Association between bronchopulmonary dysplasia severity and its risk factors and long-term outcomes in three definitions: a historical cohort study.

OBJECTIVE: To compare the association of the severity categories of the 2001-National Institutes of Health (NIH), the 2018-NIH and the 2019-Jensen bronchopulmonary dysplasia (BPD) definitions with neurodevelopmental and respiratory outcomes at 2 and 5 years' corrected age (CA), and several BPD risk factors. DESIGN: Single-centre historical cohort study with retrospective data collection. SETTING: Infants born between 2009 and 2015 at the Amsterdam University Medical Centers, location Amsterdam Medical Center. PATIENTS: Preterm infants born at gestational age (GA) <30 weeks and surviving up to 36 weeks' postmenstrual age. INTERVENTIONS: Perinatal characteristics, (social) demographics and comorbidities were collected from the electronic patient records. MAIN OUTCOME MEASURES: The primary outcomes were neurodevelopmental impairment (NDI) or late death, and respiratory morbidity at 2 and 5 years' CA. Using logistic regression and Brier scores, we investigated if the ordinal grade severity is associated with incremental increase of adverse long-term outcomes. RESULTS: 584 preterm infants (median GA: 28.1 weeks) were included and classified according to the three BPD definitions. None of the definitions showed a clear ordinal incremental increase of risk for any of the outcomes with increasing severity classification. No significant differences were found between the three BPD definitions (Brier scores 0.169-0.230). Respiratory interventions, but not GA, birth weight or small for GA, showed an ordinal relationship with BPD severity in all three BPD definitions. CONCLUSION: The severity classification of three BPD definitions showed low accuracy of the probability forecast on NDI or late death and respiratory morbidity at 2 and 5 years' CA, with no differences between the definitions.

Nutritional intake and growth until two years of age in moderate and late preterms.

BACKGROUND AND AIM: Moderate and late preterm infants (MLPTI) (gestational age 32 0/7-36 6/7 weeks), are at risk for suboptimal growth. This study evaluated adherence to nutritional recommendations until 6 months corrected age (CA), growth until 2 years CA, and associations between nutritional intake and growth until 2 years CA. METHODS: We prospectively collected nutritional intakes from 100 MLPTI during the first week of life and at 6 weeks, 3 months, and 6 months CA. Anthropometry was assessed at birth, discharge, term age, and at 6 weeks, 3 months, 6 months, 1 year, and 2 years CA. RESULTS: On day 7, <40% reached nutritional recommendations. Thereafter, >80% reached protein recommendations until 6 months of life, but <60% reached energy recommendations. Weight z-scores increased from -0.44 at term-age to 0.59 at 3 months CA, but declined to -0.53 at 2 years CA on the TNO curves. No significant associations were found between nutritional intake and growth until 2 years CA. CONCLUSION: No associations were demonstrated between nutritional intakes and growth until 2 years CA, despite not reaching recommended intakes. Despite high efforts to optimize growth, MLPTI find their own growth curve in the first 2 years of life. IMPACT: This research is pioneering in identifying how nutrition influences growth in moderate and late preterm infants (MLPTI) up to 2 years corrected age (CA). MLPTI often do not meet the recommended protein and energy intake in their first week of life, suggesting that current guidelines might be too high. No association was demonstrated between nutritional intake and growth of MLPTI in the first 2 years of life. Initially, MLPTI show an increase in weight z-scores from term age up to 3 months CA but experience a decline in weight z-scores at 2 years CA, according to TNO growth charts.

Risk Factors for Neurodevelopmental Impairment at 2- and 5-Years Corrected Age in Preterm Infants with Established Bronchopulmonary Dysplasia.

