The DUX-25 after Twenty-Five Years: New Analyses and Reference Data.

Twenty-five years after its inception, we present new analyses and reference data for the DUX-25, a questionnaire on health-related quality of life for children 8-17 years old and their parents as proxy. Data from 774 healthy children and their caregivers were collected through web-based data collection. Participants were recruited via primary and secondary schools in the Netherlands. The DUX-25 showed adequate psychometric qualities. Using exploratory and confirmatory factor analyses, we were able to support the theorized four-factor model. In addition, a model with five factors emerged in which the factor 'Social' was divided into 'Social Close' and 'Social Far'. A comparison of the outcomes of the PedsQL with those of the DUX-25 provides evidence for a high construct validity of the DUX-25. With the new updated reference data, the DUX-25 can still be used in inpatient and outpatient settings to measure health-related quality of life of children with chronic conditions.

Sex differences in children's health status as measured by the Pediatric Quality of Life Inventory (PedsQL)™: cross-sectional findings from a large school-based sample in the Netherlands.

BACKGROUND: Previous research has shown that female adolescents and adults report lower health status than their male peers. Possibly, this discrepancy already develops during childhood. We collected sex-specific data with the Pediatric Quality of Life Inventory (PedsQL) in a large school-based sample. METHODS: The online version of the PedsQL was administered to healthy Dutch children aged 5-7 years (parent proxy-report), 8-12 years (parent proxy-report and child self-report), and 13-17 years (parent proxy-report and child self-report), recruited through regular primary and secondary schools. Sex differences were assessed using t-tests or Mann-Whitney U-tests. Wilcoxon signed-rank tests and intraclass correlation coefficients served to compare parent proxy-reports with child self-reports. Multivariable linear regression analyses were used to assess the associations of sex of the child, age, and parental educational level with PedsQL scores. RESULTS: Eight hundred eighty-two parents and five hundred eighty one children were recruited from 15 different schools in the Netherlands. Parents of 8-to-12-year-olds reported higher scores on School Functioning for girls than for boys (mean difference [MD]: 6.56, p < 0.001). Parents of 13-to-17-year-olds reported lower scores on Physical and Emotional Functioning for girls than for boys (MDs: 2.14 and 5.79, p = 0.014 and p < 0.001, respectively). Girls aged 8-12 years reported lower scores than boys in this age group on Physical Functioning (MD: 3.09, p = 0.005). Girls aged 13-17 years reported lower scores than boys in this age group on Physical Functioning (MD: 3.67, p < 0.001), Emotional Functioning (MD: 8.11, p < 0.001), and the Total Score (MD 3.26, p = 0.004). No sex differences were found in children aged 5-7 years. Agreement between child self-reports and parent proxy-reports was poor to moderate. CONCLUSIONS: Girls generally had lower PedsQL scores than boys, both in parent proxy-reports and in child self-reports. We recommend to apply sex-specific data when assessing health status using the PedsQL.

Training-induced white matter microstructure changes in survivors of neonatal critical illness: A randomized controlled trial.

In a nationwide randomized controlled trial, white matter microstructure was assessed before and immediately after Cogmed Working-Memory Training (CWMT) in school-age neonatal critical illness survivors. Eligible participants were survivors (8-12 years) with an IQ ≥ 80 and a z-score of ≤ -1.5 on (working)memory test at first assessment. Diffusion Tensor Imaging was used to assess white matter microstructure. Associations between any training-induced changes and improved neuropsychological outcome immediately and one year post-CWMT were evaluated as well. The trial was conducted between October 2014-June 2017 at Erasmus MC-Sophia, Rotterdam, Netherlands. Researchers involved were blinded to group allocation. Participants were randomized to CWMT(n = 14) or no-intervention(n = 20). All children completed the CWMT. Global fractional anisotropy(FA) increased significantly post-CWMT compared to no-intervention(estimated-coefficient = .007, p = .015). Increased FA(estimated coefficient = .009, p = .033) and decreased mean diffusivity(estimated-coefficient = -.010, p = .018) were found in the left superior longitudinal fasciculus(SFL) post-CWMT compared no-intervention. Children after CWMT who improved with >1SD on verbal working-memory had significantly higher FA in the left SLF post-CWMT(n = 6; improvement = .408 ±â€¯.01) than children without this improvement post-CWMT(n = 6; no-improvement = .384 ±â€¯.02), F(1,12) = 6.22, p = .041, ηp2 = .47. No other structure-function relationships were found post-CWMT. Our findings demonstrate that white matter microstructure and associated cognitive outcomes are malleable by CWMT in survivors of neonatal critical illness.

