Developmental motor problems and health-related quality of life in 5-year-old children born extremely preterm: A European cohort study.

AIM: To measure the association between cerebral palsy (CP) and non-CP-related movement difficulties and health-related quality of life (HRQoL) among 5-year-old children born extremely preterm (<28 weeks gestational age). METHOD: We included 5-year-old children from a multi-country, population-based cohort of children born extremely preterm in 2011 to 2012 in 11 European countries (n = 1021). Children without CP were classified using the Movement Assessment Battery for Children, Second Edition as having significant movement difficulties (≤5th centile of standardized norms) or being at risk of movement difficulties (6th-15th centile). Parents reported on a clinical CP diagnosis and HRQoL using the Pediatric Quality of Life Inventory. Associations were assessed using linear and quantile regressions. RESULTS: Compared to children without movement difficulties, children at risk of movement difficulties, with significant movement difficulties, and CP had lower adjusted HRQoL total scores (ß [95% confidence interval] = -5.0 [-7.7 to -2.3], -9.1 [-12.0 to -6.1], and - 26.1 [-31.0 to -21.2]). Quantile regression analyses showed similar decreases in HRQoL for all children with CP, whereas for children with non-CP-related movement difficulties, reductions in HRQoL were more pronounced at lower centiles. INTERPRETATION: CP and non-CP-related movement difficulties were associated with lower HRQoL, even for children with less severe difficulties. Heterogeneous associations for non-CP-related movement difficulties raise questions for research about mitigating and protective factors.

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study.

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02). CONCLUSION: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. WHAT IS KNOWN: • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. WHAT IS NEW: • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Digital decision aid for prenatal counseling in imminent extreme premature labor: development and pilot testing.

BACKGROUND: In case of extreme premature delivery at 24 weeks of gestation, both early intensive care and palliative comfort care for the neonate are considered treatment options. Prenatal counseling, preferably using shared decision making, is needed to agree on the treatment option in case labor progresses. This article described the development of a digital decision aid (DA) to support pregnant women, partners and clinicians in prenatal counseling for imminent extreme premature labor. METHODS: This DA is developed following the International Patient Decision Aid Standards. The Dutch treatment guideline and the Dutch recommendations for prenatal counseling in extreme prematurity were used as basis. Development of the first prototype was done by expert clinicians and patients, further improvements were done after alpha testing with involved clinicians, patients and other experts (n = 12), and beta testing with non-involved clinicians and patients (n = 15). RESULTS: The final version includes information, probabilities and figures depending on users' preferences. Furthermore, it elicits patient values and provides guidance to aid parents and professionals in making a decision for either early intensive care or palliative comfort care in threatening extreme premature delivery. CONCLUSION: A decision aid was developed to support prenatal counseling regarding the decision on early intensive care versus palliative comfort care in case of extreme premature delivery at 24 weeks gestation. It was well accepted by parents and healthcare professionals. Our multimedia, digital DA is openly available online to support prenatal counseling and personalized, shared decision-making in imminent extreme premature labor.

Validation of an Instrument for Real-Time Assessment of Neonatal Intubation Skills: A Randomized Controlled Simulation Study.

OBJECTIVE: This study aimed to evaluate the construct validity and reliability of real-time assessment of a previously developed neonatal intubation scoring instrument (NISI). STUDY DESIGN: We performed a randomized controlled simulation study at a simulation-based research and training facility. Twenty-four clinicians experienced in neonatal intubation ("experts") and 11 medical students ("novices") performed two identical elective intubations on a neonatal patient simulator. Subjects were randomly assigned to either the intervention group, receiving predefined feedback between the two intubations, or the control group, receiving no feedback. Using the previously developed NISI, all intubations were assessed, both in real time and remotely on video. Construct validity was evaluated by (1) comparing the intubation performances, expressed as percentage scores, with and without feedback, and (2) correlating the intubation performances with the subjects' level of experience. The intrarater reliability, expressed as intraclass correlation coefficient (ICC), of real-time assessment compared with video-based assessment was determined. RESULTS: The intervention group contained 18 subjects, the control group 17. Background characteristics and baseline intubation scores were comparable in both groups. The median (IQR) change in percentage scores between the first and second intubation was significantly different between the intervention and control group (11.6% [4.7-22.8%] vs. 1.4% [0.0-5.7%], respectively; p = 0.013). The 95% CI for this 10.2% difference was 2.2 to 21.4%. The subjects' experience level correlated significantly with their percentage scores (Spearman's R = 0.70; p <0.01). ICC's were 0.95 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.89-0.97) for the first and second intubation, respectively. CONCLUSION: Our NISI has construct validity and is reliable for real-time assessment. KEY POINTS: · Our neonatal intubation scoring instrument has construct validity.. · Our instrument can be reliably employed to assess neonatal intubation skills directly in real time.. · It is suitable for formative assessment, i.e., providing direct feedback during procedural training..