INTRODUCTION: The objective of this study was to identify risk factors for neurodevelopmental impairment (NDI) at 2- and 5-years corrected age (CA) in a cohort of preterm infants with established bronchopulmonary dysplasia (BPD). METHODS: This single-center retrospective cohort study included infants born between 2009 and 2016 at a gestational age (GA) <30 weeks with moderate or severe BPD at 36 weeks' postmenstrual age. Perinatal characteristics, (social) demographics, and comorbidities were collected from the electronic patient records. Odds ratios for NDI were calculated with univariate and multivariate logistic regression analyses adjusting for potential confounders. RESULTS: Of the 602 eligible infants, 123 infants were diagnosed with BPD. NDI was present in 30.3% and 56.1% at 2- and 5-years CA, respectively. The only independent risk factors associated with NDI in the multivariate analyses were birthweight (adjusted odds ratio [aOR] 0.74, 95% CI 0.57-0.95; aOR 0.70, 95% CI 0.54-0.91, respectively), small for GA (SGA) (aOR 3.25, 95% CI 1.09-9.61; aOR 5.44, 95% CI 1.62-18.2, respectively) at both time points, and male gender at 5-years CA (OR 2.49, 95% CI 1.11-5.57). CONCLUSION: Birthweight and SGA are independent risk factors for NDI at 2- and 5-years CA and male gender at 5-years CA in preterm infants with BPD. In contrast, well-known other risk factors for NDI in the general population of preterm infants, such as GA, maternal education, and neonatal comorbidities were not independently associated with NDI.

Duration of Neonatal Antibiotic Exposure in Preterm Infants in Association with Health and Developmental Outcomes in Early Childhood.

Over 90% of preterm neonates are, often empirically, exposed to antibiotics as a potentially life-saving measure against sepsis. Long-term outcome in association with antibiotic exposure (NABE) has insufficiently been studied after preterm birth. We investigated the association of NABE-duration with early-childhood developmental and health outcomes in preterm-born children and additionally assessed the impact of GA on outcomes. Preterm children (GA < 30 weeks) participating in a multicenter cohort study were approached for follow-up. General expert-reviewed health questionnaires on respiratory, atopic and gastrointestinal symptoms were sent to parents of children > 24 months' corrected age (CA). Growth and developmental assessments (Bayley Scales of Infant and Toddler Development (BSID) III) were part of standard care assessment at 24 months' CA. Uni- and multivariate regressions were performed with NABE (per 5 days) and GA (per week) as independent variables. Odds ratios (OR) for health outcomes were adjusted (aOR) for confounders, where appropriate. Of 1079 infants whose parents were approached, 347 (32%) responded at a mean age of 4.6 years (SD 0.9). In children with NABE (97%), NABE duration decreased by 1.6 days (p < 0.001) per week of gestation. Below-average gross-motor development (BSID-III gross-motor score < 8) was associated with duration of NABE (aOR = 1.28; p = 0.04). The aOR for constipation was 0.81 (p = 0.04) per gestational week. Growth was inversely correlated with GA. Respiratory and atopic symptoms were not associated with NABE, nor GA. We observed that prolonged NABE after preterm birth was associated with below-average gross-motor development at 24 months' CA, while a low GA was associated with lower weight and stature Z-scores and higher odds for constipation.

Long-Term Follow-Up of Daily Life Functioning After Pediatric Intensive Care Unit Admission.

OBJECTIVE: To investigate the long-term impact of pediatric intensive care unit (PICU) admission on daily life functioning while exploring the potential mediating role of neurocognitive outcome. STUDY DESIGN: This cross-sectional observational study compared children aged 6-12 years with previous PICU admission (age ≤1 year) for bronchiolitis requiring mechanical ventilation ("patient group," n = 65) to demographically comparable healthy peers ("control group," n = 76). The patient group was selected because bronchiolitis is not expected to affect neurocognitive functioning in itself. Assessed daily life outcome domains were behavioral and emotional functioning, academic performance, and health-related quality of life (QoL). The role of neurocognitive outcomes in the relationship between PICU admission and daily life functioning was assessed by mediation analysis. RESULTS: The patient group did not differ from the control group regarding behavioral and emotional functioning but performed poorer on academic performance and school-related QoL (Ps ≤ .04, d = -0.48 to -0.26). Within the patient group, lower full-scale IQ (FSIQ) was associated with poorer academic performance and school-related QoL (Ps ≤ .02). Poorer verbal memory was associated with poorer spelling performance (P = .002). FSIQ mediated the observed effects of PICU admission on reading comprehension and arithmetic performance. CONCLUSIONS: Children admitted to the PICU are at risk for long-term adverse daily life outcomes in terms of academic performance and school-related QoL. Findings suggest that lower intelligence may contribute to academic difficulties after PICU admission. Findings underline the importance of monitoring daily life and neurocognitive functioning after PICU admission.

