Development of novel biomarkers for brain injury and neurodevelopmental outcome in birth asphyxia

Abstract

Background: Hypoxic-ischemic encephalopathy (HIE) in term infants following intrapartum asphyxia remains an important problem occurring in 1-3 of 1000 births with high risk of cerebral palsy, cognitive impairment and functional disability later in life. Therapeutic hypothermia (TH) is the only treatment available today for HIE. To be effective TH must start within 6 hours from delivery. It is not always possible to diagnose HIE in this time frame which can lead to infants at risk of developing brain injuries not receiving TH in time. Antecedent infections are known to increase the risk of adverse outcome. It would therefore be helpful to find biomarkers to assist in early identification of both asphyxia/HIE and infection. Aim: Explore novel biomarkers of brain injury and inflammation/infection in the umbilical cord blood (UCB) to assist in the early identification of cases with HIE and to evaluate association between the biomarkers and neurodevelopmental outcome at 19-42 months of age. Material and methods: In Paper I, II and IV we have analysed UCB levels of biomarkers in neonates with HIE, with asphyxia without HIE and healthy controls without asphyxia and HIE. The concentration of biomarkers was measured and correlated to asphyxia and to the degree of HIE (mild, moderate and severe) and neurodevelopmental outcome at 19-42 months of age. Paper III is a systematic review summarising the research done over the last decades on biomarkers in UCB and their associations with HIE and neurodevelopmental outcome. Results: In Paper I we found that the neuro-specific biomarkers NFL and tau were significantly higher in UCB in neonates with asphyxia compared to a healthy control group. In Paper II we showed that NFL, tau, GFAP and several cytokines were significantly higher in infants with moderate and severe HIE compared to a healthy control group and provided moderate prediction of moderate and severe HIE. The systematic review, Paper III, revealed that there were several studies highlighting promising biomarkers in UCB that could be subjects for future studies, both individually and in combination with existing clinical markers. We also concluded that it can be critical to distinguish between arterial and venous blood. In Paper IV we found an association between levels of immunoinflammatory biomarkers and growth factors and abnormal neurodevelopmental outcome at 19-42 months of age. Conclusion: This thesis concludes that there are several neuro-specific and immuno-inflammatory biomarkers in UCB that can assist in early identification of HIE and long-term neurodevelopmental outcome.