Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy.

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.

Adherence to the infant vitamin D supplementation policy in Ireland.

PURPOSE: From September 2010 until November 2019, Ireland's infant vitamin D supplementation policy recommended administration of 5 µg/day of vitamin D3 from birth to 12 months to all infants, regardless of feeding method. This study aims to examine policy adherence. METHODS: In the prospective COMBINE birth cohort study (recruited 2015-2017), detailed longitudinal supplement data were examined in 364 infants across the first year of life, according to product type, dose, frequency, and duration. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was compared with the BASELINE cohort (recruited 2008-2011, n = 1949). RESULTS: In COMBINE, 92% of infants initiated supplementation at birth. The median supplementation duration was 51 (40, 52) weeks, with a range of 3-52 weeks. While supplementing, most parents (92%) used an exclusive vitamin D supplement as recommended and 88% gave 5 µg/day. Half (51%) gave vitamin D daily and a further 33% supplemented at least 3-6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. A further 16% were broadly compliant, giving 5 µg frequently for the full 12 months. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was 93%, 89%, and 72%, considerably higher than our earlier BASELINE cohort at 49%, 64%, and 44% at the same time points (all P < 0.001). CONCLUSIONS: We report a high level of vitamin D supplementation initiation at birth, with full to broad policy adherence among more than half of infants. There is scope to improve overall compliance by focusing on supplementation frequency.

Listeria Meningitis in an Immunocompetent Child: Case Report and Literature Review

We present a case of a 23 month-old boy presenting with fever, irritability and diarrhea who subsequently developed symptoms of photophobia and lethargy. Cerebrospinal fluid culture grew Listeria monocytogenes. Immunology investigations were normal. This patient had a complete and uncomplicated recovery. Listeria meningitis is a rare presentation in immunocompetent children, but should be considered in the setting of diarrhea, failure to respond to cephalosporin therapy, or suspected immunodeficiency.

Organisational factors and mortality after an emergency laparotomy: multilevel analysis of 39 903 National Emergency Laparotomy Audit patients.

BACKGROUND: Studies across healthcare systems have demonstrated between-hospital variation in survival after an emergency laparotomy. We postulate that this variation can be explained by differences in perioperative process delivery, underpinning organisational structures, and associated hospital characteristics. METHODS: We performed this nationwide, registry-based, prospective cohort study using data from the National Emergency Laparotomy Audit organisational and patient audit data sets. Outcome measures were all-cause 30- and 90-day postoperative mortality. We estimated adjusted odds ratios (ORs) for perioperative processes and organisational structures and characteristics by fitting multilevel logistic regression models. RESULTS: The cohort comprised 39 903 patients undergoing surgery at 185 hospitals. Controlling for case mix and clustering, a substantial proportion of between-hospital mortality variation was explained by differences in processes, infrastructure, and hospital characteristics. Perioperative care pathways [OR: 0.86; 95% confidence interval (CI): 0.76-0.96; and OR: 0.89; 95% CI: 0.81-0.99] and emergency surgical units (OR: 0.89; 95% CI: 0.80-0.99; and OR: 0.89; 95% CI: 0.81-0.98) were associated with reduced 30- and 90-day mortality, respectively. In contrast, infrequent consultant-delivered intraoperative care was associated with increased 30- and 90-day mortality (OR: 1.61; 95% CI: 1.01-2.56; and OR: 1.61; 95% CI: 1.08-2.39, respectively). Postoperative geriatric medicine review was associated with substantially lower mortality in older (≥70 yr) patients (OR: 0.35; 95% CI: 0.29-0.42; and OR: 0.64; 95% CI: 0.55-0.73, respectively). CONCLUSIONS: This multicentre study identified low-technology, readily implementable structures and processes that are associated with improved survival after an emergency laparotomy. Key components of pathways, perioperative medicine input, and specialist units require further investigation.

Development and internal validation of a novel risk adjustment model for adult patients undergoing emergency laparotomy surgery: the National Emergency Laparotomy Audit risk model.