Structured Multidisciplinary Follow-Up After Pediatric Intensive Care: A Model for Continuous Data-Driven Health Care Innovation.

OBJECTIVES: Morbidity after PICU admission for critical illness is a growing concern. Sequelae may occur in various domains of functioning and can only appropriately be determined through structured follow-up. Here, we describe the process of designing and implementing a structured multidisciplinary follow-up program for patients and their parents after PICU admission and show the first results illustrating the significance of our program. DESIGN: Prospective observational cohort study. SETTING: Outpatient PICU follow-up clinic. PATIENTS: Patients 0-18 years old admitted to our PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In our structured multidisciplinary follow-up program, follow-up care is provided by a pediatric intensivist and psychologist and in addition, depending on patient's critical illness and received PICU treatment(s), by a pediatric pulmonologist, cardiologist, neurologist, and/or neuropsychologist. All consultations are scheduled consecutively. Collected data are stored in a hospital-wide data warehouse and used for yearly health care evaluation sessions as well as scientific research. Challenges in organizing this follow-up program include technological challenges, providing time-efficient care, participation rate, and completeness of questionnaires. In our experience, a dedicated team is essential to tackle these challenges. Our first results, obtained in 307 of 388 referred patients (79.1%), showed the diversity of problems arising after PICU discharge, including physical, neurocognitive, and psychosocial sequelae. In addition, our data also reflected the risk of psychosocial problems among parents. Within the limited operation time of our follow-up program, the program has evolved based on our experiences and the data collected. CONCLUSIONS: We successfully developed and implemented a structured multidisciplinary follow-up program for patients and their parents after PICU admission. This program may help to timely initiate appropriate interventions, improve the standard of care during and after PICU admission, and facilitate scientific research on outcome and prognosis after PICU admission.

Childhood outcomes after induction of labor or expectant management for preterm prelabor rupture of membranes: a 10-year follow-up of the PPROMEXIL trials.

BACKGROUND: Management of late preterm prelabor rupture of membranes between 34+0 and 36+6 weeks' gestation balances the risks of preterm birth with the risks of infection for both the mother and the neonate. Expectant management to prolong pregnancy showed similar risks of neonatal sepsis, but children at 2 years of age showed more neurodevelopmental delay when compared with induction of labor. Long-term outcomes on child development after 2 years of age are unknown. OBJECTIVE: This study aimed to assess the long-term outcomes of children born after singleton pregnancies complicated by late preterm prelabor rupture of membranes managed by induction of labor in comparison with expectant management. STUDY DESIGN: This was a follow-up study of the Preterm Prelabor Rupture of Membranes Expectant Management Versus Induction of Labor (PPROMEXIL) trials (randomized controlled trials between 2007 to 2011) evaluating children at 10 to 12 years of age (Netherlands Trial Register 6953). The primary outcomes were cognition, motor function, and behavior as assessed by the Wechsler Intelligence Scale for Children-V-NL, Movement Assessment Battery for Children-2, and Child Behavior Checklist, respectively. The secondary outcomes were sensory processing, respiratory problems, educational attainment, and general health. Mild delay was defined as -1 standard deviation or corresponding percentile. The relative risk and confidence intervals were calculated using standard methods. RESULTS: This follow-up study invited 711 surviving children of the 714 singleton pregnancies randomized in the original trials. In total, 248 (35%) children participated (127 induction of labor, 121 expectant management). Children born after induction of labor had no significant differences in the primary outcomes when compared with those born after expectant management. Mild cognitive delay was observed in 7 of 122 (5.7%) children born after induction of labor in comparison with in 12 of 120 (10.0%) children born after expectant management (relative risk, 0.57; 95% confidence interval, 0.23-1.41). A mild delay in motor function was observed in 42 of 122 (34.4%) children born after induction of labor vs in 55 of 120 (45.8%) children born after expectant management (relative risk, 0.75; 95% confidence interval, 0.55-1.03). Mild abnormal behavior was observed in 37 of 125 (29.6%) children born after induction of labor compared with in 33 of 118 (28.0%) children born after expectant management (relative risk, 1.05; 95% confidence interval, 0.71-1.57). Secondary outcomes were also comparable between the induction of labor and the expectant management groups except that more children born after expectant management had a hospital admission (relative risk, 0.68; 95% confidence interval, 0.52-0.89) or a surgery (relative risk, 0.58; 95% confidence interval, 0.41-0.82). CONCLUSION: In children born after pregnancies with late preterm prelabor rupture of membranes, expectant management did not improve long-term outcomes at 10 to 12 years when compared with induction of labor.

