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)

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)