The Effect of High-Dose Erythropoietin Perinatally on Retinal Function in School-Aged Children Born Extremely or Very Preterm.

PURPOSE: To investigate the long-term effects of high-dose recombinant human erythropoietin (rhEPO) administered during the perinatal period on retinal and visual function in children born extremely or very preterm. DESIGN: Randomized, double-blind clinical trial follow-up plus cohort study. METHODS:  Setting: Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland. STUDY POPULATION: Extremely or very preterm-born children aged 7 to 15 years, previously randomized to receive either high-dose rhEPO or placebo in the perinatal period. INCLUSION CRITERIA: participation in an ongoing neuropediatric study (EpoKids), written informed consent. EXCLUSION CRITERIA: previous ocular trauma or surgery; retinal or developmental disease unrelated to prematurity. Healthy control (HC) children of comparable age were recruited. INCLUSION CRITERIA: term birth, informed consent. EXCLUSION CRITERIA: any ocular/visual abnormality, high refractive error. Intervention status (rhEPO/placebo) was unknown to examiners and subjects at examination, with examiners unblinded only after completion of all analyses. OBSERVATION PROCEDURES: The electroretinogram (ERG) was performed with the RETeval device (LKC Technologies, Inc). Ophthalmological and orthoptic examinations excluded comorbidity in the prematurely born cohort and ocular diseases in the HC group. MAIN OUTCOME MEASURES: Scotopic and photopic ERG response amplitudes and peak times (6 amplitudes; 6 peak times). Secondary outcomes were habitual visual acuity and color discrimination performance (for descriptive summary only). RESULTS: No differences in ERG parameters between EPO (n = 52; 104 eyes) and placebo (n = 35; 70 eyes) subgroups were observed (all corrected P > .05). Two cone system-mediated peak times were slightly slower in the placebo than HC (n = 52; 104 eyes) subgroup (coefficient/95% confidence interval = 0.53/0.21-0.85 and 0.36/0.13-0.60; P = .012 and .022); a predominantly rod system-mediated peak time was slightly faster in the EPO than the HC subgroup (coefficient/95% confidence interval = -4.33/-6.88 to -1.78; P = .011). Secondary outcomes were comparable across subgroups. CONCLUSIONS: Administration of high-dose rhEPO to infants born extremely or very preterm during the perinatal period has no measurable effects on retinal function in childhood compared to placebo. Premature birth may cause small, likely clinically insignificant effects on retinal function in childhood, which may be partially mitigated by administration of rhEPO during the perinatal period.

The Effect of Perinatal High-Dose Erythropoietin on Retinal Structural and Vascular Characteristics in Children Born Preterm.

PURPOSE: To study the long-term effects of perinatal high-dose recombinant human erythropoietin (rhEPO) on macular structural and vascular development in preterm children. DESIGN: Randomized, double-blind clinical trial follow-up plus cohort study. METHODS: Setting: Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland. STUDY POPULATION: extremely or very preterm born children aged 7-15 years from an ongoing neuropediatric study (EpoKids). These had been previously randomized to receive either high-dose rhEPO or placebo perinatally. INCLUSION CRITERIA: participation in the EpoKids Study, written informed consent (IC). EXCLUSION CRITERIA: previous ocular trauma or surgery; retinal or developmental disease unrelated to prematurity. Term-born children of comparable age were enrolled as a healthy control (HC) group. INCLUSION CRITERIA: term birth, IC. EXCLUSION CRITERIA: any ocular or visual abnormality, high refractive error. Examiners were blinded regarding intervention status until completion of all analyses. (Participants/guardians remain blinded). OBSERVATION PROCEDURES: Spectral-domain OCT scans (Heidelberg Spectralis system) and OCTA imaging (Zeiss PlexElite 9000) were obtained. Ophthalmological and orthoptic examinations excluded ocular comorbidities. MAIN OUTCOME MEASURES: OCT (central retinal thickness, CRT; total macular volume, TMV), superficial plexus OCTA (foveal avascular zone, FAZ; vessel density, VD; vessel length density, VLD) parameters and foveal hypoplasia grade according to published criteria. RESULTS: Macular vessel density parameters (VD and VLD) were significantly lower (p =0.015, CI-95: 0.01 to 0.06 and p=0.015, CI-95: 0.74 to 3.64) in the EPO group (n= 52) when compared to placebo (n=35). No other significant differences were observed between the EPO and placebo group. When comparing the intervention subgroups to HC we found six significant differences in OCT and OCTA parameters (FAZ, VD, VLD and CRT comparing HC and EPO group; FAZ and CRT when comparing HC and placebo group). CONCLUSIONS: Early high-dose rhEPO in infants born extremely or very preterm affects macular vessel density parameters compared to placebo. Premature birth (regardless of intervention status) affects retinal structure and vascular development. Our findings on macular vascular development do not contraindicate the administration of early high-dose EPO in preterm infants. For further understanding of the role of EPO on macular development and its clinical significance, future studies are needed.