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.

Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants.

OBJECTIVE: To compare the discriminative performances of the 2018 National Institutes of Health (NIH) and the 2019 Jensen definitions of bronchopulmonary dysplasia (BPD) with the 2001 NIH definition on adverse neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age. STUDY DESIGN: In this single-center retrospective cohort study, outcomes of infants born at <30 weeks of gestational age were collected. The 3 definitions of BPD were compared by adding the different definitions to the National Institute of Child Health and Human Development's outcome prediction model for neurodevelopmental impairment (NDI) or death. Discriminative performance was compared for both outcomes at 2 years and 5 years corrected age by calculating the areas under the receiver operating characteristic curve and z-statistics. RESULTS: The presence of BPD and its severity were determined in 584 infants. There were considerable shifts in BPD grading among the different definitions. At both time points, all BPD definition models had comparable discriminating power for NDI and respiratory morbidity, with one exception. Compared with the 2001 NIH definition, the 2018 NIH definition had less predictive power for the neurologic outcome at 2 years corrected age. CONCLUSIONS: Our comparison of the 3 BPD definitions shows similar discriminative performance on long term neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age.

Preterm Birth is Associated with Lower Academic Attainment at Age 12 Years: A Matched Cohort Study by Linkage of Population-Based Datasets.

OBJECTIVE: To compare academic attainment at age 12 years in preterm children born below 30 weeks of gestation with matched term-born peers, using standardized, nationwide and well-validated school tests. STUDY DESIGN: This population-based, national cohort study was performed by linking perinatal data from the nationwide Netherlands Perinatal Registry with educational outcome data from Statistics Netherlands and included 4677 surviving preterm children born at 250/7-296/7 weeks of gestational age and 366 561 controls born at 40 weeks of gestational age in 2000-2007. First, special education participation rate was calculated. Subsequently, all preterm children with academic attainment test data derived at age 12 years were matched to term-born children using year and month of birth, sex, parity, socioeconomic status, and maternal age. Total, language, and mathematics test scores and secondary school level advice were compared between these 2 groups. RESULTS: Children below 30 weeks of gestation had a higher special education participation rate (10.2% vs 2.7%, P < .001) than term-born peers. Preterm children had lower total (-0.37 SD; 95% CI -0.42 to -0.31), language (-0.21 SD; 95% CI -0.27 to -0.15), and mathematics (-0.45 SD; 95%CI -0.51 to -0.38) z scores, and more often a prevocational secondary school level advice (62% vs 46%, P < .001). CONCLUSIONS: A substantial proportion of children born before 30 weeks of gestation need special education at the end of elementary schooling. These children have significant deficits on all measures of academic attainment at age 12 years, especially mathematics, compared with matched term-born peers.

Severity of Bronchopulmonary Dysplasia and Neurodevelopmental Outcome at 2 and 5 Years Corrected Age.

OBJECTIVE: To evaluate the association between bronchopulmonary dysplasia (BPD) severity and risk of neurodevelopmental impairment (NDI) at 2 years and 5 years corrected age and to examine whether this association changes over time. STUDY DESIGN: This single-center retrospective cohort study included patients with a gestational age <30 weeks surviving to 36 weeks postmenstrual age, divided into groups according to BPD severity. NDI was defined as having cognitive or motor abilities below -1 SD, cerebral palsy, or a hearing or a visual impairment. The association was assessed using a multivariate logistic regression model analysis, adjusting for known confounders for NDI, and mixed-model analysis. RESULTS: Of the 790 surviving infants (15% diagnosed with mild BPD, 9% with moderate BPD, and 10% with severe BPD), 88% and 82% were longitudinally assessed at 2 years and 5 years corrected age, respectively. The mixed-model analysis showed a statistically significant increase in NDI at all levels of BPD severity compared with infants with no BPD, and a 5-fold increased risk in NDI was seen from 2 years to 5 years corrected age in all degrees of BPD severity. The strength of this association between NDI and BPD severity did not change over time. CONCLUSIONS: Increased BPD severity is associated with increased risk of NDI at both 2 years and 5 years corrected age. The absolute incidence of NDI increased significantly from 2 years to 5 years corrected age for all BPD severity categories, but this increased risk was similar at both time points in each category.