Validation of an Assessment Instrument for Pediatric Basic Life Support.

OBJECTIVES: To develop a valid and reliable instrument for the assessment of pediatric basic life support (PBLS). METHODS: An assessment instrument for PBLS was developed, based on 3 existing scoring systems and the European Resuscitation Council PBLS guideline. We tested if experienced PBLS instructors performed better than medical students on a standard PBLS examination on a low-fidelity pediatric manikin (construct validity). To pass the examination, 15 penalty points or less were required. The examinations were videotaped. One researcher assessed all videos once, and approximately half of them twice (intrarater reliability). A second researcher independently assessed part of the videos (interrater reliability). The time needed to assess 1 examination was determined. RESULTS: Face and content validity were established, because PBLS experts reached consensus on the instrument and because the instrument incorporated all items of the European Resuscitation Council algorithm. Of the 157 medical students that were scored, 98 (62.4%) passed the examination. Fourteen PBLS instructors were scored; all passed (100%). Pass rate (62.4% vs 100%) and median penalty points (15 [interquartile range, 10-22.5] vs 7.5 [interquartile range, 1.25-10]) were significantly different between students and instructors (P = 0.005 and <0.001, respectively). Reassessment demonstrated a κ for intrarater reliability of 0.62 (95% confidence interval, 0.45-0.81) (substantial agreement); κ for interrater reliability was 0.51 (95% confidence interval, 0.09-0.93) (moderate agreement). It took approximately 3 minutes to assess 1 videotaped examination. CONCLUSIONS: Our instrument for the (video-based) assessment of PBLS is valid and sufficiently reliable. It is also designed to be practical, time-efficient, and applicable in various settings, including resource limited.

Adherence to the ABCDE approach in relation to the method of instruction: a randomized controlled simulation study.

BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is widely recommended and taught in many resuscitation courses. This study assessed the adherence to the ABCDE algorithm and whether this was affected by the instruction method used to teach this approach. METHODS: Randomized controlled trial in which simulation was used as investigational method. Between June 2017 and January 2018, neonatal healthcare providers routinely participated in simulated neonatal advanced life support (NALS) scenarios, using a high-fidelity manikin. They were randomly assigned to a video-based instruction (intervention group) or a conventional lecture (control group) as the method of instruction. One blinded researcher evaluated the adherence to the ABCDE approach on video with an assessment tool specifically designed and tested for this study. The primary outcomes were: 1) the overall adherence and 2) the between-group difference in individual adherence to the ABCDE approach, both expressed as a percentage score. Secondary outcomes were: 1) the scores of each profession category (nurses, neonatal ward clinicians, fellows/neonatologists) and 2) the scores for the separate domains (A, B, C, D, and E) of the algorithm. RESULTS: Seventy-two participants were assessed. Overall mean (SD) percentage score (i.e. overall adherence) was 31.5% (19.0). The video-based instruction group (28 participants) adhered better to the ABCDE approach than the lecture group (44 participants), with mean (SD) scores of 38.8% (18.7) and 27.8% (18.2), respectively (p = 0.026). The difference in adherence between both groups could mainly be attributed to differences in the adherence to domain B (p = 0.023) and C (p = 0.007). Neonatal ward clinicians (39.9% (18.2)) showed better adherence than nurses (25.0% (15.2)), independent of the study group (p = 0.010). CONCLUSIONS: Overall adherence to the ABCDE algorithm was rather low. Video-based instruction resulted in better adherence to the ABCDE approach during NALS training than lecturing. TRIAL REGISTRATION: ISRCTN registry, trial ID ISRCTN95998973 , retrospectively registered on October 13th, 2020.

Neonatal resuscitation guideline adherence: simulation study and framework for improvement.