Inhibition abilities and functional brain connectivity in school-aged term-born and preterm-born children.

BACKGROUND: Inhibition abilities are known to have impact on self-regulation, behavior, and academic success, and they are frequently impaired in children born preterm. We investigated the possible contributions of resting-state functional brain connectivity to inhibition following preterm birth. METHODS: Forty-four preterm and 59 term-born participants aged 8-13 years were administered two inhibition tasks and resting-state functional MRI was performed. Functional connectivity (FC) networks were compared between groups using network-based statistics. Associations of FCNs and inhibition abilities were investigated through multivariate linear regression models accounting for the interaction between birth status and inhibition. RESULTS: NBS revealed weaker FC in children born preterm compared to term-born peers in connections between motor and supplementary motor regions, frontal lobe, precuneus, and insula. Irrespective of birth status, connections between the cerebellum, frontal, and occipital lobes and inter-lobar, subcortical, intra-hemispheric long-range connections were positively correlated with one of the two inhibition tasks. CONCLUSIONS: Preterm birth results in long-term alterations of FC at network level but these FCN alterations do not specifically account for inhibition problems in children born very preterm. IMPACT: Irrespective of birth status, significant associations were found between the subdomain of response inhibition and functional connectivity in some subnetworks. A group comparisons of functional brain connectivity measured by rsfMRI in school-aged children born very preterm and at term. The investigation of network-level functional connectivity at rest does not appear adequate to explain differences in inhibition abilities between children born very preterm and at term, hence other imaging techniques might be more suited to explore the underlying neural mechanisms of inhibition abilities in school-aged children born very preterm.

Cerebral perfusion differences are linked to executive function performance in very preterm-born children and adolescents.

Children and adolescents born very preterm are at risk of cognitive impairment, particularly affecting executive functions. To date, the neural correlates of these cognitive differences are not yet fully understood, although converging evidence points to a pattern of structural and functional brain alterations, including reduced brain volumes, altered connectivity, and altered brain activation patterns. In very preterm neonates, alterations in brain perfusion have also been reported, but the extent to which these perfusion alterations persist into later childhood is not yet known. This study evaluated global and regional brain perfusion, measured with arterial spin labelling (ASL) MRI, in 26 very preterm children and adolescents and 34 term-born peers. Perfusion was compared between groups and relative to executive function (EF) scores, derived from an extensive EF battery assessing working memory, cognitive flexibility, and planning. Very preterm children and adolescents showed regions of altered perfusion, some of which were also related to EF scores. Most of these regions were located in the right hemisphere and included regions like the thalamus and hippocampus, which are known to play a role in executive functioning and can be affected by prematurity. In addition, perfusion decreased with age during adolescence and showed a significant interaction between birth status and sex, such that very preterm girls showed lower perfusion than term-born girls, but this trend was not seen in boys. Taken together, our results indicate a regionally altered perfusion in very preterm children and adolescents, with age and sex related changes during adolescence.

