Neonatal biomarkers and morbidity as risk factors for visual impairment in extremely low gestational age newborns
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Being born preterm imposes a risk of increased mortality and numerous morbidities on the infant. Preterm newborns carry their "birth history" with them throughout life; this implies an increased risk of problems related to brain function and vision. What neonatal factors may affect normal brain development and visual function in these children? In this PhD thesis I have used data from the Extremely Low Gestational Age Newborns (ELGAN) study to explore the relationship between ante- and neonatal factors and later visual function in children born before gestational week 28. The ELGAN study is a prospective cohort study designed to identify molecular and clinical exposures that increase the risk of neurological disorders in infants born extremely preterm. Ante- and neonatal data, and information from the follow-up assessment at two years corrected age are included in this thesis. The neonatal data included blood samples collected throughout the first postnatal month. These samples were used to analyze biomarkers related to inflammation (e.g. cytokines), and development of the vascular and nervous system (e.g. vascular growth factors and neurotrophins). Among the biomarkers analyzed, erythropoietin (EPO) was of particular interest. EPO is a growth factor that is important for the development of the vascular and nervous system in utero, and potentially protects the brain from injury. We found high concentrations of EPO in blood the two first neonatal weeks were associated with increased risk of bowel, lung, and retinal diseases in the in the newborn period, while a low EPO concentration was associated with a lowered risk of respiratory problems. Systemic inflammation is a risk factor for both retinopathy of prematurity (ROP) and neonatal brain damage. We were interested in whether specific biomarkers could tell us more about the relationships between inflammation, ROP and later visual problems. Relatively high blood concentrations of systemic inflammatory proteins during the first postnatal month were associated with increased risk of ROP, while top quartile concentrations of growth factors, angiogenic proteins, and neurotrophins correlated with a reduced risk. ROP risk was also evaluated when the sample was stratified by the top concentrations of inflammation associated proteins. Here we found that a high concentration of inflammation-associated proteins did not elevate ROP risk if an angioneurin was simultaneously at a high level. We also studied whether the concentrations of inflammatory biomarkers during the first month of life were associated with later impaired visual function. Here, no correlation between systemic elevated concentrations and strabismus, visual field deficits or inability to visually fixate at age two years was detected. When studying visual field deficits specifically, we found signs of cerebral white matter damage and ROP to be significant antecedents. Through this PhD work I have explored antecedents of ROP and later visual function in infants born extremely preterm, with particular focus on biomarkers measured in systemic circulation. EPO concentrations during the two first neonatal weeks were found to convey information about increased risk of a range of morbidities. Both inflammatory cytokines and neural and vascular growth factors the first month of life were important for ROP development, but no associations were found between these and visual function two years later. On the other hand, damage to the brain and retina was associated with impaired visual function at the two-year assessment. This study adds to the knowledge of the complex etiology of visual impairments related to preterm birth.