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The general aim of this thesis was to describe the use of early clinical and biochemical biomarkers, and its interpretation for understanding and prediction of brain development and brain injury in preterm infants. The clinical use of early biomarkers and the possible effect of confounders, such as medications was evaluated. Secondly, the relation between single and combined clinical and biochemical biomarkers and their association with brain development were discussed. In Chapter 2, the effect of morphine on aEEG/EEG was evaluated. Morphine administration had a significant effect on quantitative aEEG/EEG measures, causing depression of early brain activity. Furthermore, results suggest that sedatives should always be considered when interpreting aEEG/EEG. In Chapter 3 the role of oxidative stress was investigated. Oxygen, while essential for life, may also generate toxic free radicals species and, in preterm infants, has the potential to cause the “Free Radicals Disease” (FRD). Preterm infants were randomized at birth to receive either 100% oxygen or room air. Significantly higher levels of free radicals were found in the 100% oxygen group. Results from Chapter 3 should alert clinicians that the use of 100% oxygen in the delivery room, may cause lipid as well as protein damage. In Chapter 4, cord blood biomarkers of placental disease were evaluated. OS biomarkers were significantly increased in the histological chorioamnionitis group compared to controls. Significant associations were also found between vascular underperfusion and oxidative injury to proteins. In Chapter 5 the relationship between NIRS and quantitative EEG parameters was investigated in the first few hours after birth in babies < 28 weeks of GA. Oxygen utilization and delivery were associated with quantitative EEG metrics. These results clearly underline that oxygen delivery and utilization are directly related to functional brain activity during the first hours after birth. The results shown in Chapter 5 suggest that the simultaneous monitoring of NIRS and aEEG may be a noninvasive useful biomarker of brain function in high-risk, preterm infants. Chapter 6 we evaluated the changes in brain morphology and microstructure, detected using serial MRI, in relation to early brain activity, monitored with aEEG/EEG in extremely preterm infants. Results showed that increased early brain activity was associated with cerebellar and cortical growth, and with higher microstrusctural growth in the corpus callosum. These results underline the importance of early neuromonitoring in extremely preterm neonates to identify those at risk of altered brain development. In Chapter 7 we tested the hypothesis that early urinary metabolic profile in preterm neonates could predict abnormal MRI score at TEA. ROC curves about urinary metabolic profile could distinguish neonates who later developed a markedly abnormal cortical grey matter and white matter score from the others. Results of Chapter 7 suggest that urine metabolomics is a promising tool for early identification of neonates at high risk of brain damage. The present thesis describes the use and potentialities of biomarkers, their combination and possible use in a clinical setting, which can help clinicians to have more insight into brain development and injury and, thus, to predict outcome.

This thesis focuses on the effect of nutrition on brain development and neurodevelopmental outcome in very (gestational age 28-32 weeks) and extremely (gestational age