BACKGROUND: Among patients undergoing emergency laparotomy, 30-day postoperative mortality is around 10-15%. The risk of death among these patients, however, varies greatly because of their clinical characteristics. We developed a risk prediction model for 30-day postoperative mortality to enable better comparison of outcomes between hospitals. METHODS: We analysed data from the National Emergency Laparotomy Audit (NELA) on patients having an emergency laparotomy between December 2013 and November 2015. A prediction model was developed using multivariable logistic regression, with potential risk factors identified from existing prediction models, national guidelines, and clinical experts. Continuous risk factors were transformed if necessary to reflect their non-linear relationship with 30-day mortality. The performance of the model was assessed in terms of its calibration and discrimination. Interval validation was conducted using bootstrap resampling. RESULTS: There were 4458 (11.5%) deaths within 30-days among the 38 830 patients undergoing emergency laparotomy. Variables associated with death included (among others): age, blood pressure, heart rate, physiological variables, malignancy, and ASA physical status classification. The predicted risk of death among patients ranged from 1% to 50%. The model demonstrated excellent calibration and discrimination, with a C-statistic of 0.863 (95% confidence interval, 0.858-0.867). The model retained its high discrimination during internal validation, with a bootstrap derived C-statistic of 0.861. CONCLUSIONS: The NELA risk prediction model for emergency laparotomies discriminates well between low- and high-risk patients and is suitable for producing risk-adjusted provider mortality statistics.

Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review.

AIMS: Hypoxic ischaemic encephalopathy (HIE) remains a significant cause of long term neurodisability despite therapeutic hypothermia (TH). Infants with mild HIE, representing 50% of those with HIE, are perceived as low risk and are currently not eligible for TH [1]. This review examines the available evidence of outcome in term infants with mild HIE. METHODS: Medline, Embase and Cochrane Clinical Trials databases were searched in March 2017. Studies with well-defined HIE grading at birth and standardised neurodevelopmental assessment at ≥18 months were included. Abnormal outcome was defined as death, cerebral palsy or standardised neurodevelopmental test score more than 1 standard deviation below the mean. RESULT: Twenty studies were included. Abnormal outcome was reported in 86/341 (25%) of infants. There was insufficient evidence to examine the effect of TH on outcome. CONCLUSION: A significant proportion of infants with mild HIE have abnormal outcome at follow up.

Impact of maternal, antenatal and birth-associated factors on iron stores at birth: data from a prospective maternal-infant birth cohort.

BACKGROUND/OBJECTIVES: Low serum ferritin concentrations at birth, which reflect neonatal iron stores, track through to early childhood and have been associated with poorer neurodevelopmental outcomes. We aimed to identify maternal, antenatal and birth-associated factors that influence iron stores at birth in a prospective maternal-infant birth cohort. SUBJECTS/METHODS: In a population-based, longitudinal, birth cohort in Ireland, 413 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks' gestation had umbilical cord serum ferritin concentrations measured. Regression models were developed to identify independent factors associated with cord ferritin concentrations. RESULTS: Median (IQR) cord ferritin concentrations were 185.7 (131.7, 385.5) µg/l, and 8% (n=33) of infants had low iron stores (ferritin <76 µg/l) at birth. Maternal obesity (BMI ⩾30 kg/m2) at 15 weeks' gestation (adj. estimate (95% confidence interval (CI)): -66.4 (-106.9, -25.9) µg/l, P<0.0001) and delivery by caesarean section (-38.8 (-70.2, -7.4) µg/l, P=0.016) were inversely associated with cord ferritin concentrations. In addition, maternal smoking at 15 weeks' gestation (adj. odds ratio (95% CI): 2.9 (1.2, 7), P=0.020) and being born small-for-gestational age (3.4 (1.3, 8.9), P=0.012) were associated with an increased risk of low iron stores (ferritin <76 µg/l) at birth. CONCLUSIONS: We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth, with the important role of overall maternal health and lifestyle during pregnancy highlighted. Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation.

Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper.

Human microRNA miR-374a is downregulated in the umbilical cord blood (UCB) of infants with hypoxic-ischaemic encephalopathy (HIE). The downstream targets of this microRNA (miRNA) are unclear, but one putative target is the activin-A receptor type IIb (ACVR2B). ACVR2B is required for activin-A function and previous reports have shown alterations of activin-A levels in neonatal HIE. Our aim was to investigate the expression of the potential downstream targets of miR-374a, activin-A and ACVR2B, at birth in a cohort of full-term infants with perinatal asphyxia (PA) only, and those with PA who developed clinical and electrographic HIE. UCB was drawn and processed immediately after delivery. Levels of serum activin-A were measured using ELISA. mRNA levels of ACVR2B in whole blood were quantified using qRT-PCR. Outcome was assessed at 3 years of age using standardised developmental assessment. In total, 171 infants were enrolled: 88 healthy controls, 56 PA and 27 HIE. A statistically significant elevation of median (IQR) ACVR2B was detected in infants with severe HIE compared to moderate/mild HIE, PA and control groups (3.3 (2.94-3.67) vs. 0.91 (0.55-1.21) vs. 0.88 (0.57-1.38) vs. 0.84 (0.74-1.24), p values = 0.04, 0.027 and 0.025, respectively). Although serum activin-A levels were elevated in infants with severe HIE, this elevation did not reach significance. ACVR2B may be a potential novel marker of HIE severity. This is the first study to examine the relationship between activin-A, its receptor AVCR2B and potentially upstream miRNA miR-374a in a cohort of carefully categorised and phenotyped infants. We have shown that miRNA analysis, combined with downstream target exploration, may yield novel biomarkers for the prediction of HIE severity.