Working Memory Training Following Neonatal Critical Illness: A Randomized Controlled Trial.

OBJECTIVES: To test the immediate and long-term effectiveness of Cogmed Working Memory Training following extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. DESIGN: A nationwide randomized controlled trial assessing neuropsychologic outcome immediately and 1 year post Cogmed Working Memory Training, conducted between October 2014 and June 2017. Researchers involved in the follow-up assessments were blinded to group allocation. SETTING: Erasmus MC-Sophia Children's Hospital, Rotterdam, and Radboud University Medical Center, Nijmegen, the Netherlands. PATIENTS: Eligible participants were neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors (8-12 yr) with an intelligence quotient greater than or equal to 80 and a z score less than or equal to -1.5 on at least one (working) memory test at first assessment. INTERVENTIONS: Cogmed Working Memory Training, comprising 25 45-minute training sessions for 5 consecutive weeks at home. MEASUREMENTS AND MAIN RESULTS: Participants were randomized to Cogmed Working Memory Training (n = 19) or no intervention (n = 24) (two dropped out after T0). Verbal working memory (estimated coefficient = 0.87; p = 0.002) and visuospatial working memory (estimated coefficient=0.96, p = 0.003) significantly improved at T1 post Cogmed Working Memory Training but was similar between groups at T2 (verbal, p = 0.902; visuospatial, p = 0.416). Improvements were found at T2 on long-term visuospatial memory following Cogmed Working Memory Training (estimated coefficient = 0.95; p = 0.003). Greater improvements in this domain at T2 following Cogmed Working Memory Training were associated with better self-rated school functioning (r = 0.541; p = 0.031) and parent-rated attention (r = 0.672; p = 0.006). CONCLUSIONS: Working memory improvements after Cogmed Working Memory Training disappeared 1 year post training in neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors. Gains in visuospatial memory persisted 1 year post intervention. Cogmed Working Memory Training may be beneficial for survivors with visuospatial memory deficits.

Neurobiologic Correlates of Attention and Memory Deficits Following Critical Illness in Early Life.

OBJECTIVES: Survivors of critical illness in early life are at risk of long-term-memory and attention impairments. However, their neurobiologic substrates remain largely unknown. DESIGN: A prospective follow-up study. SETTING: Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. PATIENTS: Thirty-eight school-age (8-12 yr) survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia with an intelligence quotient greater than or equal to 80 and a below average score (z score ≤ -1.5) on one or more memory tests. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intelligence, attention, memory, executive functioning, and visuospatial processing were assessed and compared with reference data. White matter microstructure and hippocampal volume were assessed using diffusion tensor imaging and structural MRI, respectively. Global fractional anisotropy was positively associated with selective attention (ß = 0.53; p = 0.030) and sustained attention (ß = 0.48; p = 0.018). Mean diffusivity in the left parahippocampal region of the cingulum was negatively associated with visuospatial memory, both immediate (ß = -0.48; p = 0.030) and delayed recall (ß = -0.47; p = 0.030). Mean diffusivity in the parahippocampal region of the cingulum was negatively associated with verbal memory delayed recall (left: ß = -0.52, p = 0.021; right: ß = -0.52, p = 0.021). Hippocampal volume was positively associated with verbal memory delayed recall (left: ß = 0.44, p = 0.037; right: ß = 0.67, p = 0.012). Extracorporeal membrane oxygenation treatment or extracorporeal membrane oxygenation type did not influence the structure-function relationships. CONCLUSIONS: Our findings indicate specific neurobiologic correlates of attention and memory deficits in school-age survivors of neonatal extracorporeal membrane oxygenation and congenital diaphragmatic hernia. A better understanding of the neurobiology following critical illness, both in early and in adult life, may lead to earlier identification of patients at risk for impaired neuropsychological outcome with the use of neurobiologic markers.

