From the DEPARTMENT OF WOMEN’S AND CHILDREN’S HEALTH Karolinska Institutet, Stockholm, Sweden BRAIN IMAGING IN EXTREMELY PRETERM INFANTS – RELATIONS TO PERINATAL FACTORS AND OUTCOME

The survival of extremely preterm infants has improved over the last decades along with the advances in perinatal care. These immature children are born at a vulnerable stage of brain development, before entering the third trimester of gestation, and are at an increased risk for brain injuries, atypical brain development and subsequent adverse neurodevelopment. The overall aim of the works compiled in this thesis was to qualitatively and quantitatively study brain structure and volumes in extremely preterm infants at term equivalent age, and to investigate associations with neonatal risk factors and with infant and toddler age outcomes. Infants born before 27 gestational weeks in Stockholm during a four-year period were eligible for these studies. They underwent conventional Magnetic Resonance Imaging and Diffusion Tensor Imaging at term equivalent age. Conventional T1and T2weighted images were visually inspected using a scoring system for white and grey matter abnormalities. Automatic segmentation and Voxel-based morphometry with DARTEL registration were used to analyze global and regional volumes of grey and white matter. White matter microstructure was investigated with Diffusion Tensor Imaging, and analyzed using Tract-Based Spatial Statistics and Region of Interest analysis. In Paper I we investigated whether prematurity per se or perinatal risk factors could explain altered brain structure after preterm birth in extremely preterm infants without focal brain lesions on visual inspection of MRI. Brain white matter microstructural differences were investigated between extremely preterm infants and term born healthy controls using Tract-Based Spatial Statistics and subsequently associations with perinatal risk factors were explored. White matter microstructure was influenced by preterm birth and by neonatal respiratory factors, whereas the degree of prematurity within the extremely preterm range (23 – 26+6 weeks) appeared to be of less importance within the narrow range. In Paper II, the incidence of another possible, frequently present but inadequately studied, perinatal risk factor for adverse brain development, hyperglycemia, and its relation to mortality and white matter abnormalities on visual inspection of conventional MRI was studied. Hyperglycemia on the first day after birth was identified as an independent risk factor for increased mortality rates and brain damage, in terms of white matter reduction. In Paper III, the relationship between white matter microstructural and morphometric brain differences at term equivalent age and hyperglycemia in extremely preterm infants was explored with Tract-Based Spatial Statistics and Voxel-based morphometry. Early hyperglycemic exposure was associated with altered diffusion measures in major white matter tracts and reduction of regional white and grey matter volumes. In Paper IV, sex differences in brain development and neurodevelopmental outcome in children born extremely preterm were studied. In addition, associations with neonatal brain morphology were assessed with conventional structural and diffusion MRI. Sex related differences were observed on neonatal structural MRI, including differences in the patterns of correlations between brain volumes and developmental scores at both global and regional levels. Cognitive and language outcome at age 30 months was poorer in boys than in girls. LIST OF PUBLICATIONS I. Georgios Alexandrou, Gustaf Mårtensson, Beatrice Skiöld, Mats Blennow, Ulrika Ådén, Brigitte Vollmer. White Matter Microstructure Is Influenced By Extremely Preterm Birth And Neonatal Respiratory Factors. Acta Paediatr. 2013 Oct 4. doi: 10.1111/apa.12445. II. Georgios Alexandrou, Beatrice Skiöld, Jonna Karlén, Mesfin K. Tessma, Mikael Norman, Ulrika Ådén and Mireille Vanpée. Early Hyperglycemia Is A Risk Factor For Death And White Matter Reduction In Preterm Infants. Pediatrics 2010;125;e584; doi: 10.1542/peds.2009-0449. III. Georgios Alexandrou, Nelly Padilla, Gustaf Mårtensson, Finn Lennartsson, Mirelle Vanpee, Brigitte Vollmer, Ulrika Ådén. White Matter Microstructure And Brain Growth In Extremely Preterm Infants With Early Hyperglycemia.