irrespective of group. Children with CHD were reported to be more concerned about becoming infected with SARS‐CoV‐2 than were others. Child distress due to homeschooling and parents' concerns about children's academic achievements were significantly higher in VPT and CHD children than in typically developing peers (all p < 0.001). Conclusion The COVID‐19 pandemic substantially impacts the whole family and leads to additional distress in families with children at risk for neurodevelopmental impairments. These families should receive individualised counselling and assistance from healthcare providers and schools during the pandemic.

show abstract

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study

Cited by 18 publications

References 55 publications

Repetitive Erythropoietin Treatment Improves Long-Term Neurocognitive Outcome by Attenuating Hyperoxia-Induced Hypomyelination in the Developing Brain

Repetitive Erythropoietin Treatment Improves Long-Term Neurocognitive Outcome by Attenuating Hyperoxia-Induced Hypomyelination in the Developing Brain

Altered brain metabolism contributes to executive function deficits in school-aged children born very preterm

Impact of the COVID‐19 pandemic on children with and without risk for neurodevelopmental impairments

Contact Info

Product

Resources

About