Early qualitative and quantitative amplitude-integrated electroencephalogram and raw electroencephalogram for predicting long-term neurodevelopmental outcomes in extremely preterm infants in the Netherlands: a 10-year cohort study.

BACKGROUND: Extremely preterm infants (<28 weeks of gestation) are at great risk of long-term neurodevelopmental impairments. Early amplitude-integrated electroencephalogram (aEEG) accompanied by raw EEG traces (aEEG-EEG) has potential for predicting subsequent outcomes in preterm infants. We aimed to determine whether and which qualitative and quantitative aEEG-EEG features obtained within the first postnatal days predict neurodevelopmental outcomes in extremely preterm infants. METHODS: This study retrospectively analysed a cohort of extremely preterm infants (born before 28 weeks and 0 days of gestation) who underwent continuous two-channel aEEG-EEG monitoring during their first 3 postnatal days at Wilhelmina Children's Hospital, Utrecht, the Netherlands, between June 1, 2008, and Sept 30, 2018. Only infants who did not have genetic or metabolic diseases or major congenital malformations were eligible for inclusion. Features were extracted from preprocessed aEEG-EEG signals, comprising qualitative parameters grouped in three types (background pattern, sleep-wake cycling, and seizure activity) and quantitative metrics grouped in four categories (spectral content, amplitude, connectivity, and discontinuity). Machine learning-based regression and classification models were used to evaluate the predictive value of the extracted aEEG-EEG features for 13 outcomes, including cognitive, motor, and behavioural problem outcomes, at 2-3 years and 5-7 years. Potential confounders (gestational age at birth, maternal education, illness severity, morphine cumulative dose, the presence of severe brain injury, and the administration of antiseizure, sedative, or anaesthetic medications) were controlled for in all prediction analyses. FINDINGS: 369 infants were included and an extensive set of 339 aEEG-EEG features was extracted, comprising nine qualitative parameters and 330 quantitative metrics. The machine learning-based regression models showed significant but relatively weak predictive performance (ranging from r=0·13 to r=0·23) for nine of 13 outcomes. However, the machine learning-based classifiers exhibited acceptable performance in identifying infants with intellectual impairments from those with optimal outcomes at age 5-7 years, achieving balanced accuracies of 0·77 (95% CI 0·62-0·90; p=0·0020) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score. Both classifiers maintained identical performance when solely using quantitative features, achieving balanced accuracies of 0·77 (95% CI 0·63-0·91; p=0·0030) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score. INTERPRETATION: These findings highlight the potential benefits of using early postnatal aEEG-EEG features to automatically recognise extremely preterm infants with poor outcomes, facilitating the development of an interpretable prognostic tool that aids in decision making and therapy planning. FUNDING: European Commission Horizon 2020.

Early Determinants of Adverse Motor Outcomes in Preschool Children with a Critical Congenital Heart Defect.

Neurodevelopmental disabilities are common in infants with critical congenital heart disease (CCHD). A prospective, longitudinal cohort study was conducted to establish the prevalence and early determinants of adverse motor outcomes in infants who underwent cardiac surgery with cardiopulmonary bypass before six months of age. Motor development was assessed in 147 preschoolers using the Movement Assessment Battery for children-II. Although the majority displayed an average motor development, 22% of preschool children with CCHD deteriorated in their motor developmental score compared to their previous assessment at 18 months, especially in those with an aortic arch anomaly (AAA) (35%). Individual stability over time appeared to be moderate and the number of children with a motor delay increased, up to 20% in children with AAA. Motor development up to 42 months was best predicted by gestational age, cardio pulmonary bypass time, aortic cross clamp time, number of heart catheterizations up to 18 months and early motor outcomes. The increase in number of preschool children with a motor delay underlines the importance of longitudinal screening of motor skills in children with CCHD at risk for adverse motor outcomes. Offering early interventions may protect their current and future cardiovascular health as motor development is an independent predictor of exercise capacity, physical activity and participation in daily living.

Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study.

BACKGROUND: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. METHODS: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (≥36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45-50 × 106 bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. FINDINGS: Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38°C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus post-administration and, although thrombocyte levels increased (p=0·011), all were within the physiological range. Follow-up MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. INTERPRETATION: This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. FUNDING: Netherlands Organization for Health Research and Development (ZonMw).

Shape variability of the central sulcus in the developing brain: A longitudinal descriptive and predictive study in preterm infants.

Despite growing evidence of links between sulcation and function in the adult brain, the folding dynamics, occurring mostly before normal-term-birth, is vastly unknown. Looking into the development of cortical sulci in infants can give us keys to address fundamental questions: what is the sulcal shape variability in the developing brain? When are the shape features encoded? How are these morphological parameters related to further functional development? In this study, we aimed to investigate the shape variability of the developing central sulcus, which is the frontier between the primary somatosensory and motor cortices. We studied a cohort of 71 extremely preterm infants scanned twice using MRI - once around 30 weeks post-menstrual age (w PMA) and once at term-equivalent age, around 40w PMA -, in order to quantify the sulcus's shape variability using manifold learning, regardless of age-group or hemisphere. We then used these shape descriptors to evaluate the sulcus's variability at both ages and to assess hemispheric and age-group specificities. This led us to propose a description of ten shape features capturing the variability in the central sulcus of preterm infants. Our results suggested that most of these features (8/10) are encoded as early as 30w PMA. We unprecedentedly observed hemispheric asymmetries at both ages, and the one captured at term-equivalent age seems to correspond with the asymmetry pattern previously reported in adults. We further trained classifiers in order to explore the predictive value of these shape features on manual performance at 5 years of age (handedness and fine motor outcome). The central sulcus's shape alone showed a limited but relevant predictive capacity in both cases. The study of sulcal shape features during early neurodevelopment may participate to a better comprehension of the complex links between morphological and functional organization of the developing brain.

Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy.

The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.

Parents' experiences of VOICE: A novel support programme in the NICU.

BACKGROUND: Admission of an infant to a neonatal intensive care unit (NICU) is often a stressful experience for parents and can be associated with feelings of inadequacy to fulfil the desirable parental role. The values, opportunities, integration, control, and evaluation (VOICE) programme was developed to engage parents in care, to decrease stress, and to increase empowerment. AIM: To explore the experiences of parents regarding involvement in the VOICE programme during admission of their infant to the NICU. DESIGN: The VOICE programme includes at least five personal structured meetings between parents, nurses, and other health care professionals throughout the pathway from birth, NICU, and follow up. A qualitative design was adopted using semi-structured interviews. Interviews with 13 parents of 11 infants born at <27 weeks' gestational age were conducted: nine mothers and two couples of father and mother. Thematic analysis was deployed. RESULTS: The findings have been described in one overarching theme: "parental empowerment." Parents felt strengthened and were empowered in the development of their role as primary caretaker by the VOICE programme. The parental empowerment theme emerged from four related interpretive themes that were derived: (a) involvement in care, (b) personalized information and communication, (c) transition to a parental role, and (d) emotional support. CONCLUSION: The VOICE programme can be a structured approach used to implement family support in a NICU to empower parents to become a partner in the care of their infant and feel confident. RELEVANCE TO CLINICAL PRACTICE: This study encourages health care professionals to provide parental support through a structured intervention programme, which contributes to the empowerment of parents in the NICU and encouraged them to participate in care and decision-making.

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

OBJECTIVE: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation). METHODS: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth. RESULTS: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections. CONCLUSIONS: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Non-right-handedness in children born extremely preterm: Relation to early neuroimaging and long-term neurodevelopment.

OBJECTIVE: This study aimed to define the prevalence and predictors of non-right-handedness and its link to long-term neurodevelopmental outcome and early neuroimaging in a cohort of children born extremely preterm (<28 weeks gestation). METHODS: 179 children born extremely preterm admitted to the Neonatal Intensive Care Unit of our tertiary centre from 2006-2013 were included in a prospective longitudinal cohort study. Collected data included perinatal data, demographic characteristics, neurodevelopmental outcome measured by the Bayley Scales of Infant and Toddler Development at 2 years and the Movement Assessment Battery for Children at 5 years, and handedness measured at school age (4-8 years). Magnetic resonance imaging performed at term-equivalent age was used to study overt brain injury. Diffusion tensor imaging scans were analysed using tract-based spatial statistics to assess white matter microstructure in relation to handedness and neurodevelopmental outcome. RESULTS: The prevalence of non-right-handedness in our cohort was 22.9%, compared to 12% in the general population. Weaker fine motor skills at 2 years and paternal non-right-handedness were significantly associated with non-right-handedness. Both overt brain injury and fractional anisotropy of white matter structures on diffusion tensor images were not related to handedness. Fractional anisotropy measurements showed significant associations with neurodevelopmental outcome. CONCLUSIONS: Our data show that non-right-handedness in children born extremely preterm occurs almost twice as frequently as in the general population. In the studied population, non-right-handedness is associated with weaker fine motor skills and paternal non-right-handedness, but not with overt brain injury or microstructural brain development on early magnetic resonance imaging.

Motor performance, exercise tolerance, and health-related quality of life in children on dialysis.

In contrast to the adult population, little is known regarding health-related quality of life and exercise tolerance in children with end-stage renal disease (ESRD) undergoing chronic intermittent hemodialysis. We designed a pilot study to investigate whether research into this area is indicated. The aim of this study was to describe the motor skills, exercise tolerance, and health-related quality of life in children with ESRD. The study population consisted of ten hemodialysis patients (aged 7-16 years). In eight children motor proficiency according to Bruininks-Oseretsky was determined. In all ten children a progressive exercise test on a treadmill was performed. The results were compared with an age-matched healthy reference group. Nine children filled in the TNO-AZL Child Quality of Life (TACQOL) scoring list. One child had a markedly reduced fine motor skills capacity; another five children scored < or = -2 SD compared with healthy children in gross motor skills. Seven children showed a diminished VO(2)max (per kilogram body weight); six of these are physically inactive. Four of these seven children did not sustain the maximum workload. The self-assessed physical and mental health of children on dialysis seems comparable to the general population. We found no correlation between exercise performance or motor skills and hemoglobin levels, Kt/V, and time on dialysis. In conclusion, in this study most children had a reduced exercise tolerance and gross motor skills. There was no difference in fine motor skills. Pediatric dialysis patients report a good health-related quality of life.