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.

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.

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.

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 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.

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.

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.

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders.

BACKGROUND: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. OBJECTIVES: The aim of this study was to analyse complications and outcome after implementation. METHODS: Data were retrieved from an online database to which all centres had contributed. RESULTS: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. CONCLUSIONS: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

Somatosensory evoked potentials are of additional prognostic value in certain patterns of brain injury in term birth asphyxia.

OBJECTIVE: (a) To relate MRI patterns of brain injury to somatosensory evoked potentials (SEPs), and (b) to determine the prognostic value of SEPs in addition to continuous EEG monitoring (cEEG) and cerebral imaging, in term asphyxiated newborns. METHODS: Fifty one consecutive neonates were studied. Survivors were followed for at least 2 years. cEEG, started within 24h, was done for ≥ 24 h and scored. SEPs and MRIs were performed in the first week. Brain injury patterns were classified. RESULTS: Bilaterally abnormal SEPs had a sensitivity of 90% (28/31) and specificity of 85% (17/20) in predicting a poor outcome, defined as death or severe handicap. SEPs were of particular value in predicting outcome in isolated symmetrical white matter injury and predicting the development of hemiparesis in isolated asymmetrical watershed injury. Binary logistic regression analysis revealed a significant relation to outcome separately for cEEG, deep grey matter injury on MRI and SEPs. SEPs provided additional value when added to cEEG and MRI in the model (p=0.034). CONCLUSIONS: SEPs are of additional prognostic value after term birth asphyxia. SIGNIFICANCE: In certain patterns of postasphyxial neonatal brain injury like asymmetrical watershed lesions and symmetrical white matter injury, EPs are complementary to information obtained from cEEG and MRI for prognostication.

Ictal nystagmus in a newborn baby after birth asphyxia.

Ictal nystagmus (IN) is an uncommon phenomenon characterized by rhythmic saccadic eye movements occurring during epileptic seizures. We report a newborn baby with severe birth asphyxia, undergoing long-term video EEG monitoring with electro-oculogram (EOG), who showed irregular IN when eye movements crossed the midline from left to right and vice versa, resulting in large amplitude of the nystagmoid movements. The nystagmus was followed 15 to 29 seconds later by ictal discharges in the occipital regions. MRI of the brain showed features suggestive of periventricular leukomalacia. This interesting combination of findings suggests a complex mechanism for IN of cortical or subcortical ictal rhythms, which results in (a) the generation of subcortical electrical discharges in the pons and midbrain, causing nystagmoid eye movements, and (b) subsequent occipital spiking. We conclude that this clinical manifestation supports the existence of functioning cortical-subcortical connections between the brainstem ocular motor centers and the occipital cortex at birth.