Extremely preterm birth : brain imaging and outcome at early school-age

There has been a dramatic increase in the survival of extremely preterm children over the last decades, and the awareness of the consequences of extremely preterm birth on the developing brain is increasing. This thesis aimed at investigating the neurodevelopmental outcome of extremely preterm children at early school-age, focusing on visual-motor integration and motor impairments, and their relation to findings on early magnetic resonance imaging of the brain. We used a population-based cohort study design, including all 6.5 year old children that had been born before 27 gestational weeks during three years in Stockholm for paper I and II, and in the whole of Sweden for Paper III and Paper IV- the EXPRESS (Extremely Preterm infants in Sweden Study) cohort. In paper I we found that the preterm children with and without isolated subtle white matter changes, present on magnetic resonance imaging of the brain at term age in about half of extremely preterm children, was not related to visual-motor integration performance, motor function or other neurodevelopment at 6.5 years. In paper II we found correlations between the extremely preterm children’s neonatal brain volumes in the precentral gyrus, the cerebellum and the brainstem - areas known to be involved in visual-motor integration and fine motor skills – and visual-motor integration performance and/or fine motor skills at 6.5 years of age. In paper III we found that 55% of the preterm children had poor visual-motor integration at 6.5 years compared to term-born controls, 78% among children born at 22-23 weeks, and that visual-motor integration scores were associated with cognitive function and fine motor skills. In paper IV we found that motor impairments, defined as developmental coordination disorder, was common and present in 37.1% of apparently healthy extremely preterm children and in 5.5% of term-born controls (adjusted odds ratio 7.92, 99% confidence interval, 3.69-17.20) at 6.5 years. Developmental coordination disorder was associated with various behavioral problems and lower cognition. In half of the children the parents had not noticed the child´s motor problems. In summary, this thesis demonstrated that the extremely preterm children had affected visual-motor integration and motor function, associated with several other problems, at 6.5 years. Also, extremely preterm children with and without isolated subtle white matter changes had similar neurodevelopment at 6.5 years of age, and neonatal brain volumes correlated with visual-motor integration and fine motor skills scores at 6.5 years, indicating that the brain growth is affected already at the time of expected birth. The thesis provides information that can be used when counselling parents about subtle findings on magnetic resonance imaging, and supports the importance of structured long-term follow-up of extremely preterm children

Perinatal risk factors for developmental coordination disorder in children born extremely preterm

Peer reviewe

Clinical implications of diffuse excessive high signal intensity (DEHSI) on neonatal MRI in school age children born extremely preterm

Objective: Magnetic resonance imaging (MRI) of the brain carried out during the neonatal period shows that 55–80% of extremely preterm infants display white matter diffuse excessive high signal intensity (DEHSI). Our aim was to study differences in developmental outcome at the age of 6.5 years in children born extremely preterm with and without DEHSI.Study Design: This was a prospective cohort study of 83 children who were born in Stockholm, Sweden, between 2004 and 2007, born at gestational age of < 27 weeks + 0 days and who underwent an MRI scan of their brain at term equivalent age. The outcome measures at 6.5 years included testing 66 children with the modified Touwen neurology examination, the Movement Assessment Battery for Children 2, the Wechsler Intelligence Scale for Children—Fourth Edition, Beery Visual-motor Integration test—Sixth Edition, and the Strengths and Difficulties Questionnaire. Group-wise comparisons were done between children with and without DEHSI using Student t-test, Mann Whitney U test, Chi square test and regression analysis.Results: DEHSI was detected in 39 (59%) of the 66 children who were assessed at 6.5 years. The presence of DEHSI was not associated with mild neurological dysfunction, scores on M-ABC assessment, cognition, visual-motor integration, or behavior at 6.5 years.Conclusion: The presence of qualitatively defined DEHSI on neonatal MRI did not prove to be a useful predictor of long-term impairment in children born extremely preterm

Minor neurological dysfunction and associations with motor function, general cognitive abilities, and behaviour in children born extremely preterm