Long-term follow-up of children exposed in-utero to progesterone treatment for prevention of preterm birth: study protocol of the AMPHIA follow-up.

INTRODUCTION: Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development. METHODS AND ANALYSIS: This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16-20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11-14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers. MAIN OUTCOMES ARE CHILD COGNITION AND BEHAVIOUR: Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used. ETHICS AND DISSEMINATION: Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: NL8933.

Child outcomes after induction of labour or expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks of gestation: study protocol of the PPROMEXIL Follow-up trial. A long-term follow-up study of the randomised controlled trials PPROMEXIL and PPROMEXIL-2.

INTRODUCTION: Late preterm prelabour rupture of membranes (PROM between 34+0 and 36+6 weeks gestational age) is an important clinical dilemma. Previously, two large Dutch randomised controlled trials (RCTs) compared induction of labour (IoL) to expectant management (EM). Both trials showed that early delivery does not reduce the risk of neonatal sepsis as compared with EM, although prematurity-related risks might increase. An extensive, structured long-term follow-up of these children has never been performed. METHODS AND ANALYSIS: The PPROMEXIL Follow-up trial (NL6623 (NTR6953)) aims to assess long-term childhood outcomes of the PPROMEXIL (ISRCTN29313500) and PPROMEXIL-2 trial (ISRCTN05689407), two multicentre RCTs using the same protocol, conducted between 2007 and 2010 evaluating IoL versus EM in women with late preterm PROM. The PPROMEXIL Follow-up will analyse children of mothers with a singleton pregnancy (PPROMEXIL trial n=520, PPROMEXIL-2 trial n=191, total IoL n=359; total EM n=352). At 10-12 years of age all surviving children will be invited for a neurodevelopmental assessment using the Wechsler Intelligence Scale for Children-V, Color-Word Interference Test and the Movement Assessment Battery for Children-2. Parents will be asked to fill out questionnaires assessing behaviour, motor function, sensory processing, respiratory problems, general health and need for healthcare services. Teachers will fill out the Teacher Report Form and answer questions regarding school attainment. For all tests means with SDs will be compared, as well as predefined cut-off scores for abnormal outcome. Sensitivity analyses consisting of different imputation techniques will be used to deal with lost to follow-up. ETHICS AND DISSEMINATION: The study has been granted approval by the Medical Centre Amsterdam (MEC) of the AmsterdamUMC (MEC2016_217). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: NL6623 (NTR6953).

Executive function training in very preterm children: a randomized controlled trial.

Objective of the current study was to assess whether game-formatted executive function (EF) training, is effective in improving attention, EF and academic performance in very preterm and/or extremely low birthweight children aged 8-12 years. A multi-center, double-blind, placebo- and waitlist controlled randomized trial (NTR5365) in two academic hospitals in The Netherlands was performed. Eighty-five very preterm children with parent-rated attention problems on the Child Behavior Checklist were randomized to one of three treatment conditions: EF training, placebo training or waitlist condition. EF or placebo training was completed at home (6 weeks, 25 sessions of 30-45 min each). At baseline, 2 weeks after training or being on the waitlist, and five months after first follow-up visit, children underwent assessments of primary outcomes (parent and teacher ratings of attention) and secondary outcomes (parent and teacher ratings of daily-life EF, computerized EF tasks and academic performance). Linear mixed model analyses were performed for all outcome measures. There were no significant differences in improvement over time on parent- and teacher ratings of attention, parent- and teacher ratings of daily-life EF, computerized EF tasks, and academic performance (arithmetic and reading) between the EF training, placebo training and waitlist condition. In conclusion, game-formatted EF training does not improve attention, EF or academic performance in very preterm children with parent-rated attention problems.

Subtypes of behavioral functioning in 8-12 year old very preterm children.