Early Cord Metabolite Index and Outcome in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy.

BACKGROUND: A 1H-NMR-derived metabolomic index based on early umbilical cord blood alterations of succinate, glycerol, 3-hydroxybutyrate and O-phosphocholine has shown potential for the prediction of hypoxic-ischaemic encephalopathy (HIE) severity. OBJECTIVE: To evaluate whether this metabolite score can predict 3-year neurodevelopmental outcome in infants with perinatal asphyxia and HIE, compared with current standard biochemical and clinical markers. METHODS: From September 2009 to June 2011, infants at risk of perinatal asphyxia were recruited from a single maternity hospital. Cord blood was drawn and biobanked at delivery. Neonates were monitored for development of encephalopathy both clinically and electrographically. Neurodevelopmental outcome was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development, ed. III (BSID-III). Death and cerebral palsy were also considered as abnormal end points. RESULTS: Thirty-one infants had both metabolomic analysis and neurodevelopmental outcome at 36-42 months. No child had a severely abnormal BSID-III result. The metabolite index significantly correlated with outcome (ρ2 = 0.30, p < 0.01), which is robust to predict both severe outcome (area under the receiver operating characteristic curve: 0.92, p < 0.01) and intact survival (0.80, p = 0.01). There was no correlation between the index score and performance in the individual BSID-III subscales (cognitive, language, motor). CONCLUSIONS: The metabolite index outperformed other standard biochemical markers at birth for prediction of outcome at 3 years, but was not superior to EEG or the Sarnat score.

Eating behaviour and weight status at 2 years of age: data from the Cork BASELINE Birth Cohort Study.

BACKGROUND/OBJECTIVES: To conduct an analysis of associations between eating behaviours and weight status in 2-year-old children. SUBJECTS/METHODS: Data were collected prospectively in the maternal-infant dyad Cork BASELINE Birth Cohort Study. The weight status of children aged 2 years (n=1189) was assigned using the International Obesity Task Force BMI cutoffs using measured heights and weights. Eating behaviours were assessed using the Children's Eating Behaviour Questionnaire (CEBQ). RESULTS: Eighty percent of children were of normal weight, 14% were overweight or obese and 6% were underweight. From the CEBQ, food approach behaviours including Enjoyment of Food (odds ratio (OR)=1.90, 95% confidence interval (CI)=1.46-2.48) and Food Responsiveness (OR=1.73, 95% CI=1.47-2.03) were associated with overweight/obesity (all P<0.001). The food avoidant behaviours of Satiety Responsiveness (OR=2.03, 95% CI=1.38-2.98) and Slowness in Eating (OR=1.44, 95% CI=1.01-2.04) were associated with underweight at 2 years (all P<0.05). CONCLUSIONS: Eating behaviours are associated with weight status as early as 2 years of age.

The effect of haemolysis on the metabolomic profile of umbilical cord blood.

OBJECTIVES: Metabolomics is defined as the comprehensive study of all low molecular weight biochemicals, (metabolites) present in an organism. Using a systems biology approach, metabolomics in umbilical cord blood (UCB) may offer insight into many perinatal disease processes by uniquely detecting rapid biochemical pathway alterations. In vitro haemolysis is a common technical problem affecting UCB sampling in the delivery room, and can hamper metabolomic analysis. The extent of metabolomic alteration which occurs in haemolysed samples is unknown. DESIGN AND METHODS: Visual haemolysis was designated by the laboratory technician using a standardised haemolysis index colour chart. The metabolomic profile of haemolysed and non-haemolysed UCB serum samples from 69 healthy term infants was compared using both (1)H-NMR and targeted DI and LC-MS/MS approach. RESULTS: We identified 43 metabolites that are significantly altered in visually haemolysed UCB samples, acylcarnitines (n=2), glycerophospholipids (n=23), sphingolipids (n=7), sugars (n=3), amino acids (n=4) and Krebs cycle intermediates (n=4). CONCLUSION: This information will be useful for researchers in the field of neonatal metabolomics to avoid false findings in the presence of haemolysis, to ensure reproducible and credible results.

