Early visuospatial attention and processing and related neurodevelopmental outcome at 2 years in children born very preterm.

BACKGROUND: The ability to perceive and process visuospatial information is a condition for broader neurodevelopment. We examined the association of early visuospatial attention and processing with later neurodevelopmental outcome in very preterm infants. METHODS: Visuospatial attention and processing was assessed in 209 children (<30 weeks gestation) using an easy applicable eye tracking-based paradigm at 1 and 2 years. Average reaction times to fixation (RTF) on specific visual stimuli were calculated, representing time needed for overall attention (Cartoon stimuli) and processing (Motion and Form stimuli). Associations between RTFs and various measures of development at 2 years including cognitive and motor development (Bayley Scales of Infant and Toddler Development-Third edition; Bayley-III), language (Lexi test) and behavior (Child Behavior Checklist) were examined. RESULTS: At 1 year, 100 ms slower Cartoon and Motion RTFs were associated with lower cognitive Bayley-III scores (-4.4 points, 95%CI: -7.4; -1.5 and -1.0 points, -1.8; -0.2, respectively). A 100 ms slower Cartoon RTF was associated with a 3.5 (-6.6; -0.5) point decrease in motor Bayley-III score. CONCLUSIONS: Visuospatial attention and motion processing at 1 year is predictive of overall cognitive and motor development 1 year later. The nonverbal eye tracking-based test can assist in early detection of preterm children at risk of adverse neurodevelopment. IMPACT: Visuospatial attention and processing at 1 year corrected age is predictive for overall cognitive and motor development 1 year later in preterm infants. First study to relate early visuospatial attention and processing with later neurodevelopmental outcome in preterm children. Early detection of preterm children at risk of adverse neurodevelopment, which allows for more timely interventions.

Neurodevelopmental outcome at 5.5 years in Dutch preterm infants born at 24-26 weeks' gestational age: the EPI-DAF study.

OBJECTIVE: After lowering the Dutch threshold for active treatment from 25 to 24 completed weeks' gestation, survival to discharge increased by 10% in extremely preterm live born infants. Now that this guideline has been implemented, an accurate description of neurodevelopmental outcome at school age is needed. DESIGN: Population-based cohort study. SETTING: All neonatal intensive care units in the Netherlands. PATIENTS: All infants born between 240/7 and 266/7 weeks' gestation who were 5.5 years' corrected age (CA) in 2018-2020 were included. MAIN OUTCOME MEASURES: Main outcome measure was neurodevelopmental outcome at 5.5 years. Neurodevelopmental outcome was a composite outcome defined as none, mild or moderate-to-severe impairment (further defined as neurodevelopmental impairment (NDI)), using corrected cognitive score (Wechsler Preschool and Primary Scale of Intelligence Scale-III-NL), neurological examination and neurosensory function. Additionally, motor score (Movement Assessment Battery for Children-2-NL) was assessed. All assessments were done as part of the nationwide, standardised follow-up programme. RESULTS: In the 3-year period, a total of 632 infants survived to 5.5 years' CA. Data were available for 484 infants (77%). At 5.5 years' CA, most cognitive and motor (sub)scales were significantly lower compared with the normative mean. Overall, 46% had no impairment, 36% had mild impairment and 18% had NDI. NDI-free survival was 30%, 49% and 67% in live born children at 24, 25 and 26 weeks' gestation, respectively (p<0.001). CONCLUSIONS: After lowering the threshold for supporting active treatment from 25 to 24 completed weeks' gestation, a considerable proportion of the surviving extremely preterm children did not have any impairment at 5.5 years' CA.

Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Relationship of EEG sources of neonatal seizures to acute perinatal brain lesions seen on MRI: a pilot study.

Even though it is known that neonatal seizures are associated with acute brain lesions, the relationship of electroencephalographic (EEG) seizures to acute perinatal brain lesions visible on magnetic resonance imaging (MRI) has not been objectively studied. EEG source localization is successfully used for this purpose in adults, but it has not been sufficiently explored in neonates. Therefore, we developed an integrated method for ictal EEG dipole source localization based on a realistic head model to investigate the utility of EEG source imaging in neonates with postasphyxial seizures. We describe here our method and compare the dipole seizure localization results with acute perinatal lesions seen on brain MRI in 10 full-term infants with neonatal encephalopathy. Through experimental studies, we also explore the sensitivity of our method to the electrode positioning errors and the variations in neonatal skull geometry and conductivity. The localization results of 45 focal seizures from 10 neonates are compared with the visual analysis of EEG and MRI data, scored by expert physicians. In 9 of 10 neonates, dipole locations showed good relationship with MRI lesions and clinical data. Our experimental results also suggest that the variations in the used values for skull conductivity or thickness have little effect on the dipole localization, whereas inaccurate electrode positioning can reduce the accuracy of source estimates. The performance of our fused method indicates that ictal EEG source imaging is feasible in neonates and with further validation studies, this technique can become a useful diagnostic tool.