We wanted to assess newborn life support (NLS) knowledge and guideline adherence, and provide strategies to improve (neonatal) resuscitation guideline adherence. Pediatricians completed 17 multiple-choice questions (MCQ). They performed a simulated NLS scenario, using a high-fidelity manikin. The literature was systematically searched for publications regarding guideline adherence. Forty-six pediatricians participated: 45 completed the MCQ, 34 performed the scenario. Seventy-one percent (median, IQR 56-82) of the MCQ were answered correctly. Fifty-six percent performed inflation breaths ≤ 60 s, 24% delivered inflation breaths of 2-3 s, and 85% used adequate inspiratory pressures. Airway patency was ensured 83% (IQR 76-92) of the time. Median events/min, compression rate, and percentage of effective compressions were 138/min (IQR 130-145), 120/min (IQR 114-120), and 38% (IQR 24-48), respectively. Other adherence percentages were temperature management 50%, auscultation of initial heart rate 100%, pulse oximeter use 94%, oxygen increase 74%, and correct epinephrine dose 82%. Ten publications were identified and used for our framework. The framework may inspire clinicians, educators, researchers, and guideline developers in their attempt to improve resuscitation guideline adherence. It contains many feasible strategies to enhance professionals' knowledge, skills, self-efficacy, and team performance, as well as recommendations regarding equipment, environment, and guideline development/dissemination.Conclusion: NLS guideline adherence among pediatricians needs improvement. Our framework is meant to promote resuscitation guideline adherence. What is Known: • Inadequate newborn life support (NLS) may contribute to (long-term) pulmonary and cerebral damage. • Video-based assessment of neonatal resuscitations has shown that deviations from the NLS guideline occur frequently; this assessment method has its audiovisual shortcomings. What is New: • The resuscitation quality metrics provided by our high-fidelity manikin suggest that the adherence of Dutch general pediatricians to the NLS guideline is suboptimal. • We constructed a comprehensive framework, containing multiple strategies to improve (neonatal) resuscitation guideline adherence.

Improvement of exercise capacity following neonatal respiratory failure: A randomized controlled trial.

Exercise capacity deteriorates in school-aged children born with major anatomical foregut anomalies and/or treated with extracorporeal membrane oxygenation. The aim of the present study was to evaluate whether exercise capacity can be improved in the short term and long term in children born with anatomical foregut anomalies and/or treated with extracorporeal membrane oxygenation. Therefore, we evaluated two different interventions in this single-blinded randomized controlled trial. Forty participants were randomly assigned to group A: standardized anaerobic high-intensity interval training plus online lifestyle coaching program, B: online lifestyle coaching program only, or C: standard of care. Inclusion criteria were as follows: score ≤-1 standard deviation (SD) on the Bruce protocol. Exercise capacity was assessed at baseline (T0), after 3 months (T1), and after 12 months (T2). Exercise capacity improved over time: mean (SD) standard deviation score (SDS) endurance time: T0 -1.91 (0.73); T1 -1.35 (0.94); T2 -1.20 (1.03): both P < .001. No significant differences in maximal endurance time were found at T1 (group A-C: estimated mean difference (SDS): 0.06 P = .802; group B-C: -0.17 P = .733) or T2 (group A-C: -0.13 P = .635; group B-C: -0.18 P = .587). Exercise capacity improved significantly over time, irrespective of the study arm. Not only residual morbidities may be responsible for reduced exercise capacity. Parental awareness of reduced exercise capacity rather than specific interventions may have contributed. Monitoring of exercise tolerance and providing counseling on lifestyle factors that improve physical activity should be part of routine care, and aftercare should be offered on an individual basis.

Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration: Netherlands National Trial Register Identifier: NTR2768.

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.

Defining outcomes following congenital diaphragmatic hernia using standardised clinical assessment and management plan (SCAMP) methodology within the CDH EURO consortium.

Treatment modalities for neonates born with congenital diaphragmatic hernia (CDH) have greatly improved in recent times with a concomitant increase in survival. In 2008, CDH EURO consortium, a collaboration of a large volume of CDH centers in Western Europe, was established with a goal to standardize management and facilitate multicenter research. However, limited knowledge on long-term outcomes restricts the identification of optimal care pathways for CDH survivors in adolescence and adulthood. This review aimed to evaluate the current practice of long-term follow-up within the CDH EURO consortium centers, and to review the literature on long-term outcomes published from 2000 onward. Apart from having disease-specific morbidities, children with CDH are at risk for impaired neurodevelopmental problems and failure of educational attainments which may affect participation in society and the quality of life in later years. Thus, there is every reason to offer them long-term multidisciplinary follow-up programs. We discuss a proposed collaborative project using standardized clinical assessment and management plan (SCAMP) methodology to obtain uniform and standardized follow-up of CDH patients at an international level.

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

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.

The validity of the observed-to-expected lung-to-head ratio in congenital diaphragmatic hernia in an era of standardized neonatal treatment; a multicenter study.

OBJECTIVE: To assess the predictive value of observed-to-expected lung-to-head ratio (O/E LHR) for survival and chronic lung disease (CLD) in survivors of left-sided congenital diaphragmatic hernia (CDH) in an era of standardized neonatal treatment, and to evaluate the predictive value of the O/E LHR trajectory for survival. METHODS: This retrospective cohort study was performed in two high-volume CDH centers in the Netherlands in prenatally detected, isolated left-sided CDH patients born between 2008 and 2014. O/E LHR and liver position were determined using 2D-ultrasonography at three time points during gestation from 19 weeks onwards. Ultrasound measurements were performed on stored ultrasound data by one single experienced operator blinded to postnatal outcome. RESULTS: Of the 122 included cases, 77.9% survived of whom 38.9% developed CLD. A significant association was found between the first measured O/E LHR and survival and development of CLD in survivors. Prenatal liver position did not have additional predictive value. No significant association was found between the trajectory of the O/E LHR and survival. CONCLUSION: In an era of standardized neonatal treatment for neonates with CDH, the first measured O/E LHR per patient significantly predicts survival and development of CLD in survivors in isolated left-sided CDH infants. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

The early postnatal nutritional intake of preterm infants affected neurodevelopmental outcomes differently in boys and girls at 24 months.