AIM: To study the prevalence of minor neurological dysfunction (MND) at 6 years of age in a cohort of children born extremely preterm without cerebral palsy (CP) and to investigate associations with motor function, cognitive abilities, and behaviour.METHOD: This study assessed 80 children born at less than 27 weeks of gestation and 90 children born at term age between 2004 and 2007 at a mean age of 6 years 6 months. The assessments included a simplified version of the Touwen Infant Neurological Examination, the Movement Assessment Battery for Children, Second Edition (MABC-2), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), the Strengths and Difficulties Questionnaire (SDQ), and the parent version of the Five to Fifteen questionnaire.RESULTS: Fifty-one of the children born preterm had normal neurology, 23 had simple MND, and six had complex MND compared with 88 who had normal neurology and two simple MND in the term-born group (p<0.001). There were significant differences between the children with normal neurology and MND in the preterm group in MABC-2-assessed motor function (p<0.001), general cognitive abilities with WISC-IV (p=0.005), and SDQ overall behavioural problems and peer problems reported by the parents (p=0.021 and p=0.003 respectively). SDQ teacher-reported overall behavioural and hyperactivity problems were significantly different between children with normal and simple MND (p=0.036 and p=0.019).INTERPRETATION: Children born extremely preterm, in the absence of CP, are at risk of MND and this is associated with motor function, cognitive ability, and behaviour.WHAT THIS PAPER ADDS: Extremely preterm birth carries a risk of minor neurological dysfunction (MND). MND in children born extremely preterm is associated with impaired motor function and cognitive abilities, and behavioural problems. Male sex is associated with MND in children born extremely preterm

Adverse motor outcome after paediatric ischaemic stroke : A nationwide cohort study

Background Various frequencies of adverse motor outcomes (cerebral palsy and hemiplegia) after paediatric ischaemic stroke have been reported. Few reports on the risks of adverse motor outcomes in nationwide cohorts and contributing risk factors are available. Objectives To assess risk of adverse motor outcome and potential risk factors thereof after paediatric ischaemic stroke in a nationwide cohort. Methods This nationwide matched cohort study identified 877 children &amp;lt;18 years of age diagnosed with ischaemic stroke through the Swedish national health registers from 1997 to 2016. These children, exposed to ischaemic stroke, alive 1 week after stroke, were matched for age, sex and county of residence with 10 unexposed children. Using Cox regression, we estimated the risk of adverse motor outcomes in children with stroke compared to that in unexposed children. Logistic regression was applied to compare the characteristics of children with and without adverse motor outcomes after stroke. Results Out of the 877 children with ischaemic stroke, 280 (31.9%) suffered adverse motor outcomes compared with 21 (0.2%) of the 8770 unexposed: adjusted hazard ratio (aHR) 167.78 (95% confidence interval (CI) 107.58, 261.66). There were no differences between risk estimates of adverse motor outcome according to age at stroke: perinatal stroke (aHR 124.11, 95% CI 30.45, 505.84) and childhood stroke (aHR 182.37, 95% CI 113.65, 292.64). An association between adverse motor outcome and childhood stroke aOR 1.56 (95% CI 1.05, 2.31) was found when analysing only children with ischaemic stroke. No associations were found between adverse motor outcome and sex, gestational age or parental age at birth. Conclusions The risk of adverse motor outcome is substantial after paediatric ischaemic stroke, especially childhood stroke, confirming results of previous smaller studies. This study found no associations between sex, gestational age or parental age and adverse motor outcome after paediatric ischaemic stroke.Funding Agencies|Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation; Region Ostergotland Research Council; Jerring foundation; Petrus and Augusta Hedlunds foundation; Sachs children and youth hospital; Linnea and Josef Carlsson foundation</p

Association of Perinatal and Childhood Ischemic Stroke With Attention-Deficit/Hyperactivity Disorder

