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Background: Neonatal encephalopathy (NE) is a leading cause of global child mortality. Survivor outcomes in low-resource settings are poorly described. We present early childhood outcomes after NE in Uganda. Methods: We conducted a prospective cohort study of term-born infants with NE (n = 210) and a comparison group of term non-encephalopathic (non-NE) infants (n = 409), assessing neurodevelopmental impairment (NDI) and growth at 27–30 months. Relationships between early clinical parameters and later outcomes were summarised using risk ratios (RR). Findings: Mortality by 27–30 months was 40·3% after NE and 3·8% in non-NE infants. Impairment-free survival occurred in 41·6% after NE and 98·7% of non-NE infants. Amongst NE survivors, 29·3% had NDI including 19·0% with cerebral palsy (CP), commonly bilateral spastic CP (64%); 10·3% had global developmental delay (GDD) without CP. CP was frequently associated with childhood seizures, vision and hearing loss and mortality. NDI was commonly associated with undernutrition (44·1% Z-score < − 2) and microcephaly (32·4% Z-score < − 2). Motor function scores were reduced in NE survivors without CP/GDD compared to non-NE infants (median difference − 8·2 (95% confidence interval; − 13·0, − 3·7)). Neonatal clinical seizures (RR 4.1(2.0–8.7)), abnormalities on cranial ultrasound, (RR 7.0(3.8–16.3), nasogastric feeding at discharge (RR 3·6(2·1–6·1)), and small head circumference at one year (Z-score < − 2, RR 4·9(2·9–5·6)) increased the risk of NDI. Interpretation: In this sub-Saharan African population, death and neurodevelopmental disability after NE were common. CP was associated with sensorineural impairment, malnutrition, seizures and high mortality by 2 years. Early clinical parameters predicted impairment outcomes.
Uganda is a low-income country (LIC) with a neonatal mortality rate of 27 per 1000 live births [11]. Mulago National Referral Hospital in Kampala receives high-risk pregnancies from the surrounding areas. In 2012, more than 33,000 deliveries occurred on the low- (21%) and high-risk (79%) labour wards. In labour, fetal monitoring was by intermittent auscultation using a Pinard stethoscope and women were not routinely examined at the start of the second stage. Ventouse/forceps assisted deliveries were not routinely offered. A fifth of deliveries were by caesarean section (few are electively planned). Intravenous fluids, antibiotics and syntocinon were available. Midwife-led neonatal resuscitation included oxygen and bag-mask ventilation. Care on the 70-bed Special Care Baby Unit included simple continuous positive airway pressure ventilation, intravenous fluids including glucose (but not regular glucose monitoring), antibiotics and anti-seizure medication, but not mechanical ventilation, therapeutic hypothermia, cerebral function monitoring or brain imaging. The study protocol was approved by the Uganda Virus Research Institute Research Ethics Committee, Mulago Ethics Committee, London School of Hygiene and Tropical Medicine, University College London and the Uganda National Council of Science and Technology. This study was a hospital-based prospective cohort study of neurodevelopmental outcomes at 27–30 months amongst term-born infants affected by NE and a contemporaneously recruited unmatched comparison group of term-born infants without NE (non-NE group). All participants were born at ≥ 37 weeks gestation and originally recruited to the ABAaNA case-control study [12] designed to investigate perinatal risk factors for NE in a low-resource African setting. NE was defined as a Thompson score [13] ≥ 6 within 12 h of birth [12]. For the controls, mothers and infants were systematically sampled from the labour ward admission book and were eligible for recruitment if their Thompson score was 20 km from the hospital (up to 20 km was deemed a reasonable distance for a new mother to travel for the 4–6 week postpartum study assessment), out-born infants, and no informed written consent. Infants with congenital abnormalities or other pathology were not excluded but a major anomaly was uncommon. Full study procedures and findings of the original case-control study have been described previously [12], [14], [15]. Socio-economic status was derived using principal components analysis of household characteristics and assets and categorised into tertiles. Encephalopathy was graded (mild, moderate or severe) from the most severe day (days 1–5) using a modified Sarnat classification [16]. Methods for measuring clinical predictors of outcome such as clinical seizures, hypothermia and neonatal serious bacterial infection have previously been described [14]. Cranial ultrasound scans (cUS) were performed on encephalopathic infants and the first 100 comparison children on recruitment (previously reported [15]) and again between days 3 and 5, using a portable machine (z.one ultra-Convertible Ultrasound System; Zonare Medical Systems Inc. Mountain View, California, USA). Images were anonymised and downloaded (OsiriX software, Geneva, Switzerland) and reported (by FC and CH), blinded to clinical data. The presence of recent and evolving injury was defined as clearly demarcated focal bilateral echogenicity in BGT and/or diffuse moderate, severe or dense echogenicity in WM [15]. After discharge, families were contacted from comprehensive locator information collected at recruitment. Where a death was reported information was collected on date of death and parental report of causation. Surviving children were assessed at 4–6 weeks as part of the original study. Further funding was later awarded to see the children first at 12–15 months