To Örebro University

Children born extremely preterm (EPT) are at increased risk for brain injury and developmental impairments. CP and non-CP motor difficulties are common. The overall aim of this thesis was to describe longitudinal motor development, deepen understanding of underpinning brain morphology, and study access to motor-related health care in this population.

Study I showed that the prevalence of a non-optimal neurological condition declined with age. Nevertheless, at 12 years, such conditions still remained significantly more frequent among children born EPT than among term-born peers, and were associated with reduced motor function.

Study II found that discrete white matter abnormalities were commonly observed at 8–11 years of age in children born EPT, but were not associated with neurodevelopmental outcomes.

Study III revealed a high prevalence of significant non-CP motor difficulties in children born EPT, although only a small proportion of affected children had received motor-related health care by 5.5 years of age. Access to motor-related health care was associated with bronchopulmonary dysplasia, hyperactivity, and involvement with additional health services beyond physiotherapy.

Study IV demonstrated that children born EPT with discrete white matter abnormalities exhibited greater mean and regional cortical thickness at 10 years of age compared with those without such abnormalities. Fine motorfunction at 2.5 years was a strong predictor of full-scale IQ in children born EPT with discrete white matter abnormalities.

A better understanding of the long-term consequences of EPT birth may, over time, inform strategies to improve clinical care and societal support for these children. Such knowledge can help create conditions that allow children born EPT to fully develop their abilities and reach their developmental potential.

AIM: To describe the cortical brain development and full-IQ performance in middle school age children after extremely preterm (EPT) birth considering discrete white matter abnormalities (WMA). In addition, to assess possible early motor predictors of cortical brain development and full-IQ in children born EPT with and without discrete WMA diagnosed at 10 years. METHODS: T1-weighted MRI images from fifty-one children born before 27 weeks' gestation and 40 full-term born controls (Mage=10.09 years; SDage=0.77) were scored for discrete WMA and analyzed with Freesurfer (v7.2.0). The assessments included motor assessments (i.e., fine- and gross motor function) of Bayley Scales of Infant and Toddler Development - Third Edition (BSID-III) at a mean age of 2½ years. Full-IQ was also assessed with Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) at 12 years. RESULTS: No differences were displayed in motor function or full-IQ score between children born EPT with and without discrete WMA at 10 years. Moreover, no global differences were found in cortex volume. However, bilateral mean cortical thicknesses (CTh) were exhibited to be thicker in children born EPT with discrete WMA. Children born EPT with discrete WMA exhibited regional increases mainly in the frontal and temporal lobes apart from left caudal anterior cingulate gyrus (mean difference = -0.11 (-0.22, -0.01), p = 0.026). Full-IQ was predicted by impairments in fine motor skills in children born EPT with discrete WMA, explaining 42.9% of the variance. CONCLUSIONS: Bilateral mean and regional CTh were found to be greater in children born EPT with discrete WMA at 10 years compared to those without. Fine motor function at 2½ years was a strong predictor of full-IQ dependent in children with discrete WMA.

Aim: To assess prevalence of non-optimal neurological condition and associations with motor function in children born extremely preterm (EPT) up to early adolescence, and to examine potential changes in neurological con-dition between 6.5 and 12 years.

Method: A prospective cohort of one hundred six children (EPT n = 62, term n = 44) was assessed at 6.5 and 12 years. Four domains derived from the Touwen Neurological Examination (coordination and balance, posture and muscle tone, reflexes, and nerve function of the eyes and face) were used to assess the presence of a non-optimal neurological condition (defined as the presence of any abnormal domain). The Movement Assessment Battery for Children 2nd ed. was used to evaluate motor function.

Results: Twenty-seven children born EPT (44%) were assessed as having a non-optimal neurological condition compared with 4 (9%) in the control group (p=<0.001) at 12 years. Between age 6.5 and 12 years the number of children born EPT with a non-optimal neurological condition decreased from 37 to 27 (p = 0.007). At 12 years these children also had significantly lower MABC-2 total test scores, compared to those with normal neurology: median (range) 57 (32-79) versus 75 (43-99), respectively (p=<0.001). The same was shown for subscale scores; manual dexterity (p=<0.001), aiming/catching (p = 0.004), and balance (p = 0.004).

Conclusion: The prevalence of a non-optimal neurological condition reduced with increasing age. However, still, at 12 years, these neurological impairments remained significantly more common in the EPT group than in their term-born peers and was shown to be related to a reduced motor function.

Children born extremely preterm, especially those with intraventricular haemorrhage (IVH), are at increased risk of adverse cognitive outcomes during childhood. The present study aimed to explore the effects of IVH (grades I-II) on hippocampal volumes, and their correlates with cognitive performance. The sample consisted of 94 participants, including 54 children born extremely preterm (19 with IVH, grades I-II), and 40 children born at term. All participants underwent a magnetic resonance imaging study at the age of 10 (M-age = 10.20 years; SDage = 0.78), and 74 of them (45 extremely preterm and 29 full-term) carried out a cognitive assessment at 12 years old. Children born extremely preterm had lower scores in cognitive performance compared to their full-term peers. Significant positive partial correlations were observed between global bilateral hippocampus, left CA-field, and left subiculum volumes with processing speed in the full-term group, while no significant correlations were found in the extremely preterm group. Moderation analyses in the extremely preterm sample revealed that low-grade IVH moderated the relationship between right hippocampal volume and full-IQ (F((4,40) = )5.42, p = 0.001, R-2 = 0.35). Having greater right hippocampal volume had a protective effect on full-IQ in those children born extremely preterm with low-grade IVH.

Aim: Little is known about the prevalence of discrete white matter abnormalities (WMA) beyond the first years in children born extremely preterm (EPT) and the relation to neurodevelopmental outcomes. Our aim was to investigate the prevalence of discrete WMA in children born EPT and the relationship to neonatal white matter injuries (WMI), white matter (WM) volume, WM diffusivity and neurodevelopment.

Methods: The study was a part of a longitudinal follow-up study of EPT neonates. All children were scanned at Karolinska University hospital 2004-2007 (neonates) and 2014-2015 (children at 8-11 years). WMA was qualitatively assessed by visual inspection. Developmental assessment was conducted at 12 years.

Results: In total, 112 children (median age 10.3 years, 56 girls) underwent MRI of the brain (68 EPT, 45 controls). In the EPT group, a subset had MRI around term equivalent age (n = 61). In the EPT group, the prevalence of discrete WMA at 8-11 years was 52%. There was a positive association between WMI at TEA and 8-11 years. There was no association between WMI and WM volumes or diffusivity at 8-11 years. Discrete WMA was not related to neurodevelopmental outcomes.

Conclusion: Discrete WMA was prevalent in children born EPT at 8-11 years but were not related to neurodevelopmental outcomes.