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

Hypoglycemia in infants with hypoxic-ischemic encephalopathy is associated with additional brain injury and worse neurodevelopmental outcome

Objective: To determine the incidence of hypoglycemia among infants with hypoxic-ischemic encephalopathy (HIE) who received therapeutic hypothermia, and to assess whether infants with hypoglycemia had more brain injury on magnetic resonance imaging (MRI) or differences in neurodevelopmental outcome. Study design: Single-center, retrospective cohort study including infants cooled for HIE. Hypoglycemia (blood glucose <36.0 mg/dL <2 hours and <46.8 mg/dL ≥2 hours after birth) was analyzed in the period before brain MRI. Brain injury was graded using a validated score. Motor and neurocognitive outcomes were assessed at 2 years for all survivors, and 5.5 years for a subset who had reached this age. Results: Of 223 infants analyzed, 79 (35.4%) had hypoglycemia. MRI was performed in 187 infants. Infants with hypoglycemia (n = 65) had higher brain injury scores (P = .018). After adjustment for HIE severity, hypoglycemia remained associated with higher injury scores (3.6 points higher; 95% CI, 0.8-6.4). Hyperglycemia did not affect MRI scores. In survivors at 2 years (n = 154) and 5.5 years (n = 102), a univariable analysis showed lower 2-year motor scores and lower motor and cognitive scores at preschool age in infants with hypoglycemia. After adjustment for HIE severity, infants with hypoglycemia had 9 points lower IQs (P = .023) and higher odds of adverse outcomes at preschool age (3.6; 95% CI, 1.4-9.0). Conclusions: More than one-third of infants cooled for HIE had hypoglycemia. These infants had a higher degree of brain injury on MRI and lower cognitive function at preschool age. Strategies to avoid hypoglycemia should be optimized in this setting

Role of patent ductus arteriosus in preterms in long-term outcome

Objective: This study aimed to determine long-term neurodevelopmental outcome and cerebral oxygenation in extremely preterm infants, comparing those with a hemodynamic significant patent ductus arteriosus (hsPDA) to those without. Study design: We included infants born before 28 weeks of gestation from 2008 to 2010 with routine echocardiography. Prior to echocardiography, regional cerebral oxygen saturation was measured. At 5 years of age, we evaluated neurodevelopmental outcomes using the Movement Assessment Battery for Children 2nd Dutch edition for motor skills and the Wechsler Preschool and Primary Scale of Intelligence 3rd Dutch edition for cognition. Results: A total of 66 infants (gestational age 26.6 ± 0.9 weeks, birth weight 912 ± 176 g) were included, 34 infants with a hsPDA (including treatment). The group infants with hsPDA showed lower pre-closure cerebral saturation levels (58.2 % ±7.8 % versus 62.8 % ±7.0 %; p = 0.01). At 5 years, impaired motor outcome occurred more often in infants with hsPDA (17 (53 %) vs. 7 (23 %); p = 0.01). In multivariate analysis existence of hsPDA remained unfavourably related to the motor subdomain “aiming and catching”. There were no potential effects of hsPDA on cognitive performance at 5 years of age. Conclusion: Treatment-receiving infants with hsPDA appear to exhibit motor deficits, specifically in “aiming and catching”, by the age 5. Persistent ductal patency could be a contributing factor

Additional Value of 3-Month Cranial Magnetic Resonance Imaging in Infants with Neonatal Encephalopathy following Perinatal Asphyxia

Objective: To assess the evolution of neonatal brain injury noted on magnetic resonance imaging (MRI), develop a score to assess brain injury on 3-month MRI, and determine the association of 3-month MRI with neurodevelopmental outcome in neonatal encephalopathy (NE) following perinatal asphyxia. Methods: This was a retrospective, single-center study including 63 infants with perinatal asphyxia and NE (n = 28 cooled) with cranial MRI <2 weeks and 2-4 months after birth. Both scans were assessed using biometrics, a validated injury score for neonatal MRI, and a new score for 3-month MRI, with a white matter (WM), deep gray matter (DGM), and cerebellum subscore. The evolution of brain lesions was assessed, and both scans were related to 18- to 24-month composite outcome. Adverse outcome included cerebral palsy, neurodevelopmental delay, hearing/visual impairment, and epilepsy. Results: Neonatal DGM injury generally evolved into DGM atrophy and focal signal abnormalities, and WM/watershed injury evolved into WM and/or cortical atrophy. Although the neonatal total and DGM scores were associated with composite adverse outcomes, the 3-month DGM score (OR 1.5, 95% CI 1.2-2.0) and WM score (OR 1.1, 95% CI 1.0-1.3) also were associated with composite adverse outcomes (occurring in n = 23). The 3-month multivariable model (including the DGM and WM subscores) had higher positive (0.88 vs 0.83) but lower negative predictive value (0.83 vs 0.84) than neonatal MRI. Inter-rater agreement for the total, WM, and DGM 3-month score was 0.93, 0.86, and 0.59. Conclusions: In particular, DGM abnormalities on 3-month MRI, preceded by DGM abnormalities on the neonatal MRI, were associated with 18- to 24-month outcome, indicating the utility of 3-month MRI for treatment evaluation in neuroprotective trials. However, the clinical usefulness of 3-month MRI seems limited compared with neonatal MRI