Normative levels of Interleukin 16 in umbilical cord blood.

OBJECTIVES: The need for early and accurate prediction of outcome in hypoxic-ischaemic encephalopathy (HIE) remains critical. We have previously demonstrated that Interleukin 16 (IL-16) is raised in the umbilical cord blood (UCB) of infants with moderate and severe HIE and has the potential to be developed as a predictive biomarker. Normal reference ranges for IL-16 in UCB have not been previously described. The aim of this study was to determine normative levels of IL-16 in full term neonates using UCB following uncomplicated deliveries and to examine the effect of labour on cord IL-16 values. DESIGN AND METHODS: Full term infants were recruited as part of an ongoing birth cohort study, the Cork BASELINE Birth Cohort Study. All had UCB drawn and bio-banked at -80°C, within 3hours of birth. Samples for this experiment were chosen from this population based cohort study to represent uncomplicated pre-labour caesarean sections and spontaneous vaginal deliveries. Analysis was performed on plasma EDTA, using ELISA Quantikine® (R&D Systems, Europe). RESULTS: Samples were analysed from 48 infants with two modes of delivery; spontaneous vaginal delivery (n=12 male, n=12 female) and elective caesarean section (n=12 male, n=12 female). The range of all samples was normally distributed between 87.0 and 114.6pg/ml. Overall mean (SD) for IL-16 was 102.9 (21.5) pg/ml. Levels were not affected by spontaneous vaginal delivery or gender. CONCLUSION: For the first time we have described the expected range of cord plasma IL-16 levels in healthy term infants following pre-labour and post-labour delivery.

Association of nucleated red blood cells and severity of encephalopathy in normothermic and hypothermic infants.

AIM: To determine whether hypothermia alters the discriminative ability of postnatal nucleated red blood cells (NRBCs) to distinguish between mild and moderate/severely encephalopathic infants. METHODS: A prospective cohort study recruited full-term neonates with hypoxic ischaemic encephalopathy (HIE) from 2003 to 2012 (prehypothermic and hypothermic eras). The NRBC count was analysed in the first 24 h in all infants and compared between normothermic and hypothermic cohorts. The severity of encephalopathy was categorized using both clinical Sarnat score and continuous multichannel EEG. RESULTS: Eighty-six infants with HIE were included: in the normothermic group, 19 were clinically mild, 24 moderate/severe; in the hypothermic group, 22 were mild, 21 moderate/severe encephalopathy. NRBC count discriminated between mild and moderate/severe Sarnat scores in the normothermic group (p = 0.03) but not in the hypothermic group (p = 0.9). This change was due to a decrease in NRBCs among moderately encephalopathic infants in the hypothermic cohort. CONCLUSION: Postnatal NRBCs distinguished between mild and moderate/severe encephalopathy in normothermic infants but not in infants undergoing therapeutic hypothermia. We advise caution when using postnatal blood samples to study diagnostic biomarkers for HIE without first analysing the potential impact of hypothermia upon these markers.

The use of conventional EEG for the assessment of hypoxic ischaemic encephalopathy in the newborn: a review.

Neonatal hypoxic ischaemic encephalopathy continues to be one of the leading causes of morbidity and mortality among neonates around the globe. With the advent of therapeutic hypothermia, the need to accurately classify the severity of injury in the early neonatal period is of great importance. As clinical measures cannot always accurately estimate the severity early enough for treatment to be initiated, clinicians have become more dependent on conventional and amplitude integrated EEG. Despite this, there is currently no single agreed classification scheme for the neonatal EEG in hypoxic ischaemic encephalopathy. In this review we discuss classification schemes of neonatal background EEG, published over the past 35 years, highlighting the urgent need for a universal visual analysis scheme.

Nucleated red blood cells and early EEG: predicting Sarnat stage and two year outcome.