Effect of systemic hydrocortisone in ventilated preterm infants on parent-reported behavioural outcomes at 2 years' corrected age: follow-up of a randomised clinical trial.

OBJECTIVE: To report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Parent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 1½-5). RESULTS: Parents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). CONCLUSION: This study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. TRIAL REGISTRATION NUMBER: NTR2768; EudraCT 2010-023777-19.

Necrotizing Enterocolitis in a Dutch Cohort of Very Preterm Infants: Prevalence, Mortality, and Long-Term Outcomes.

INTRODUCTION: To improve counseling of parents and to guide care strategies, we studied the disease course and outcomes of necrotizing enterocolitis (NEC) up to 2 years of corrected age (CA) from a multidisciplinary perspective. MATERIALS AND METHODS: This was a retrospective cohort study in preterm infants (birth weight < 1,500 g, gestational age < 32 weeks), diagnosed with NEC (Bell's stage ≥ II) from 2008 through 2020. Data on prevalence, mortality, surgery, intestinal failure (IF), growth, and neurodevelopment at 2-year follow-up were separately analyzed for medically and surgically treated children. RESULTS: Of 3,456 preterm infants, 200 (6%) were diagnosed with NEC, of whom 135 developed an indication for surgery within 7 days after the diagnosis; 28/135 died before surgery, and 37/107 died after an open-and-close procedure. An enterostomy was constructed in 62 patients and an end-to-end anastomosis in 15. The postoperative course was described for 77 patients, of whom 23 developed surgical complications (12/23 incisional hernias, 9/23 anastomotic strictures), 13/77 a short bowel, and 25/77 IF. Sixty-day survival after birth for medical NEC patients was 88% (hazard ratio [HR]: 0.698; p = 0.318), and for surgically treated NEC patients was 40% (HR: 3.729; p < 0.001). At 2-year follow-up, one patient received parenteral nutrition. Severe delay in weight for age, motor, and cognitive development was seen in 3, 6, and 2%, respectively. CONCLUSION: In this cohort, the mortality rate was high, especially in surgically treated NEC patients. The surgical complication rate is comparable to previous studies, but in surviving patients, persisting IF and severe delay in growth and neurodevelopment at 2 years CA were relatively rare.

Two-year neurodevelopmental outcome in children born extremely preterm: the EPI-DAF study.

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth.

Validity of an early parent-report questionnaire for language disorder in very preterm children from 2 to 10 years of age.

BACKGROUND: Language problems at an early age in very preterm (VP) children can have a detrimental effect on other developmental domains and often persist throughout childhood. The aim of this study was to examine the concurrent and predictive validity of an early language parent-report questionnaire for language disorder in VP children from 2 to 10 years of age. MATERIALS AND METHODS: In 80 VP children (<32 weeks' gestation) without major disabilities, a parent-questionnaire and formal language assessment, both normed for the general population, were administered at 2 years corrected age (CA). Of these infants, 62 were seen for follow-up formal language assessment at age 4 and 61 were seen at age 10. Sensitivity and specificity values were calculated. RESULTS: The Lexi-list showed acceptable concurrent validity for word production scores obtained at age 2 CA. The predictive validity was good for sentence production and acceptable for word production scores obtained at age 4, and low for language production scores obtained at age 10. A Lexi-list cut-off score of <85 (i.e., <-1 SD) was found optimal. INTERPRETATION: A norm-referenced parent-report questionnaire is a useful, first screening tool in a neonatal follow-up. It not only detected early language disorder at age 2 CA but also proved to be a good predictor for language disorder at age 4. However, it did not predict language disorder at age 10. Formal language assessment at age 4 would therefore be recommended for children with an abnormal parent-report language score at age 2 CA.

Early Screening of Visual Processing Dysfunctions in Children Born Very or Extremely Preterm.