Mental sequelae of the COVID-19 pandemic in children with and without complex medical histories and their parents: well-being prior to the outbreak and at four time-points throughout 2020 and 2021.

The objective of this study is to understand the long-term mental sequelae for families over the course of the COVID-19 pandemic by longitudinally investigating the well-being of children with and without complex medical histories and their parents. Well-being of 200 children (between 7 and 18 years of age; 73 typically developing, 46 born very preterm, 73 with complex congenital heart disease) and 175 of their parents was assessed prior to and during the first (April-May 2020), second (October-November 2020), third (April-May 2021), and fourth wave (October-November 2021) of the pandemic with standardized questionnaires. Linear mixed models were used to investigate longitudinal changes in child and parent well-being compared to before the pandemic. Social and COVID-19-specific determinants were investigated as predictors of impaired well-being. To illustrate clinical relevance, the proportion of children and parents scoring > 1 SD below normative mean/median was reported. Compared to before the pandemic, child proxy-reported well-being was lower during the first but not the second, third, and fourth waves. Child self-reported well-being was not lower during the pandemic compared to before. Parent well-being dropped during the first wave and remained low throughout the subsequent waves. Proxy-reported child and self-reported parent well-being was lower in families with sparse social support and poor family functioning. Parents of typically developing children reported lower well-being than parents of children born very preterm or with a complex congenital heart disease. In November 2021, 20% of children (both self- and proxy-report) and 24% of parents scored below the normal range compared to 11% (child self-report), 10% (child proxy-report), and 16% (parent self-report), respectively, before the pandemic. The pandemic continues to impact the well-being of parents of school-aged children with and without complex medical histories more than 1 year after its outbreak. Children's well-being was specifically affected during the first wave of the pandemic and has recovered thereafter. Families with sparse social support and poor family functioning are particularly at risk for compromised well-being and support should be provided to them.

Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial.

Importance: Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. Objective: To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. Design, Setting, and Participants: Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. Interventions: Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. Main Outcomes and Measures: Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). Results: Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. Conclusions and Relevance: This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02076373.

Similarities and Differences in the Neurodevelopmental Outcome of Children with Congenital Heart Disease and Children Born Very Preterm at School Entry.

OBJECTIVE: To describe the similarities and differences in the neurodevelopmental outcome of children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery compared with children born very preterm (VPT) at school entry. STUDY DESIGN: IQ, motor abilities, behavior, and therapy use were assessed in 155 children with CHD as part of a prospective, single-center, longitudinal study, and in 251 children born VPT as part of a national follow-up register at the same center. Group differences were tested using independent t-tests and χ2-tests. Equivalence testing was used to investigate similarities between the groups. RESULTS: Mild (ie, 70 ≤ IQ < 85) and severe intellectual impairments (ie, IQ < 70) occurred in 17.4% and 4.5% of children with CHD compared with 22.1% and 5.5% in children VPT, respectively. Motor and behavioral functions were impaired in 57.0% and 15.3% of children with CHD compared with 37.8% and 11.5% of children born VPT, respectively. Children with CHD had poorer global motor abilities (d = -0.26) and poorer dynamic balance (d = -0.62) than children born VPT, and children born VPT had poorer fine motor abilities than children with CHD (d = 0.34; all P < .023). Peer problems were statistically similar between the groups (P = .020). Therapies were less frequent in children with CHD compared with children born VPT (23.4% vs 40.3%; P < .001). CONCLUSIONS: Children with CHD undergoing cardiopulmonary bypass surgery and children born VPT share an overall risk for neurodevelopmental impairments that manifest in different domains. Despite this, children with CHD receive fewer therapies, indicating a lack of awareness of the neurodevelopmental burden these children face.

Postoperative Improvement of Brain Maturation in Infants With Congenital Heart Disease.