Neuropsychological Follow-up After Neonatal ECMO.

OBJECTIVE: To assess the longitudinal development of intelligence and its relation to school performance in a nationwide cohort of neonatal extracorporeal membrane oxygenation (ECMO) survivors and evaluate predictors of outcome at 8 years of age. METHODS: Repeated measurements assessed intelligence of neonatal ECMO survivors at 2, 5, and 8 years (n = 178) with the use of validated, standardized instruments. Selective attention (n = 148) and type of education were evaluated in the 8-year-olds. RESULTS: Intelligence remained stable and average across development (mean ± SD IQ: at 2 years, 102 ± 18; at 5 years, 100 ± 17; and at 8 years, 99 ± 17 [P = .15]). Children attending regular education without the need for help (n = 101; mean z score: -1.50 ± 1.93) performed significantly better on the selective attention task compared with those children who needed extra help (n = 65; mean z score: -2.54 ± 3.18) or those attending special education (n = 13; mean z score: -4.14 ± 3.63) (P = .03). However, only children attending special education had below-average intelligence (mean IQ: 76 ± 15), compared with average intelligence for those attending regular education, both with help (mean IQ: 95 ± 15) and without help (mean IQ: 105 ± 16). Compared with children with other diagnoses, children with congenital diaphragmatic hernia (CDH) scored significantly lower on both IQ (CDH, mean IQ: 93 ± 20; meconium aspiration syndrome, mean IQ: 100 ± 15; other diagnoses, mean IQ: 100 ± 19 [P = .04]) and selective attention (CDH, mean z score: -3.48 ± 3.46; meconium aspiration syndrome, mean z score: -1.60 ± 2.13; other diagnoses, mean z score: -1.65 ± 2.39 [P = .002]). CONCLUSIONS: For the majority of neonatal ECMO survivors, intelligence testing alone did not identify those at risk for academic problems. We propose internationally standardized follow-up protocols that focus on long-term, problem-oriented neuropsychological assessment.

A randomized controlled trial studying the effectiveness of group medical appointments on self-efficacy and adherence in sickle cell disease (TEAM study): study protocol.

BACKGROUND: Sickle cell disease (SCD) is endemic in non-Western countries. Due to migration, the prevalence of SCD in the Netherlands has increased. Adherence to medical treatment is recognized as a major problem area. Therefore, new effective interventions to increase adherence are urgently needed. METHODS/DESIGN: The TEAM study is an ongoing randomized controlled trial (RCT) to compare protocolized individual medical appointments (IMA's; care-as-usual) with protocolized group medical appointments (GMA's; novel intervention) in pediatric (n = 40) and adult (n = 60) patients. The study aims to assess the effectiveness of GMA's (over a three year period) on patients' self-efficacy, adherence, quality of life, morbidity, hospital admissions and satisfaction with the treating professional; as well as to test the cost-effectiveness of GMA's. In both the IMA and GMA groups structured assessments will be performed at baseline (start of the study), after 1.5 and after 3 years. DISCUSSION: This is the first RCT to investigate the effectiveness of GMA's on self-efficacy and adherence in pediatric and adult patients with SCD, including a cost-effectiveness analysis. TRIAL REGISTRATION: NTR4750 (NL42182.000.12). Registered 13 August 2014.

Growing Up After Critical Illness: Verbal, Visual-Spatial, and Working Memory Problems in Neonatal Extracorporeal Membrane Oxygenation Survivors.