IMPORTANCE Early detection of attention-deficit/hyperactivity disorder (ADHD) plays a crucial role in reducing negative effects on everyday life, including academic failure and poor social functioning. Children who survive ischemic strokes risk major disabilities, but their risk of ADHD has not been studied in nationwide cohorts. OBJECTIVE To assess the risk of ADHD in children after pediatric ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS Participants in this Swedish nationwide cohort study included 1320 children diagnosed with ischemic stroke recorded in linked Swedish national registers from January 1, 1969, to December 31, 2016, without prior ADHD diagnosis. Ten matched controls were identified for each index case, and first-degree relatives were identified for index individuals and controls. Analyses were stratified by perinatal and childhood strokes and presence of comorbid adverse motor outcomes and/or epilepsy. End of follow-up was the date of ADHD diagnosis, death, or December 31, 2016, whichever occurred first. Data analyses were performed August 1 to 28, 2021. EXPOSURES Pediatric ischemic stroke. MAIN OUTCOMES AND MEASURES Attention-deficit/hyperactivity disorder identified using codes from the International Classification of Diseases, Ninth Revision, and international Statistical Classification of Diseases and Related Health Problems, Tenth Revision, and/or prescribed ADHD medication recorded in the Medical Birth Register, National Patient Register, or Prescribed Drug Register after stroke. Cox proportional hazards regression was used to assess adjusted hazard ratios (aHRs) for ADHD after pediatric stroke, adjusting for parental age and ADHD in first-degree relatives. RESULTS Of 1320 children with stroke included in the analysis (701 boys [53.1%]), 75 (45 boys [60.0%]) were diagnosed with ADHD after stroke compared with 376 (252 boys [67.0%]) among the controls (aHR, 2.00 [95% CI, 1.54-2.60]). The risk was increased after both perinatal (aHR, 2.75 [95% CI, 1.65-4.60]) and childhood (aHR, 1.82 [95% CI, 1.34-2.48]) strokes and were similar if children born preterm or small for gestational age were excluded. Compared with controls, risks of ADHD were higher among children with perinatal stroke and adverse motor outcomes and/or epilepsy (aHR, 6.17 [95% CI, 2.80-13.62]) than among those without these comorbidities (aHR, 1.65 [95% CI, 0.80-3.42]). However, findings were similar in childhood stroke for children with adverse motor outcomes and/or epilepsy (aHR, 1.80 [95% CI, 1.12-2.89]) and among those without these comorbidities (aHR, 1.92 [95% CI, 1.28-2.90]). CONCLUSIONS AND RELEVANCE This cohort study of 1320 children with pediatric ischemic stroke suggests that there is an increased risk of ADHD. particularly in children with adverse motor outcomes and/or epilepsy, compared with controls. The risk increases after childhood strokes regardless of comorbidities.Funding Agencies|Knut and AliceWallenberg Foundation; Jerring Foundation; Crown Princess Lovisas Foundation; Petrus and Augusta Hedlunds Foundation; Sachs Children and Youth Hospital; Samariten Foundation; Linnea and Josef Carlsson Foundation; Region Stockholm [2019-1138]; Region Ostergotland Research Council</p

Neurological development in children born moderately or late preterm: national cohort study

International audienceAbstract Objective To assess long term neurodevelopmental outcomes of children born at different gestational ages, particularly 32-33 weeks (moderately preterm) and 34-36 weeks (late preterm), compared with 39-40 weeks (full term). Design Nationwide cohort study. Setting Sweden. Participants 1 281 690 liveborn singleton children without congenital malformations born at 32 +0 to 41 +6 weeks between 1998 and 2012. Main outcome measures The primary outcomes of interest were motor, cognitive, epileptic, hearing, and visual impairments and a composite of any neurodevelopmental impairment, diagnosed up to age 16 years. Hazard ratios and 95% confidence intervals were estimated using Cox regression adjusted for parental and infant characteristics in the study population and in the subset of full siblings. Risk differences were also estimated to assess the absolute risk of neurodevelopmental impairment. Results During a median follow-up of 13.1 years (interquartile range 9.5-15.9 years), 75 311 (47.8 per 10 000 person years) liveborn singleton infants without congenital malformations had at least one diagnosis of any neurodevelopmental impairment: 5899 (3.6 per 10 000 person years) had motor impairment, 27 371 (17.0 per 10 000 person years) cognitive impairment, 11 870 (7.3 per 10 000 person years) epileptic impairment, 19 700 (12.2 per 10 000 person years) visual impairment, and 20 393 (12.6 per 10 000 person years) hearing impairment. Children born moderately or late preterm, compared with those born full term, showed higher risks for any impairment (hazard ratio 1.73 (95% confidence interval 1.60 to 1.87) and 1.30 (1.26 to 1.35); risk difference 4.75% (95% confidence interval 3.88% to 5.60%) and 2.03% (1.75% to 2.35%), respectively) as well as motor, cognitive, epileptic, visual, and hearing impairments. Risks for neurodevelopmental impairments appeared highest from 32 weeks (the earliest gestational age), gradually declined until 41 weeks, and were also higher at 37-38 weeks (early term) compared with 39-40 weeks. In the sibling comparison analysis (n=349 108), most associations remained stable except for gestational age and epileptic and hearing impairments, where no association was observed; for children born early term the risk was only higher for cognitive impairment compared with those born full term. Conclusions The findings of this study suggest that children born moderately or late preterm have higher risks of adverse neurodevelopmental outcomes. The risks should not be underestimated as these children comprise the largest proportion of children born preterm. The findings may help professionals and families achieve a better risk assessment and follow-up