Children with severe congenital heart disease are at risk for neurodevelopmental impairments. We examined brain maturation in infants undergoing neonatal cardiopulmonary bypass surgery or hybrid procedure for hypoplastic left heart syndrome compared to controls. This is a prospective cohort study on term-born infants with congenital heart disease with cerebral MRI pre- and postoperatively. Healthy infants served as controls. Brain maturation was measured using a semiquantitative scoring system. The progress of brain maturation from the preoperative to postoperative MRI within patients was compared. Neurodevelopment was assessed at 1 year with the Bayley Scales of Infant and Toddler Development III. A total of 92 patients with congenital heart disease and 46 controls were studied. Median total maturation score in patients was 12 (interquartile range 10.6-13.0) preoperatively and 14 (12.0-15.0) postoperatively, in controls it was 14 (13.0-15.0). Median time interval between scans was 19 days (interquartile range 14-26). After correction for postmenstrual age at MRI, the pre- and postoperative maturation score was lower in patients compared to controls (preoperative P = 0.01, postoperative P = 0.03) and increased between pre- and postoperative assessment (P ≤ 0.001). Brain maturation scores did not correlate with neurodevelopmental outcome at 1 year, when corrected for socioeconomic status and postmenstrual age at MRI. This study confirms delayed brain maturation in children with congenital heart disease, and despite neonatal cardiac bypass surgery followed by postoperative intensive care medicine brain maturation is ongoing. We encourage further investigation in outcome prediction in this population, potentially by combining more advanced MRI measures with clinical methods.

Effects of Correcting for Prematurity on Executive Function Scores of Children Born Very Preterm at School Age.

OBJECTIVE: To investigate whether correction for prematurity affects executive function scores in school-aged children born very preterm. STUDY DESIGN: Executive functions were assessed with standardized neuropsychological tests in 142 children born very preterm (born at ≤32 weeks of gestational age or with a birth weight of ≤1500 g) and 391 control children, aged 7-13 years. Four-month age bands were established from the data of control children. Differences between uncorrected and corrected scores were compared against zero difference and between very preterm children born before and after 28 weeks of gestation. Regression models were used to compare the uncorrected and corrected scores of children born very preterm with control children. RESULTS: For all executive functions, significant, larger-than-zero differences between uncorrected and corrected scores were apparent in children born very preterm. Mean differences ranged from 0.04 to 0.18 SDs. Weak evidence was found that the effect of age correction is more pronounced in very preterm children born before 28 weeks of gestation than in those born after 28 weeks. Differences in executive function scores between children born very preterm and control children were attenuated if scores were corrected for prematurity. CONCLUSIONS: Test scores based on corrected rather than uncorrected age may more accurately determine the developmental stage of very preterm children's executive functions at school age. Potential consequences for clinical and research practice need to be discussed in the future.

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

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.

Inhibition is associated with whole-brain structural brain connectivity on network level in school-aged children born very preterm and at term.

Inhibition abilities are often impaired in children born very preterm. In typically-developing individuals, inhibition has been associated with structural brain connectivity (SC). As SC is frequently altered following preterm birth, this study investigated whether aberrant SC underlies inhibition deficits in school-aged children born very preterm. In a group of 67 very preterm participants aged 8-13 years and 69 term-born peers, inhibition abilities were assessed with two tasks. In a subgroup of 50 very preterm and 62 term-born participants, diffusion tensor imaging (DTI) data were collected. Using network-based statistics (NBS), mean fractional anisotropy (FAmean) was compared between groups. Associations of FAmean and inhibition abilities were explored through linear regression. The composite score of inhibition abilities was lower in the very preterm group (M â€‹= â€‹-0.4, SD â€‹= â€‹0.8) than in the term-born group (M â€‹= â€‹0.0, SD â€‹= â€‹0.8) but group differences were not significant when adjusting for age, sex and socio-economic status (ߠ​= â€‹-0.13, 95%-CI [-0.30, 0.04], p â€‹= â€‹0.13). In the very preterm group, FAmean was significantly lower in a network comprising thalamo-frontal, thalamo-temporal, frontal, cerebellar and intra-hemispheric connections than in the term-born group (t â€‹= â€‹5.21, lowest p-value â€‹= â€‹0.001). Irrespective of birth status, a network comprising parietal, cerebellar and subcortical connections was positively associated with inhibition abilities (t â€‹= â€‹4.23, lowest p-value â€‹= â€‹0.02). Very preterm birth results in long-term alterations of SC at network-level. As networks underlying inhibition abilities do not overlap with those differing between the groups, FAmean may not be adequate to explain inhibition problems in very preterm children. Future studies should combine complementary measures of brain connectivity to address neural correlates of inhibition abilities.