OBJECTIVES: To assess neuropsychologic outcome in 17- and 18-year-old neonatal extracorporeal membrane oxygenation survivors. DESIGN: A prospective longitudinal follow-up study. SETTING: Follow-up program at the Erasmus MC-Sophia Children's Hospital in Rotterdam, The Netherlands. PATIENTS: Thirty adolescents 17 or 18 years old, treated between 1991 and 1997, underwent neuropsychologic assessment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Attention, memory, executive functioning, visual-spatial functions, social-emotional functioning, and behavior were assessed with validated instruments, and data were compared with reference data. Included predictors for analysis of adverse outcome were diagnosis, age at start extracorporeal membrane oxygenation, convulsions, and use of antiepileptics. Adolescents' performance (expressed as mean [SD] z score) was significantly lower than the norm on short-term and long-term verbal memory (z score = -1.40 [1.58], p = 0.016; z score = -1.54 [1.67], p = 0.010, respectively), visual-spatial memory (z score = -1.65 [1.37], p = 0.008; z score = -1.70 [1.23], p = 0.008, respectively), and working memory (32% vs 9% in the norm population). Parents reported more problems for their children regarding organization of materials (z score = -0.60 [0.90]; p = 0.03) and behavior evaluation (z score = -0.53 [0.88]; p = 0.05) on a questionnaire. Patients reported more withdrawn/depressed behavior (z score = -0.47 [0.54]; p = 0.02), somatic complaints (z score = -0.43 [0.48]; p = 0.03), and social problems (z score = -0.41 [0.46]; p = 0.04). Patients reported more positive feelings of self-esteem and an average health status. CONCLUSIONS: Adolescents treated with neonatal extracorporeal membrane oxygenation are at risk of verbal, visual-spatial, and working memory problems. Future research should focus on 1) the longitudinal outcome of specific neuropsychologic skills in adolescence and adulthood; 2) identifying risk factors of neuropsychologic dysfunction; 3) evaluating to what extent "severity of illness" is responsible for acquired brain injury; and 4) effects of timely cognitive rehabilitation.

Neurodevelopmental, educational and behavioral outcome at 8 years after neonatal ECMO: a nationwide multicenter study.

PURPOSE: Reporting neurodevelopmental outcome of 8-year-old children treated with neonatal extracorporeal membrane oxygenation (ECMO). METHODS: In a follow-up study in 135 8-year-old children who received neonatal ECMO between 1996 and 2001 we assessed intelligence (Revised Amsterdam Intelligence Test), concentration (Bourdon-Vos test), eye-hand coordination (Developmental Test of Visual-Motor Integration) and behavior (Child Behavior Checklist and Teacher Report Form). RESULTS: Intelligence fell within normal range (mean IQ 99.9, SD 17.7, n = 125) with 91 % of the children following regular education. Significantly more children attended special education (9 %) or received extra support in regular education (39 %) compared with normative data. Slower working speed (χ(2) = 132.36, p < 0.001) and less accuracy (χ(2) = 12.90, p < 0.001) were found on the Bourdon-Vos test (n = 123) compared with normative data. Eye-hand coordination fell within the normal range (mean 97.6, SD 14.3, n = 126); children with congenital diaphragmatic hernia scored lowest but still normally (mean 91.0, SD 16.4, n = 28). Mothers (n = 117) indicated more somatic and attention behavior problems; teachers (n = 115) indicated more somatic, social, thought, aggression and total problems compared with normative data. Mothers indicated more somatic problems than teachers (p = 0.003); teachers reported more attention problems than mothers (p = 0.036; n = 111). CONCLUSIONS: Eight-year-old children treated with neonatal ECMO fall in the normal range of intelligence with problems with concentration and behavior. Long-term follow-up for children treated with neonatal ECMO should focus on early detection of (subtle) learning deficits.

Congenital diaphragmatic hernia with(out) ECMO: impaired development at 8 years.

OBJECTIVE: To evaluate developmental and social-emotional outcomes at 8 years of age for children with congenital diaphragmatic hernia (CDH), treated with or without neonatal extracorporeal membrane oxygenation (ECMO) between January 1999 and December 2003. DESIGN: Cohort study with structural prospective follow-up. SETTING: Level III University Hospital. PATIENTS: 35 children (ECMO: n=16; non-ECMO: n=19) were assessed at 8 years of age. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Intelligence and motor function. Concentration, behaviour, school performance, competence and health status were also analysed. RESULTS: Mean (SD) intelligence for the ECMO group was 91.7 (19.5) versus 111.6 (20.9) for the non-ECMO group (p=0.015). Motor problems were apparent in 16% of all participants and differed significantly from the norm (p=0.015) without differences between treatment groups. For all participants, problems with concentration (68%, p<0.001) and with behavioural attention (33%, p=0.021) occurred more frequently than in reference groups, with no difference between treatment groups. School performance and competence were not affected. CONCLUSIONS: Children with CDH-whether or not treated with neonatal ECMO-are at risk for long-term morbidity especially in the areas of motor function and concentration. Despite their impairment, children with CDH have a well-developed feeling of self-competence.