AIMS: Hypoxic Ischaemic Encephalopathy (HIE) causes characteristic changes of the electroencephalogram (EEG), and a raised Nucleated Red Blood Cell (NRBC) count compared to controls. We wished to examine whether combining these markers could improve their ability to predict HIE severity in the first 24h. METHODS: Term infants with HIE were recruited. NRBC count and continuous multi-channel EEG were recorded within the first 24h. Neurological assessment was carried out at 24 months. A control population with NRBC counts in the first 24h was recruited. RESULTS: 44 infants with HIE and 43 control infants were recruited. Of the HIE population 39 completed a 2 year follow-up. The median NRBC count differed significantly between the controls and those with HIE (3/100 WBC [range of 0-11] vs 12.3/100 WBC [0-240]) (p<0.001). Within the HIE population the median NRBC count was significantly greater in infants with moderate/severe HIE than mild (16/100 WBC [range of 0-240] vs 8/100 WBC [1-23]) (p=0.016), and among infants with abnormal outcome compared to normal (21.3/100 WBC [1-239.8] vs 8.3/100 WBC [0-50])(p=0.03). The predictive ability of EEG changed with time post-delivery, therefore results are given at both 12 and 24h of age. At both time points the combined marker had a stronger correlation than EEG alone; with HIE severity (12h: r=0.661 vs r=0.622), (24h: r=0.645 vs r=0.598), and with outcome at 2 years (12h: r=0.756 vs r=0.652), (24h: r=0.802 vs r=0.746). CONCLUSION: Combining early EEG and NRBC count to predict HIE severity and neurological outcome, improved the predictive ability of either in isolation.

Quantitative EEG analysis in neonatal hypoxic ischaemic encephalopathy.

OBJECTIVE: To test the hypothesis that quantitative EEG (qEEG) measures are associated with a grading of HIE based on the visual interpretation of neonatal EEG (EEG/HIE). METHODS: Continuous multichannel video-EEG data were recorded for up to 72 h. One-hour EEG segments from each recording were visually analysed and graded by two electroencephalographers (EEGers) blinded to clinical data. Several qEEG measures were calculated for each EEG segment. Kruskal-Wallis testing with post hoc analysis and multiple linear regression were used to assess the hypothesis. RESULTS: Fifty-four full-term infants with HIE were studied. The relative delta power, skewness, kurtosis, amplitude, and discontinuity were significantly different across four EEG/HIE grades (p<0.05). A linear combination of these qEEG measures could predict the EEG/HIE grade assigned by the EEGers with an accuracy of 89%. CONCLUSION: Quantitative analysis of background EEG activity has shown that measures based on the amplitude, frequency content and continuity of the EEG are associated with a visual interpretation of the EEG performed by experienced EEGers. SIGNIFICANCE: Identifying qEEG measures that can separate between EEG/HIE grades is an important first step towards creating a classifier for automated detection of EEG/HIE grades.

Predicting the neurodevelopmental outcome in newborns with hypoxic-ischaemic injury.

The prediction of outcome in newborns with hypoxic ischemic encephalopathy (HIE) is a problematic task. Here, the ability of a combination of clinical, heart rate and EEG measures to predict outcome at 2 years is investigated. One hour of EEG and ECG recordings were obtained from newborns 24 hours after birth. Each newborn was reassessed at 24 months to investigate their neurodevelopmental outcome. From the EEG and ECG recordings, a set of 12 features was extracted. To classify each baby's outcome this data, along with clinical information was fed to a support vector machine. On a per patient basis an ROC area of 0.768 was achieved with 73.68% of newborns being assigned the correct outcome. Overall, this system presents a promising step towards the use of multimodal data for the prediction of neurodevelopmental outcome in newborns with HIE.

EEG in the healthy term newborn within 12 hours of birth.

OBJECTIVE: To characterise and quantify the EEG during sleep in healthy newborns in the early newborn period. METHODS: Continuous multi-channel video-EEG data was recorded for up to 2 hours in normal newborns within 12 hours of birth. The total amount of active (AS) and quiet sleep (QS) was calculated in the first hour of recording. The EEG signal was quantitatively analysed for symmetry and synchrony. Spectral edge frequency (SEF), spectral entropy (H) and relative delta power (delta(R)) were calculated for a ten-minute segment of AS and QS in each recording. Paired t-test and Wilcoxon rank sum test were used for data analysis. RESULTS: Thirty normal newborn babies were studied, 10 within 6 hours of birth and 20 between 6 and 12 hours. All babies showed continuous symmetrical and synchronous EEG activity and well-developed sleep-wake cycling (SWC) with the median percentage of AS--48.5% and QS--36.6%. Quantitative EEG analysis of sleep epochs showed that SEF and H were significantly higher (p<0.0001) and delta(R) was significantly lower (p<0.0001) in AS than in QS. CONCLUSION: The normal newborn EEG shows symmetrical and synchronous continuous activity and well-developed SWC as early as within the first 6 hours of birth. Quantitative analysis of the EEG in the early postnatal period reveals differences in SEF, H and delta(R) for AS and QS periods. SIGNIFICANCE: These findings may have implications for quantitative analysis of the newborn EEG, including the EEG of babies with hypoxic ischaemic encephalopathy.