CRADLE - Circadian Rhythm Alteration anD neonataL Encephalopathy

Abstract

Background: Neonatal Encephalopathy (NE) is a clinically defined syndrome of disturbed neurological function in the earliest days of life in term and near-term newborns. NE remains a major cause of mortality and morbidity in the neonatal population, but remains poorly defined. An increasing number of interventions are available for infants at risk of adverse neurodevelopmental outcome, but prognostication remains a significant challenge with diagnostic uncertainty with MRI and biochemical biomarkers. Dysregulated immune function is associated with worse outcome in NE. Circadian rhythms (CR) have an important role in the regulation of the immune system. Studies have shown that infants with NE and dysregulated CRs have worse outcomes. We investigated different diagnostic criteria of NE, the prognostic value of MRI and different biomarkers in NE, the evidence for melatonin treatment for those with NE, and the influence of melatonin on systemic inflammation in NE.

Methods: Systematic reviews were conducted according to PRISMA or Cochrane guidelines. Patients with NE and age-matched controls were recruited during the first week of life and blood samples obtained. Samples were examined ex-vivo to assess the response in serum cytokine production, inflammasome gene and circadian gene expression, neutrophil and monocyte cell marker expression, and microRNA gene expression to melatonin treatment and LPS stimulation. Sleep quality and sleep wake cycling was analysed and correlated with measures of systemic inflammation.

Results: NE remains poorly defined and inconsistent diagnostic criteria are applied. A significant but unclear distinction between NE and hypoxic ischaemic encephalopathy (HIE) persists despite many attempts over recent years. MRI provides superior prognostic accuracy compared to other techniques, and MR spectroscopy provides the best prognostic value overall. Melatonin appears to provide neuroprotection in NE, however the evidence to date is very uncertain. Melatonin is a potent immune regulating agent in infants with NE, although it induces a complex immune response which requires further evaluation.

Conclusion: Lack of a clear definition of NE, consistent use of terminology, and variation in diagnostic criteria limits research into the condition and requires consensus approach as efforts to date have not resulted in greater uniformity in understanding or terminology use. A wide variety of biomarkers and other prognostic markers have been investigated in recent years. MR spectroscopy provides the most accurate prognostic value but requires further evaluation for best implementation. Phase III studies of melatonin treatment are urgently required as it appears to provide neuroprotection in NE but evidence is very limited to date. Melatonin is a potent immune-modulating agent in NE, however further investigations into these effects are required.