Extreme prematurity and perinatal risk factors related to extremely preterm birth are associated with complex patterns of regional brain volume alterations at 10 years of age: a voxel-based morphometry study

ObjectiveStructural brain volumetric differences have been investigated previously in very preterm children. However, children born extremely preterm, at the border of viability, have been studied to a lesser degree. Our group previously analyzed children born extremely preterm at term using voxel-based morphometry. In this study, we aimed to examine regional gray and white matter differences for children born extremely preterm derived from the same cohort during childhood. We also aimed to explore the effect of perinatal risk factors on brain volumes in the same group.MethodsAt 10 years of age, 51 children born extremely preterm (before 27 weeks and 0 days) and 38 term-born controls with high-quality 3.0 Tesla magnetic resonance images were included. Statistical analyses using voxel-based morphometry were conducted on images that were normalized using age-specific templates, modulated, and smoothed. Analyses were also performed in stratified groups of children born extremely preterm in the absence or presence of perinatal risk factors that have previously been shown to be associated with volumetric differences at term.ResultsWe found volumetric decreases in gray and white matter in the temporal lobes, gray matter decreases in the precuneus gyri, and white matter decreases in the anterior cingulum for children born extremely preterm (all p &lt; 0.001, and pfwe &lt; 0.05). Gray and white matter increases were predominantly observed in the right posterior cingulum and occipital lobe (all p &lt; 0.001, and pfwe &lt; 0.05). Of the examined perinatal risk factors, intraventricular hemorrhage grades I-II compared with no intraventricular hemorrhage and patent ductus arteriosus ligation compared with no treated patent ductus arteriosus or patent ductus arteriosus treated with ibuprofen led to volumetric differences at 10 years of age (all p &lt; 0.001, and pfwe &lt; 0.05).ConclusionsChildren born extremely preterm exhibit volumetric alterations in a pattern overlapping that previously found at term, where many regions with differences are the main hubs of higher order networks. Some, but not all, risk factors known to be associated with structural alterations at term were associated with alterations at 10 years of age

Cerebral visual impairment captured with a structured history inventory in extremely preterm born children aged 6.5 years

Abstract Purpose To investigate whether a questionnaire can identify cerebral visual impairment (CVI) in a group of 6.5-year-old children born extremely preterm (EPT) as accurately as direct assessments. Methods This prospective population-based study included 120 children born before 27 weeks\u2019 gestational age (66 males; mean, 25.4 \ub1 1.0 weeks) and 97 full-term controls (56 males; mean, 39.9 \ub1 1.1 weeks) at the age of 6.5 years, as part of the Extremely Preterm Infants in Sweden Study (EXPRESS). A questionnaire for detection of CVI was evaluated and compared with visual, perceptual, and cognitive assessments. Results Parents of children born EPT reported more CVI features than the parents of control children, with median sum scores of 25 (95% CI, 18.1-31.9) and 11 (95% CI, 8.8-13.2), respectively (P &lt; 0.001), and a median difference of 14 (95% CI, 6.6-21.4). Low rates of reported CVI features were significantly associated with better results from direct assessments within the EPT group and with less pronounced differences compared to controls. Conclusions The questionnaire discriminated well between children born EPT and controls, and the scores were congruent with other evidence of visual, perceptual, and cognitive deficits. The easily used questionnaire compared favorably with direct assessment in identifying CVI in children born EPT and also provides valuable information to clinicians, pedagogues, and parents about the daily life problems associated with CVI

Outcomes at 6.5 years in children with and without DEHSI.

<p>Outcomes at 6.5 years in children with and without DEHSI.</p