Executive function deficits mediate the association between very preterm birth and behavioral problems at school-age.

BACKGROUND & AIMS: Children and adolescents born very preterm are at increased risk to develop executive function deficits and to suffer from social, emotional and attentional problems. This study investigated whether executive function deficits contribute to behavioral problems in children and adolescents born very preterm at school-age. STUDY DESIGN: Thirty-eight children and adolescents born very preterm and 41 age-matched term-born peers were assessed at a mean age of 12.9 (±1.8) years with a comprehensive battery of executive function tests, including working memory, planning, cognitive flexibility, and verbal fluency. A composite score was calculated to reflect overall executive function abilities. To assess behavioral problems, parents completed the Strengths and Difficulties Questionnaire (SDQ). Mediation analysis was applied to quantify the effect of preterm birth on behavioral problems with executive function abilities as a mediating variable. RESULTS: Executive function abilities were poorer in the very preterm compared to the term-born group (d = 0.62, p = .005) and the parents of very preterm children reported more behavioral problems on the SDQ Total Difficulties Score (d = 0.54, p = .01). The effect of birth status on behavioral problems was significantly mediated by executive function abilities while adjusting for age at assessment, sex, and socioeconomic status (F(2, 76) = 6.42, p = .002, R2 = 0.14). CONCLUSION: Results from this study suggest that the increase in behavioral symptoms in very preterm children at school-age compared to term-born peers may partly be explained by their executive function deficits. These findings highlight the importance of continuously monitoring the development of children born very preterm to provide optimal care as they grow up.

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r â€‹= â€‹.53 â€‹± .10; range â€‹= â€‹0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 â€‹± .06; 0.35 to 0.51 and 0.43 â€‹± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r â€‹= â€‹.43 â€‹± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r â€‹= â€‹-.53 â€‹± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.

Altered resting-state functional connectivity in children and adolescents born very preterm short title.

The formation of resting-state functional networks in infancy has been reported to be strongly impacted by very preterm birth. Studies in childhood and adolescence have largely focused on language processing networks and identified both decreased and increased functional connectivity. It is unclear, however, whether functional connectivity strength is altered globally in children and adolescents born very preterm and whether these alterations are related to the frequently occurring cognitive deficits. Here, resting-state functional MRI was assessed in a group of 32 school-aged children and adolescents born very preterm with normal intellectual and motor abilities and 39 healthy term-born peers. Functional connectivity within and between a comprehensive set of well-established resting-state networks was compared between the groups. IQ and executive function abilities were tested with standardized tasks and potential associations with connectivity strength were explored. Functional connectivity was weaker in the very preterm compared to the term-born group between the sensorimotor network and the visual and dorsal attention network, within the sensorimotor network and within the central executive network. In contrast, functional connectivity was stronger in the very preterm group between the sensorimotor network and parts of the salience and the central executive network. Little evidence was found that these alterations underlie lower IQ or poorer executive function abilities. This study provides evidence for a long-lasting impact of very preterm birth on the organization of resting-state networks. The potential consequence of these alterations for other neurodevelopmental domains than the ones investigated in the current study warrants further investigation.

