Neurodevelopmental outcome in perinatal asphyxia: prediction and measurement

The aim of this thesis was to improve our ability to predict and measure neurodevelopmental outcome in early childhood with particular reference to high-risk infants with perinatal asphyxia. Methods: 1) Promising umbilical cord blood biomarkers were analysed for ability to predict performance in the Bayley Scales of Infant and Toddler Development (Edition 3) at three years. 2) A retrospective cohort was analysed for performance of a low-risk cohort on the Bayley-3 at two years and compared to standardised scores. 3) A survey asked parents to report prevalence and quality of touch-screen usage in their toddlers. 4) Pilot testing of a novel cognitive assessment tool, the“Babyscreen App”, was performed on a prospective low risk cohort. The Babyscreen App was administered alongside the Bayley-3 at age 18 months to 2 years. Results: 1) IL-16 predicted severe outcome with an area under the ROC curve of 0.83 (p= Levels ≥ 514 pg/mL predicted a severe outcome with a sensitivity of 83% and a specificity of 81%. 2 metabolite models were tested. Model A predicted abnormal outcome with an area under ROC curve of 0.77, p<0.01. Model B was robust to predict both severe outcome (area under ROC curve of 0.92, p<0.01) and intact survival (0.80, p=0.01). 2) 240 two year olds were analysed for performance on the Bayley-3. Language and fine motor scores were significantly higher compared to U.S standardised norms, 109 ± 13 v. 100 ± 15 , p<0.001, and 11.5 ± 2 v. 10 ± 3, p<0.001 respectively. 3) For the examination of touch-screen usage in toddlers, 82 questionnaires were completed by parents of typically developing children aged 12 to 36 months. 71% of toddlers included had access to touch-screen devices for a median (IQR) of 15 (9-26) minutes per day. By 24 months the majority of children were able to swipe, unlock and actively look for touch-screen features. 4) 95 children underwent administration of the Babyscreen App and the Bayley-3. Significant medium sized correlations occurred between various measures of app performance and cognitive composite scores on the Bayley-3. Combined measures of overall app performance could predict cognitive scores less than 90 (1SD below the mean of our cohort) with an area under the ROC curve of 0.69 (0.55-0.83), p=0.02. Conclusion: This thesis has shown that novel biomarkers measured in umbilical cord blood at birth can predict neuro developmental outcome and that a novel touch-screen application can assess cognition in toddlers

Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy.

Aim: To examine the relationship between electrographic seizures and long-term outcome in neonates with hypoxic-ischemic encephalopathy (HIE). Method: Full-term neonates with HIE born in Cork University Maternity Hospital from 2003 to 2006 (pre-hypothermia era) and 2009 to 2012 (hypothermia era) were included in this observational study. All had early continuous electroencephalography monitoring. All electrographic seizures were annotated. The total seizure burden and hourly seizure burden were calculated. Outcome (normal/abnormal) was assessed at 24 to 48 months in surviving neonates using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales; a diagnosis of cerebral palsy or epilepsy was also considered an abnormal outcome. Results: Continuous electroencephalography was recorded for a median of 57.1 hours (interquartile range 33.5-80.5h) in 47 neonates (31 males, 16 females); 29 out of 47 (62%) had electrographic seizures and 25 out of 47 (53%) had an abnormal outcome. The presence of seizures per se was not associated with abnormal outcome (p=0.126); however, the odds of an abnormal outcome increased over ninefold (odds ratio [OR] 9.56; 95% confidence interval [95% CI] 2.43-37.67) if a neonate had a total seizure burden of more than 40 minutes (p=0.001), and eightfold (OR: 8.00; 95% CI: 2.06-31.07) if a neonate had a maximum hourly seizure burden of more than 13 minutes per hour (p=0.003). Controlling for electrographic HIE grade or treatment with hypothermia did not change the direction of the relationship between seizure burden and outcome. Interpretation: In HIE, a high electrographic seizure burden is significantly associated with abnormal outcome, independent of HIE severity or treatment with hypothermia

Microcytosis is associated with low cognitive outcomes in healthy 2-year-olds in a high-resource setting

Fe deficiency in early childhood is associated with long-term consequences for cognitive, motor and behavioural development; however explorations in healthy children from low risk, high-resource settings have been limited. We aimed to explore associations between Fe status and neurodevelopmental outcomes in low risk, healthy 2-year-olds. This study was a secondary analysis of a nested case–control subgroup from the prospective, maternal-infant Cork Babies after Screening for Pregnancy Endpoints: Evaluating the Longitudinal Impact using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study. At 2 years, serum ferritin, Hb and mean corpuscular volume (MCV) were measured and neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development (n 87). Five children had Fe deficiency (ferritin <12 µg/l) and no child had Fe deficiency anaemia (Hb<110 g/l+ferritin<12 µg/l). Children with microcytosis (MCV<74 fl, n 13) had significantly lower mean cognitive composite scores (88·5 (sd 13·3) v. 97·0 (sd 7·8), P=0·04, Cohen’s d effect size=0·8) than those without microcytosis. The ferritin concentration which best predicted microcytosis was calculated as 18·4 µg/l (AUC=0·87 (95% CI 0·75, 0·98), P<0·0001, sensitivity 92 %, specificity 75 %). Using 18·5 µg/l as a threshold, children with concentrations <18·5 µg/l had significantly lower mean cognitive composite scores (92·3 (sd 10·5) v. 97·8 (sd 8·1), P=0·012, Cohen’s d effect size=0·6) compared with those with ferritin ≥18·5 µg/l. All associations were robust after adjustment for potential confounding factors. Despite a low prevalence of Fe deficiency using current diagnostic criteria in this healthy cohort, microcytosis was associated with lower cognitive outcomes at 2 years. This exploratory study emphasises the need for re-evaluation of the diagnostic criteria for Fe deficiency in young children, with further research in adequately powered studies warranted