Introduction: Children with early brain damage or dysfunction are at risk of developing cerebral visual impairment (CVI), including visual processing dysfunctions (VPD), which currently remain largely undetected until school age. Our aim was to systematically screen for possible VPD in children born very or extremely preterm from 1 to 2 years corrected age (CA) and to evaluate the effectiveness of early referral. Method: We included N = 48 children born < 30 weeks from 1 year CA. They underwent a two-step VPD screening based on (1) neurological signs indicative of visual brain damage evaluated by neonatologists and/or pediatric neurologist and (2) a functional assessment of visual orienting functions (VOF) with an eye tracking-based test. If at least one of these assessments was abnormal for their age, the children were classified as a risk of VPD and referred to undergo conventional visual diagnostics: ophthalmic exam and visual function assessment (VFA). At 2 years CA, VOF screening was repeated and neurodevelopment was assessed. Results: 18 children (38%) were classified as at risk of VPD at 1 year CA. 7 children had abnormal neurological signs, 5 children had abnormal VOF, and 6 children had both. Subsequent ophthalmic exams (N = 14) showed severe hypermetropia in 21% and strabismus in 14%. VFA (N = 10) showed abnormal visual function and behavior in only 1 child. At 2 years CA, the total group showed an increase in abnormal VOF. Whereas the children at risk showed some normalization, the group without VPD risk at 1 year CA showed deterioration of VOF. Neurodevelopmental outcome did not clearly differ between risk groups. Conclusion: Our findings show a substantial risk of VPD during visual screening (in 38%) at 1 year CA, but relatively few deficits on subsequent conventional ophthalmic exams and VFA. The data suggest that most conventional visual diagnostic methods at this young age are not related to the established VPD risks. VOF assessment should be used complimentary to these methods. The fact that at 2 years CA the number of children with a VPD risk based on abnormal VOF increased argues for more extensive and continuous screening in risk groups, at least until school age.

Brain Damage and Visuospatial Impairments: Exploring Early Structure-Function Associations in Children Born Very Preterm.

BACKGROUND: To provide insight into early neurosensory development in children born very preterm, we assessed the association between early structural brain damage and functional visuospatial attention and motion processing from one to two years corrected age. METHODS: In 112 children born at less than 32 weeks gestational age, we assessed brain damage and growth with a standardized scoring system on magnetic resonance imaging (MRI; 1.5 Tesla) scans performed at 29 to 35 weeks gestational age. Of the children with an MRI scan, 82 participated in an eye tracking-based assessment of visuospatial attention and motion processing (Tobii T60XL) at one year corrected age and 59 at two years corrected age. RESULTS: MRI scoring showed good intra- and inter-rater reproducibility. At one year, 10% children had delayed attentional reaction times and 23% had delayed motion reaction times. Moderate to severe brain damage significantly correlated with slower visuospatial reaction times. At two years, despite attention and motion reaction times becoming significantly faster, 20% had delayed attentional reaction times and 35% had delayed motion reaction times, but no correlations with MRI scores were found. The presence of structural brain damage was associated with abnormal functional performance over age. CONCLUSIONS: The present study indicates an association between moderate to severe brain damage and visuospatial attention and motion processing dysfunction at one year corrected age. This provides a new perspective on comprehensive MRI scoring and quantitative functional visuospatial assessments and their applicability in children born very preterm in their first years of life.

Early intervention for children at risk of visual processing dysfunctions from 1 year of age: a randomized controlled trial protocol.

BACKGROUND: An increasing number of children are suffering from brain damage-related visual processing dysfunctions (VPD). There is currently a lack of evidence-based intervention methods that can be used early in development. We developed a visual intervention protocol suitable from 1 year of age. The protocol is structured, comprehensive and individually adaptive, and is paired with quantitative outcome assessments. Our aim is to investigate the effectiveness of this first visual intervention program for young children with (a risk of) VPD. METHODS: This is a single-blind, placebo-controlled trial that is embedded within standard clinical care. The study population consists of 100 children born very or extremely preterm (< 30 weeks) at 1 year of corrected age (CA), of whom 50% are expected to have VPD. First, children undergo a visual screening at 1 year CA. If they are classified as being at risk of VPD, they are referred to standard care, which involves an ophthalmic and visual function assessment and a (newly developed) visual intervention program. This program consists of a general protocol (standardized and similar for all children) and a supplement protocol (adapted to the specific needs of the child). Children are randomly allocated to an intervention group (starting upon inclusion at 1 year CA) or a control group (postponed: starting at 2 years CA). The control group will receive a placebo treatment. The effectiveness of early visual intervention will be examined with follow-up visual and neurocognitive assessments after 1 year (upon completion of the direct intervention) and after 2 years (upon completion of the postponed intervention). DISCUSSION: Through this randomized controlled trial we will establish the effectiveness of a new and early visual intervention program. Combining a general and supplement protocol enables both structured comparisons between participants and groups, and custom habilitation that is tailored to a child's specific needs. The design ensures that all included children will benefit from participation by advancing the age at which they start receiving an intervention. We expect results to be applicable to the overall population of children with (a risk of) VPD early in life. TRIAL REGISTRATION: Netherlands Trial Register: NTR6952. Registered 19 January 2018.

Imaging patterns of brain injury in term-birth asphyxia.

AIM: To develop an extended asphyxia-score based on cerebral ultrasound (US) and MRI in order to gain further insight into the pathophysiology of asphyxia. PATIENTS AND METHODS: First week cerebral US and MRI of 80 asphyxiated term infants were scored according to a new scoring system based on separate grading of injury to deep grey matter and to (sub)cortical/white matter. Our findings were compared with published scoring systems. RESULTS: Six patterns of brain injury were derived: deep grey matter injury with either limited or extensive cortical involvement, damage to deep grey matter with watershed injury, isolated watershed injury, isolated white matter injury (leukomalacia) and isolated cortical necrosis. The mortality rate was considerable in patterns with extensive cortical injury. CONCLUSION: Six patterns of brain injury, following term-birth asphyxia were found using a new imaging score.

Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis.

BACKGROUND: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. OBJECTIVES: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. METHODS: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280-5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. RESULTS: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. CONCLUSION: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants.

Structural and functional ventilatory impairment in infants with severe bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes. METHODS: We included preterm infants born ≤32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age. RESULTS: We included 49 infants (median [IQR] GA of 25.7 [24.6-26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (ß coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, -0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (ß coefficient [95% CI]: 2.09 [0.49, 3.70]). CONCLUSION: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth.

Postnatal onset cortical dysplasia associated with infarction of white matter.

On MRI at 35 weeks of a boy born at 25 weeks, focal disorganization of the cortex was observed near a frontal venous infarct developed in the first week. Disruption of the final steps of cell migration, injury to the subplate and/or disruption of corticospinal axons are possible mechanisms behind it. Preterms with white matter lesions at or below 25 weeks postconceptional age should be scrutinized for cortical dysplasia.

Improving Reliability of Monitoring Background EEG Dynamics in Asphyxiated Infants.

The goal of this study is to develop an automated algorithm to quantify background electroencephalography (EEG) dynamics in term neonates with hypoxic ischemic encephalopathy. The recorded EEG signal is adaptively segmented and the segments with low amplitudes are detected. Next, depending on the spatial distribution of the low-amplitude segments, the first part of the algorithm detects (dynamic) interburst intervals (dIBIs) and performs well on the relatively artifact-free EEG periods and well-defined burst-suppression EEG periods. However, on testing the algorithm on EEG recordings of more than 48 h per neonate, a significant number of misclassified and dubious detections were encountered. Therefore, as the next step, we applied machine learning classifiers to differentiate between definite dIBI detections and misclassified ones. The developed algorithm achieved a true positive detection rate of 98%, 97%, 88%, and 95% for four duration-related dIBI groups that we subsequently defined. We benchmarked our algorithm with an expert diagnostic interpretation of EEG periods (1 h long) and demonstrated its effectiveness in clinical practice. We show that the detection algorithm effectively discriminates challenging cases encountered within mild and moderate background abnormalities. The dIBI detection algorithm improves identification of neonates with good clinical outcome as compared to the classification based on the classical burst-suppression interburst interval.

Bacillus cereus meningoencephalitis in preterm infants: neuroimaging characteristics.

BACKGROUND AND PURPOSE: Meningoencephalitis can severely damage the developing brain. Preterms are more prone for nosocomial infections with pathogens other than Group B streptococci and Escherichia coli. In this report we focus on the deleterious clinical course and imaging characteristics of proven Bacillus cereus meningoencephalitis. METHODS: We collected 3 cases of proven Bacillus cereus meningoencephalitis. In the medical records we focused on prenatal, perinatal, and postnatal risk factors. Imaging data of several brain ultrasounds, MR images, and diffusion-weighted images were reevaluated. RESULTS: The ultrasound and MR images show a typical pattern of mainly hemorrhagic and early cavitating, selective white matter destruction. CONCLUSION: Knowledge of this paradigm of acquired brain injury may help to better understand the natural course of these severe neonatal infections.

The Ages and Stages Questionnaire and Neurodevelopmental Impairment in Two-Year-Old Preterm-Born Children.

OBJECTIVE: To test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two. METHODS: We studied the test results of 224 children, born at <32 postmenstrual weeks, who had scores on ASQ3 and Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII) and neurological examination at 22-26 months' corrected age. We defined NDI as a score of <70 on the cognitive--or motor composite scale of BSIDIII, or impairment on neurological examination or audiovisual screening. We compared NDI with abnormal ASQ3 scores, i.e., < -2SDs on any domain, and with ASQ3 total scores. To correct for possible overestimation of BSIDIII, we also analyzed the adjusted BSIDIII thresholds for NDI, i.e., scores <80 and <85. RESULTS: We found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (<70). Twelve children had NDI at BSIDIII thresholds at <80, and 15 had <85. None of the 163 (73%) children who passed ASQ3 had NDI. The sensitivity of ASQ3 to detect NDI was excellent (100%), its specificity was acceptable (76%), and its negative predictive value (NPV) was 100%. Sensitivity and NPV remained high with the adjusted BSIDIII thresholds. CONCLUSION: The Ages and Stages Questionnaire is a simple, valid and cost-effective screening tool to help identify and exclude NDI in very preterm-born children at the corrected age of two years.

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.

BACKGROUND: Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS: In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS: Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION: Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING: European Community's Seventh Framework Programme.