Sleep EEG maps the functional neuroanatomy of executive processes in adolescents born very preterm.

Executive function deficits are among the most frequent sequela of very preterm birth but the underlying neuronal mechanisms are not fully understood. We used high-density electroencephalography (EEG) recordings during sleep to assess alterations in the functional neuroanatomy of executive processes in adolescents born very preterm. The topographical distribution of sleep slow wave activity (SWA; 1-4.5 Hz EEG power) has previously been used to map cognitive abilities and is known to reflect the intensity of the prior use of the respective neuronal networks. We assessed 38 adolescents born before 32 weeks of gestation [age at assessment: 12.9 (SD: 1.7), range: 10.6-16.7 years] and 43 term-born peers [13.1 (2.0), 10.0-16.9]. Executive function abilities were quantified with a composite score derived from a comprehensive task battery. All-night high-density EEG (128 electrodes) was recorded and SWA of the first hour of sleep was calculated. Abilities were significantly poorer in the very preterm compared to the term-group, particularly, if the tasks demands were high (p < .01). The score was positively correlated with sleep SWA in a cluster of 15 electrodes over frontal and negatively in a cluster of 14 electrodes over central brain regions after controlling for age at assessment and correcting for multiple comparisons. Within the frontal cluster, sleep SWA was higher in very preterm compared to term-born participants when controlling for executive function performance and age at assessment (p = .02). No difference in SWA between very preterm and term-born participants was found for the central cluster (p = .29). Our results demonstrate a local increase of sleep SWA over brain regions associated with executive processes in adolescents born very preterm compared to similarly performing term-born peers. Thus, sleep SWA seems to map the higher effort needed for executive function tasks in adolescents born very preterm.

Very preterm adolescents show impaired performance with increasing demands in executive function tasks.

BACKGROUND: Very preterm birth is often associated with executive function deficits later in life. The transition to adolescence increases personal autonomy, independence and, in parallel, the demands placed on executive functions at home and in school. AIM: To assess the impact of increasing demands on executive function performance in very preterm children and adolescents with normal intellectual and motor functions. METHODS: Forty-one very preterm children and adolescents with normal intellectual and motor functions and 43 healthy term-born peers were assessed at a mean age of 13.0 years (SD: 1.9; range: 10.0-16.9). A comprehensive battery of performance-based executive function measures with different demand levels as well as a parent-rating questionnaire evaluating executive functions relevant for everyday life was applied. Standardized mean differences between groups of d ≥ .41 were regarded as clinically relevant. RESULTS: No group differences were found at the lowest demand levels of working memory (d=.09), planning (d=-.01), cognitive flexibility (d=-.21) and verbal fluency (d=-.14) tasks, but very preterm participants scored significantly below their term-born peers in the most demanding levels (d=-.50, -.59, -.43 and -.55, respectively). These differences were clinically relevant. Executive functions relevant for everyday life were strongly impaired in very preterm participants, e.g., global executive composite (d=-.66). CONCLUSION: Very preterm children and adolescents with normal intellectual and motor functions are at high risk for executive function deficits that may only become apparent with increasing demands, potentially leading to academic and other deficits.

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair).

BACKGROUND: Preterm infants suffering from intraventricular hemorrhage (IVH) are at increased risk for neurodevelopmental impairment. Observational data suggest that recombinant human erythropoietin (rEPO) improves long-term cognitive outcome in infants with IVH. Recent studies revealed a beneficial effect of early high-dose rEPO on white matter development in preterm infants determined by magnetic resonance imaging (MRI). OBJECTIVES: To summarize the current evidence and to delineate the study protocol of the EpoRepair trial (Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants). METHODS: The study involves a review of the literature and the design of a double-blind, placebo-controlled, multicenter trial of repetitive high-dose rEPO administration, enrolling 120 very preterm infants with moderate-to-severe IVH diagnosed by cranial ultrasound in the first days of life, qualitative and quantitative MRI at term-equivalent age and long-term neurodevelopmental follow-up until 5 years of age. RESULTS AND CONCLUSIONS: The hypothesis generated by observational data that rEPO may improve long-term cognitive outcomes of preterm infants suffering from IVH are to be confirmed or refuted by the randomized controlled trial, EpoRepair.

Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants.

Despite improved survival, many preterm infants undergo subsequent neurodevelopmental impairment. To date, no neuroprotective therapies have been implemented into clinical practice. Erythropoietin, a haematopoietic cytokine used for treatment of anaemia of prematurity, has been shown to have neuroprotective and neuroregenerative effects on the brain in many experimental studies. The aim of the study was to assess the effect of recombinant human erythropoietin on the microstructural development of the cerebral white matter using tract-based spatial statistics performed at term equivalent age. A randomized, double-blind placebo-controlled, prospective multicentre study applying recombinant human erythropoietin in the first 42 h after preterm birth entitled 'Does erythropoietin improve outcome in preterm infant' was conducted in Switzerland (NCT00413946). Preterm infants were given recombinant human erythropoietin (3000 IU) or an equivalent volume of placebo (NaCl 0.9%) intravenously before 3 h of age after birth, at 12-18 h and at 36-42 h after birth. High resolution diffusion tensor imaging was obtained at 3 T in 58 preterm infants with mean (standard deviation) gestational age at birth 29.75 (1.44) weeks, and at scanning at 41.1 (2.09) weeks. Imaging was performed at a single centre. Voxel-wise statistical analysis of the fractional anisotropy data was carried out using tract-based spatial statistics to test for differences in fractional anisotropy between infants treated with recombinant human erythropoietin and placebo using a general linear model, covarying for the gestational age at birth and the corrected gestational age at the time of the scan. Preterm infants treated with recombinant human erythropoietin demonstrated increased fractional anisotropy in the genu and splenium of the corpus callosum, the anterior and posterior limbs of the internal capsule, and the corticospinal tract bilaterally. Mean fractional anisotropy was significantly higher in preterm infants treated with recombinant human erythropoietin than in those treated with placebo (P < 0.001). We conclude that early recombinant human erythropoietin administration improves white matter development in preterm infants assessed by diffusion tensor imaging and tract-based spatial statistics.

Adaptive neonate brain segmentation.

Babies born prematurely are at increased risk of adverse neurodevelopmental outcomes. Recent advances suggest that measurement of brain volumes can help in defining biomarkers for neurodevelopmental outcome. These techniques rely on an accurate segmentation of the MRI data. However, due to lack of contrast, partial volume (PV) effect, the existence of both hypo- and hyper-intensities and significant natural and pathological anatomical variability, the segmentation of neonatal brain MRI is challenging. We propose a pipeline for image segmentation that uses a novel multi-model Maximum a posteriori Expectation Maximisation (MAP-EM) segmentation algorithm with a prior over both intensities and the tissue proportions, a B0 inhomogeneity correction, and a spatial homogeneity term through the use of a Markov Random Field. This robust and adaptive technique enables the segmentation of images with high anatomical disparity from a normal population. Furthermore, the proposed method implicitly models Partial Volume, mitigating the problem of neonatal white/grey matter intensity inversion. Experiments performed on a clinical cohort show expected statistically significant correlations with gestational age at birth and birthweight. Furthermore, the proposed method obtains statistically significant improvements in Dice scores when compared to the a Maximum Likelihood EM algorithm.

Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in Uganda: study protocol.

BACKGROUND: There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective. AIMS: Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine:(i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles(ii) The temperature profile of encephalopathic infants with standard care(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age METHODS/DESIGN: Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months. DISCUSSION: We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future. TRIAL REGISTRATION: Current controlled trials ISRCTN92213707.