BACKGROUND: Very preterm children often have difficulties in behavioral functioning, but there is large heterogeneity in the severity of these difficulties and in the combination of the difficulties observed. Few studies so far addressed this heterogeneity by examining whether more homogeneous subtypes of behavioral functioning can be identified. AIMS: To identify behavioral subtypes in a group of very preterm children, examine whether such subtypes are related to neonatal medical complications and/or parental education level (to better understand origins) and to examine whether such subtypes are associated with IQ and neurocognitive deficits in attention and executive function (to study underlying mechanisms of dysfunction). STUDY DESIGN: Cross-sectional cohort study. SUBJECTS: 135 very preterm (gestational age < 30 weeks and/or birthweight < 1000 g) children aged 8-12 years. MEASURES: Parent and teacher questionnaires covering a broad range of behavioral domains, parental education level, neonatal medical complications, short-form Wechsler Intelligence Scale for Children-III and performance-based attention and executive function measures. RESULTS: Cluster analysis indicated two behavioral subtypes: a subtype characterized by low behavioral problems (76% of children) and a subtype characterized by high behavioral problems across behavioral domains (24% of children). Lower parental education level, lower IQ and poorer verbal working memory, visuospatial working memory and inhibition were associated with the high problems subtype, but neonatal medical complications were not. CONCLUSIONS: The majority of very preterm children was assigned to the low behavioral problems subtype. However, if problems do occur, they are wide-spread across behavioral domains and accompanied by problems in neurocognitive domains.

Eight-year-old very and extremely preterm children showed more difficulties in performance intelligence than verbal intelligence.

AIM: This study determined possible discrepancies between verbal IQ and performance IQ in 8-year-old very preterm (VPT) and extremely preterm (EPT) children, and examined associations between verbal IQ and performance IQ, and sociodemographic factors, perinatal factors, early cognitive outcomes and also with school achievement scores. METHODS: This prospective cohort study included 120 eight-year-old VPT/EPT children. Cognitive development was assessed at the ages of 2, 5 and 8 years. Eight years' school achievement results in arithmetic, reading and spelling were collected. Multiple regression analyses were performed to determine predictors of verbal IQ and performance IQ at the age of 8 years and to determine associations with school achievement scores. RESULTS: Mean performance IQ (89.8) was significantly lower than mean verbal IQ (99.4; Cohen's d = 0.59) at the age of 8 years. Gestational age (GA), small for GA status, and cognitive scores at the ages of 2 and 5 years significantly predicted verbal IQ and performance IQ at the age of 8 years. Performance IQ at age 8 years was an important predictor for arithmetic scores (ß = 0.42). CONCLUSION: Performance IQ was more strongly affected than verbal IQ in 8-year-old VPT/EPT children and was strongly related to mathematical difficulties.

Effects of Executive Function Training on Attentional, Behavioral and Emotional Functioning and Self-Perceived Competence in Very Preterm Children: A Randomized Controlled Trial.

OBJECTIVE: Very preterm children have poorer attentional, behavioral and emotional functioning than term-born children. Problems on these domains have been linked to poorer executive function (EF). This study examined effects of a game-formatted, comprehensive EF training on attentional, behavioral and emotional functioning and self-perceived competence in very preterm children. STUDY DESIGN: Eighty-five children participated in a multi-center, double-blind, placebo and waitlist-controlled randomized trial. Children were recruited from neonatal follow-up units of two academic medical centers in The Netherlands. Eligible for inclusion were 8-12 year old children born very preterm (<30 weeks of gestation) and/or with extremely low birthweight (<1000 g) with parent reported attention problems. Children were randomly assigned to one of three treatment arms: EF training, placebo training or waitlist. The EF and placebo training involved a 6 weeks, 25 (30-45 min) sessions training program. Attentional functioning (Attention Network Test), behavioral and emotional functioning (parent and teacher Strengths and Difficulties questionnaire) and self-perceived competence (Self-Perception Profile for Children) were assessed at baseline, at the end of the training program and 5 months after the training was finished. Data analyses involved linear mixed model analyses. RESULTS: Children in the EF training arm significantly improved on all training tasks over the course of the EF training program. Despite these improvements on the EF training tasks, there were no significant differences over time on any of the outcome measures between the three treatment arms, indicating that this computerized EF training program had no beneficial effects. CONCLUSION: Although there were significant improvements in the EF training tasks, there was no generalization of these improvements to any of the outcome measures. Thus, our findings do not support the use of computerized EF training programs. Future research should investigate effectivity of more ecologically valid, real-world like EF training programs.

Executive function deficits in children born preterm or at low birthweight: a meta-analysis.