and then again at 27–30 months of age. Informed consent was taken individually at each of these visits. Transport costs were remunerated. Families not contactable by phone were visited at home (< 5%). Informed written consent from caregivers was obtained. This article focuses on neurodevelopmental and nutritional outcomes at 27–30 months. We used the Griffiths Mental Developmental Scales-II (GMDS) to derive an overall Development Quotient (DQ) from the six subscales (A to F) [17]. Assessors were trained study staff (MMB, FC, CT, RL, JS, KB, JM, EDB, KN) and all certified in GMDS and blind to presence of NE, all clinical history and imaging results. All children were examined neurologically using a standardised scorable assessment, the Hammersmith Infant Neurological Examination (HINE), that has been validated as a predictor of motor outcome in different cohorts [18], [19]. The HINE is accessible, easy to perform and has good inter-observer reliability, even with inexperienced staff [18]. Optimal scores in term-born infants at 18 months are 75–78. A score of ≥ 67 at 9–14 months was predictive of independent walking at 2 years in a term-born cohort following hypoxic-ischaemic encephalopathy [20]. CP was diagnosed and classified according to the Surveillance of Cerebral Palsy in Europe hierarchical classification [21]; spastic bilateral, spastic unilateral, dyskinetic, dystonic, choreo-athetotic, ataxic or non-classifiable. CP severity was classified using the Gross Motor Function Classification System for Cerebral Palsy (GMFCS) [22]. Videos for all children with a suboptimal HINE score were reviewed by a minimum of two investigators (blind to NE status and other clinical data) with expertise in neurodevelopmental impairment (CT, FC and MMB) to type and classify the NDI. There was consensus between experts on impairment type and classification for all impaired children. Neurodevelopmental impairment (NDI) was defined as a global DQ < 70 on GMDS and/or HINE score < 67 and/or diagnosis of CP. Poor outcome was defined as a composite of death or NDI at 27–30 months. Visual and hearing assessments were conducted according to HINE standardised procedures. In the HINE, intermittent or continuous deviation of the eyes or abnormal movements are noted as well as the ability to fix and follow on a clear black/white target; a hearing response is noted by a reaction to a stimulus (a rattle) held behind a visual range on each side. A score of 2 years of age (27–30 months) when important outcomes, such as cerebral palsy, can be confidently diagnosed and classified. Secondary outcomes included GMDS and its subscales, HINE, CP, vision and hearing impairment, GDD without CP, and nutritional outcomes, all at 27–30 months. All-cause mortality to 30 months and poor outcome at 30 months (NDI or death, as described above) were also included as secondary outcomes. The primary comparisons were done between the NE cohort and non-NE children. Secondary comparisons were made between the same groups after excluding those with defined NDI from both groups. We aimed to assess outcomes in at least 110 children with NE and 220 non-NE children, a sample size giving 80% power to detect a difference in mean DQ of 3.75 between the two groups, using Satterthwaite’s t-test with unequal variances and assuming SD of 12 and 10 in exposed and unexposed cohorts, respectively [3]. Neonatal mortality was calculated as the percentage of neonatal deaths amongst those for whom vital status was known at 28 days. Post-neonatal mortality was calculated as the percentage of deaths amongst participants who survived to 28 days and for whom vital status was known at the end of 27 months of follow-up. Kaplan-Meier graphs were plotted, with children censored at loss to follow-up. Post-neonatal mortality was compared between NE and non-NE groups using chi-squared and log rank tests. Socio-demographic and baseline characteristics of participants were compared between NE and non-NE groups, using chi-squared tests and t-tests, as appropriate. Neurodevelopmental outcomes were compared between NE and non-NE groups; deviation from normality for GMDS and HINE scores meant median scores were calculated and compared using generalised Hodges-Lehmann median differences and 95% confidence intervals (CI), and the Wilcoxon rank sum test. The proportion of children with neurodevelopmental, vision and hearing impairment at 27–30 months was calculated, with risk ratios and 95% CI using the non-NE cohort as the reference group, and P-values from chi-squared/Fisher’s exact test. World Health Organisation data [24] were used to calculate weight-for-age and height-for-age Z-scores. OFC Z-scores were derived using the mean and SD from the non-NE group. Proportions with Z-scores < − 2 and − 3 were compared using risk ratios as above. In secondary analyses, to assess whether outcomes after NE differed from the non-NE cohort, in the absence of defined NDI, analyses were repeated, comparing non-NDI encephalopathy survivors and non-NDI comparison cohort members. Clinical characteristics of children with NDI amongst both cohorts, including type and severity, were described. The risk of poor outcome (death or NDI) and the risk of NDI amongst NE survivors were calculated according to severity of NE and other early clinical findings. Early clinical predictors of poor outcome were reported using risk ratios. The study funders have no role in the study design, development or execution, data collection, analysis or interpretation, nor in the paper design, writing or decision to submit for publication. CJT had full access to all study data and final responsibility for the decision to submit for publication.
