Birth asphyxia in African newborns (Baby BRAiN study): Developing a feasibility cohort in Uganda

Background: Neonatal encephalopathy (NE) is the third leading cause of under 5-year mortality and contributes substantially to long-term neurological morbidity worldwide [1]. The nature and timing of brain injury amongst African neonates with NE has, to date, been poorly defined, however important clinical risk factors, such as perinatal infection and poorly controlled seizures, may substantially contribute to adverse outcomes[2,3]. Improving our understanding of NE in an African context is crucial if we are to develop intervention strategies applicable for use in diverse settings. Aims & objectives : The primary aims of the Baby BRAiN study are to establish the feasibility of a facility-based cohort of neonates with NE in Uganda to enhance our understanding of NE in a low resource sub-Saharan African setting and provide infrastructure to conduct high-impact research on neuroprotective and neurorestorative strategies. Specific objectives are to i) investigate the clinical course, role of infection and nature and timing of perinatal brain injury ii) describe electrographic brain activity and duration and type of seizure burden amongst neonates with NE and their relationship with neurological and neurodevelopmental outcomes iii) develop capacity for neonatal brain magnetic resonance imaging (MRI). Methods: This study is a prospective feasibility cohort study amongst neonates with NE at Kawempe National Referral Hospital in Kampala, Uganda’s capital city. Recruitment criteria include; term neonate (≥36 weeks); birth weight ≥1.8kg; Thompson score ≥5 (<48 hrs from birth); prolonged resuscitation after birth; written informed parental consent. Baseline data is collected on pre-conception, antepartum and intrapartum exposures from clinical records and structured maternal interviews and are recorded on standardized eCRFs (RedCap). Study procedures include daily Thompson & Sarnat classification, blood culture (BACTEC) for neonatal bacteraemia, continuous video electroencephalography (EEG) (days 1-4), cranial ultrasound imaging (cUS) (days 1-3, 5, 10 and 28), MRI at or soon after discharge, and neurodevelopmental follow-up (Malawi Development Assessment Tool, Bayley Scales of Infant Development III, Hammersmith Infant Neurological Examination, head circumference, weight and height) to two years of age. Samples for storage for future studies include serum samples & dried blood spots (days 1-2). Continuous video EEG polygraphic recordings (with simultaneously displayed aEEG) are retrospectively analysed and reported including grading of background pattern [4], seizure burden, seizure duration and type (modified ILAE classification [5]). Standard cUS image views and resistance index are reported and abnormalities in the basal ganglia and thalami, white matter and cortex scored [6]. MRI imaging (conventional, diffusion and diffusion tensor) will be examined for quality and artefact, pattern of brain injury, potential aetiology and timing of injury.  All EEG, cUSs and MRIs will be reported by neonatal experts in their field. The findings, from cUS, EEG and MRI will be correlated with each other and neurodevelopmental outcome. Findings: Recruitment commenced on 18/10/19 and is ongoing, though suspended from 23/03/20-21/07/20 due to the Covid-19 pandemic. To date, 40 neonates meeting eligibility criteria have been recruited, 39 with continuous video aEEG and all with blood cultures and serial cUS imaging. Of 29 infants surviving to discharge, 25 remain under neurodevelopmental follow-up (1 withdrawn, 3 lost to follow-up). Preliminary analysis of video EEG data from the first 27 neonates recruited show 16 with EEG confirmed seizures, including 8 with long periods of status epilepticus. To date 17 surviving infants have brain MR imaging, and a further 4 are awaited. Five were not imaged due to Covid-19 related study suspension, 11 died prior to imaging and 3 did not attend.    Early findings from the Baby BRAiN Study indicate that it is feasible to conduct important, much needed, high-impact NE research including continuous video EEG, cUS and neonatal brain MRI in a Ugandan setting. References 1.  Lee et al, 2013. nature.com  2.Tann et al, 2018. thelancet.com)30051-8/fulltex t 3.Tann et al, 2018 fn.bmj.com  4. Murray et al, 2009. pediatrics.org  5. Pressler et al, 2018. ilae.org  6. Tann et al, 2016. nature.com