AIM: To investigate the magnitude of executive function deficits and their dependency on gestational age, sex, age at assessment, and year of birth for children born preterm and/or at low birthweight. METHOD: PubMed, PsychINFO, Web of Science, and ERIC were searched for studies reporting on executive functions in children born preterm/low birthweight and term controls born in 1990 and later, assessed at a mean age of 4 years or higher. Studies were included if five or more studies reported on the same executive function measures. RESULTS: Thirty-five studies (3360 children born preterm/low birthweight, 2812 controls) were included. Children born preterm/low birthweight performed 0.5 standardized mean difference (SMD) lower on working memory and cognitive flexibility and 0.4 SMD lower on inhibition. SMDs for these executive functions did not significantly differ from each other. Meta-regression showed that heterogeneity in SMDs for working memory and inhibition could not be explained by study differences in gestational age, sex, age at assessment, or year of birth. INTERPRETATION: Children born preterm/low birthweight since 1990 perform half a SMD below term-born peers on executive function, which does not seem to improve with more recent advances in medical care or with increasing age. WHAT THIS PAPER ADDS: Children born preterm/low birthweight perform below term-born children on core executive functions. Lower gestational age or male sex are not risk factors for poorer executive functions. Executive function difficulties in children born preterm/low birthweight remain stable across childhood. Executive function difficulties are similar for children born recently and children born in earlier eras.

Developmental outcomes of very preterm children with high parental education level.

BACKGROUND: Compared to their term-born peers, children born very preterm are at risk for poorer cognitive, academic and behavioral outcomes, however this finding may have been confounded by lower parental education level in the very preterm children. Studies that compare very preterm and term-born children with comparable (high) parental education level are needed to assess the true effect of very preterm birth on outcomes. AIMS: To compare cognitive, academic and behavioral functioning in very preterm and term-born children of highly educated parents. To examine whether outcomes differ for children of whom one or both parents are highly educated. STUDY DESIGN: Cross-sectional study with a term-born comparison group. SUBJECTS: 113 very preterm children and 38 term-born children aged 8-12 years old, with highly educated parents. MEASURES: Cognitive functioning (Intelligence Quotient), academic functioning (arithmetic facts and reading) and parent and teacher rated behavioral functioning (attention, executive function, hyperactivity, and emotional, conduct and peer problems). Parental education was considered high when children had two highly educated parents or one highly- and one middle educated parent. RESULTS: Very preterm children had significantly poorer cognitive (difference of 10 IQ points) and behavioral functioning than their term-born peers, but did not differ on academic functioning. Children with one highly educated parent performed poorer than children with two highly educated parents on most outcome measures. CONCLUSIONS: Performance of very preterm children should be compared to term-born peers with parents having comparable educational levels for accurate assessment of outcomes. The number of highly educated parents also impacts outcomes.

Duration of mechanical ventilation and neurodevelopment in preterm infants.

OBJECTIVE: To investigate the association between invasive mechanical ventilation (IMV) duration and long-term neurodevelopmental outcomes in preterm infants in an era of restricted IMV. DESIGN: Retrospective cohort study. SETTING: Single neonatal intensive care unit in Amsterdam. PATIENTS: All ventilated patients with a gestational age between 24 and 30 weeks born between 2010 and 2015. MAIN OUTCOME MEASURES: Neurodevelopmental impairment (NDI) at 24 months corrected age (CA). Data on patient characteristics, respiratory management, neonatal morbidities, mortality and bronchopulmonary dysplasia were collected. The relationship between IMV duration and NDI was determined by multivariate logistic regression analysis. RESULTS: During the study period, 368 admitted infants received IMV for a median duration of 2 days. Moderate and severe bronchopulmonary dysplasia was diagnosed in 33% of the infant. Multivariate regression analysis with adjustment for gestational age, small for gestational age and socioeconomic status showed a significant association between every day of IMV and NDI at 24 months CA (adjusted OR [aOR] 1.08, 95% CI 1.004 to 1.16, p=0.04). This association only reached borderline significance when also adjusting for severe neonatal morbidity (aOR 1.08, 95% CI 1.00 to 1.17, p=0.05). CONCLUSION: Even in an era of restricted IMV, every additional day of IMV in preterm infants is strongly associated with an increased risk of NDI at 24 months CA. Limiting IMV should be an important focus in the treatment of preterm infants.