Sensorineural hearing loss and language development following neonatal extracorporeal membrane oxygenation.

OBJECTIVES: To determine the prevalence of hearing loss in school-age children who have undergone neonatal extracorporeal membrane oxygenation treatment and to identify any effects of hearing loss on speech- and language development [corrected] . DESIGN: Prospective longitudinal follow-up study within the framework of a structured post-extracorporeal membrane oxygenation follow-up program. SETTING: Outpatient clinic of a level III university hospital. RESULTS: Tone audiometry was performed by standardized protocol in 136 children aged 5-12 yrs. Hearing loss was considered clinically significant when >20 dB. Hearing was normal in 75.7% of children. Five children (3.7%) had bilateral sensorineural or combined hearing loss; three of them received special audiological care (2.2% of total sample). Of the 24 children with congenital diaphragmatic hernia, 19 (79.2%) had normal hearing and only two (8.3%) had mild sensorineural hearing loss, unilateral in one of them. Follow-up at 24 months of age had shown normal verbal and nonverbal developmental scores. Language development and intelligence median (range) scores at 5 yrs of age were also normal: receptive language development 104 (55-133), syntactical development 104 (68-132), and lexical development 101 (50-141) for 89 children; intelligence quotient 104 (68-132) for 106 children. Scores did not differ among those with normal hearing, mild hearing loss, and moderate-to-severe hearing loss (p = 0.800, p = 0.639, p = 0.876, and p = 0.886, for the respective developmental tests). CONCLUSIONS: We found normal language development and intelligence in a cohort of neonatal extracorporeal membrane oxygenation survivors. The prevalence of bilateral sensorineural hearing loss was in accordance with that of a larger series in the United States-which exceeds the prevalence in the normal population.

Neonatal extracorporeal membrane oxygenation: impaired health at 5 years of age.

OBJECTIVE: Children treated with neonatal extracorporeal membrane oxygenation may show physical and mental morbidity at a later age. We compared the health-related quality of life of these children with normative data. DESIGN: Prospective longitudinal follow-up study. SETTING: Outpatient clinic of a level III university hospital. PATIENTS: Ninety-five 5-yr-old children who had received neonatal extracorporeal membrane oxygenation support between January 1999 and December 2005. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pediatric quality of life inventory was administered at 5 yrs of age. The mothers (n = 74) as proxy-reporters assigned significantly lower health-related quality of life scores for their children than did the parents in the healthy reference group for the total functioning scale of the pediatric quality of life inventory (mean difference: 8.1; p < 0.001). Mothers' scores for 31 children (42%) were indicative of impaired health-related quality of life (≥-1 SD below the reference norm). The children (n = 78) themselves scored significantly lower than did their healthy peers on total functioning (mean difference: 11.0; p < 0.001). Thirty-two children (41%) indicated an impaired health-related quality of life themselves. For the mother proxy- reports, the duration of extracorporeal membrane oxygenation support (R = 0.009; p = 0.010) and the presence of chronic lung disease (R = 0.133; p = 0.002) were negatively related to total functioning. Children with a disabled health status for neuromotor functioning, maximum exercise capacity, behavior, and cognitive functioning at 5 yrs of age had a higher odds ratio of also having a lower health-related quality of life. Health status had no influence on reported emotional functioning. CONCLUSIONS: Overall, children treated with extracorporeal membrane oxygenation in the neonatal period reported low health-related quality of life at 5 yrs of age. Because only emotional health-related quality of life was not associated with health status, the pediatric quality of life inventory might be a measure of health status rather than of health-related quality of life. In contrast with conclusions from others, we found that 5-yr-old children might be too young to rate their own health-related quality of life.