Prenatal screening for orofacial clefts in the Netherlands: A preliminary report on the impact of a national screening system

In the Netherlands a new and countrywide routine screening system for physical congenital anomalies was introduced by legislation in 2007. The screening was aimed initially at Down syndrome, but under specific conditions secondary screening for cleft lip and palate and other congenital malformations is performed as well. This article gives an overview of the Dutch system, with a focus on cleft lip (and palate) and the report of one center's experience. In general, voluntary termination of pregnancy in the second trimester has increased slightly since the introduction of the current system, but the termination-of-pregnancy rate for isolated cleft lip and palate remains limited in the Netherlands

Hearing-related quality of life, developmental outcomes and performance in children and young adults with unilateral conductive hearing loss due to aural atresia

Background: While research has shown that children with single sided deafness have a lower quality of life and developmental outcomes compared to normal hearing peers, little is known about these domains in children with unilateral congenital conductive hearing loss due to aural atresia. Objectives: This study aims to investigate the hearing-related quality of life, developmental outcomes and educational performance in children and young adults with unilateral conductive hearing loss due to aural atresia. Methods: Nineteen children and young adults with unilateral aural atresia received a set of five questionnaires. Hearing-related quality of life (SSQ), general quality of life (Kidscreen-27), speech and language development (CCC-2-Nl), educational performance and problems in social-emotional and behavioral domains (CBCL/YSR/ASR) were measured with validated questionnaires. Scores on the questionnaires were compared to their norm scores. Mann-Whitney U tests and independent t-tests were used to identify significant differences between age groups. Results: Mean scores on the SSQ subscales were speech 6.78, spatial 5.00 and quality 6.98. Mean scores on the Kidscreen-27, CCC-2-NL, CBCL/YSR/ASR fell within normal or non-clinical range. A high number of cases needed speech therapy (60.7%) or special measures in class (79.3%) or showed grade repetition (>30%) in primary or secondary school. Conclusion: Children and young adults with unilateral conductive hearing loss due to congenital aural atresia showed lower scores regarding hearing-related quality of life compared to normal-hearing peers. The result show similarities with children with single sided deafness. Regarding general quality of life, speech and language development and in social-emotional and behavioral domains the studied children and young adults seem to develop according to norm scores. It is important to observe these children closely as they may need guidance during education to allow them to thrive

Explaining the variable penetrance of CNVs : Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences

Explaining the variable penetrance of CNVs : Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences

Behavioral phenotype in children with 22q11Ds : Agreement between parents and teachers

Patients with the 22q11-deletion syndrome (22q11DS) are at an increased risk of developing schizophrenia. Besides the effects of genetic variation, environmental factors could also be important in modifying the risk of schizophrenia in 22q11DS patients. In particular, previous studies have shown the importance of stress as a precipitating factor of psychosis. An incongruence between the perceived and actual severity of behavioral and cognitive domains could lead caregivers, and even the children themselves, to make demands that are insufficiently adapted to the child's abilities, causing stress and anxiety. Here, we investigate whether such diagnostic discrepancies are indeed present by comparing parent and teacher reports on behavioral concerns in children with 22q11DS. Behavioral questionnaires (CBCL and TRF) were prepared for both parents and teachers of 146 children with 22q11DS. We found that in line with previous reports, internalizing behavior was more frequently reported than externalizing behavior. While the behavioral profiles reported by parents and teachers were remarkably similar, the teachers' ratings were significantly lower (Total problem score p = .002). Age and IQ were not significantly associated with the severity of reported concerns. Our results indicate that indeed a disparity often exists between parents' and teachers' perceptions of the severity of a child's behavioral deficits. This may result in (substantially) different demands and expectations being placed on the child from the two fronts. We speculate that the stress resulting from this lack of cohesion between parents and teachers could precipitate, at least in some 22q11DS children, the emergence of psychosis