Protocol for the Birth Asphyxia in African Newborns (Baby BRAiN) Study: a Neonatal Encephalopathy Feasibility Cohort Study

Abstract

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality worldwide and contributes substantially to stillbirths and long-term disability. Ninety-nine percent of deaths from NE occur in low-and-middle-income countries (LMICs). Whilst therapeutic hypothermia significantly improves outcomes in high-income countries, its safety and effectiveness in diverse LMIC contexts remains debated. Important differences in the aetiology, nature and timing of neonatal brain injury likely influence the effectiveness of postnatal interventions, including therapeutic hypothermia. METHODS: This is a prospective pilot feasibility cohort study of neonates with NE conducted at Kawempe National Referral Hospital, Kampala, Uganda. Neurological investigations include continuous video electroencephalography (EEG) (days 1-4), serial cranial ultrasound imaging, and neonatal brain Magnetic Resonance Imaging and Spectroscopy (MRI/ MRS) (day 10-14). Neurodevelopmental follow-up will be continued to 18-24 months of age including Prechtl's Assessment of General Movements, Bayley Scales of Infant Development, and a formal scored neurological examination. The primary outcome will be death and moderate-severe neurodevelopmental impairment at 18-24 months. Findings will be used to inform explorative science and larger trials, aiming to develop urgently needed neuroprotective and neurorestorative interventions for NE applicable for use in diverse settings. DISCUSSION: The primary aims of the study are to assess the feasibility of establishing a facility-based cohort of children with NE in Uganda, to enhance our understanding of NE in a low-resource sub-Saharan African setting and provide infrastructure to conduct high-quality research on neuroprotective/ neurorestorative strategies to reduce death and disability from NE. Specific objectives are to establish a NE cohort, in order to 1) investigate the clinical course, aetiology, nature and timing of perinatal brain injury; 2) describe electrographic activity and quantify seizure burden and the relationship with adverse outcomes, and; 3) develop capacity for neonatal brain MRI/S and examine associations with early neurodevelopmental outcomes.

Keywords: Electroencephalography; Low- and Middle-Income Countries; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Neonatal Encephalopathy; Uganda; neurodevelopmental impairment; outcomes.

Figure 1.. Flow of participants.

Planned flow of participants through the study from screening to analysis.

Figure 2.. Study procedures and follow-up.

Study procedures, including inclusion/ exclusion criteria, from screening to follow-up. Abbreviations: KNRH= Kawempe National Referral Hospital; EEG= Electroencephalogram; cUS= Cranial Ultrasound; CRP= C-Reactive Protein; EDTA= Ethylenediaminetetraacetic acid; MRI= Magnetic Resonance Imaging; MRS= Magnetic Resonance Spectroscopy; CPAP= Continuous Positive Airway Pressure; IV= Intravenous; HINE= Hammersmith Infant Neurological Examination; GMA= Prechtl’s Assessment of General Movements; MDAT= Malawi Development Assessment Tool; BSID-III= Bayley Scales of Infant and Toddler Development III; GMFCS= Gross Motor Function Classification System; PEDSQL= Pediatric Quality of Life Inventory; SDQ= Strengths and Difficulties Questionnaire.