AIM: This study assessed whether increased amino acid and energy intake in preterm infants during the first week of life was associated with improved neurodevelopment at the corrected age (CA) of 24 months. METHODS: We evaluated preterm infants from two consecutive cohorts in 2004 (Cohort 1) and 2005 (Cohort 2) with different nutritional intakes in the Netherlands. Nutritional intake and growth were recorded until week 5 and after discharge. Neurodevelopment was determined using the Bayley Scales of Infant Development - Second Edition at a CA of 24 months. RESULTS: Compared to Cohort 1 (n = 56), Cohort 2 (n = 56) received higher nutritional intake during week 1 (p < 0.001). The weight gain in Cohort 2 was higher until week 5, especially among boys (p < 0.002). The mean Mental Developmental Index (MDI) scores did not differ, but Cohort 2 was associated with an increased chance of having an MDI ≥ 85, with an odds ratio of 6.4 and 95% confidence interval (CI) of 1.5-27.4, among all girls with a higher protein intake (5.3, 1.2-23.3). The Psychomotor Developmental Index increased with increasing nutritional intake, especially among boys (ß-coefficient 3.1, 95% CI 0.2-6.0). CONCLUSION: Higher nutritional intake was associated with different improvements in growth and neurodevelopment in boys and girls.

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.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.

Detection and quantification of left-to-right shunting using transpulmonary ultrasound dilution (TPUD): a validation study in neonatal lambs.

OBJECTIVES: We investigated the accuracy of left-to-right shunt detection using transpulmonary ultrasound dilution (TPUD) and compared the agreement between pulmonary over systemic blood flow (Qp/Qs) ratio measured by TPUD [Qp/Qs(tpud)] and ultrasonic flow probes [Qp/Qs(ufp)]. METHODS: Seven newborn lambs under general anesthesia were connected to the TPUD monitor (COstatus™) after insertion of arterial and central venous catheters. A Gore-Tex® shunt, inserted between the descending aorta and left pulmonary artery, was intermittently opened and closed while cardiac output was varied by blood withdrawals. Flow probes were placed around the main pulmonary artery (Qufp) and the descending aorta proximal (Qpre) and distal (Qpost) to the shunt insertion. Qp/Qs(ufp) was calculated as (Qufp+Qpre-Qpost)/Qufp. RESULTS: Seventy-two paired measurement sessions were analyzed. Shunts were detected by TPUD with a positive predictive value of 86%, a negative predictive value of 100%, a sensitivity of 100% and a specificity of 83%. The Bland-Altman analysis comparing Qp/Qs(tpud) and Qp/Qs(ufp) showed an overall mean bias (SD) of 0.1 (0.3), limits of agreement (LOA) of ±0.6 and a percentage error of 34.8%. CONCLUSIONS: The qualitative diagnostic accuracy of TPUD for shunt detection is high. Modification of the algorithm seems required as shunt quantification by TPUD is accurate, but not yet very precise.

Tubular Injury Biomarkers to Detect Gentamicin-Induced Acute Kidney Injury in the Neonatal Intensive Care Unit.

OBJECTIVE: We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. STUDY DESIGN: We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D-glucosaminidase (NAG), and π- and α-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. RESULTS: Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 µmol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. CONCLUSION: GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates.

Hemodynamic volumetry using transpulmonary ultrasound dilution (TPUD) technology in a neonatal animal model.

To analyze changes in cardiac output and hemodynamic volumes using transpulmonary ultrasound dilution (TPUD) in a neonatal animal model under different hemodynamic conditions. 7 lambs (3.5-8.3 kg) under general anesthesia received arterial and central venous catheters. A Gore-Tex(®) shunt was surgically inserted between the descending aorta and the left pulmonary artery to mimic a patent ductus arteriosus. After shunt opening and closure, induced hemorrhagic hypotension (by repetitive blood withdrawals) and repetitive volume challenges, the following parameters were assessed using TPUD: cardiac output, active circulating volume index (ACVI), central blood volume index (CBVI) and total end-diastolic volume index (TEDVI). 27 measurement sessions were analyzed. After shunt opening, there was a significant increase in TEDVI and a significant decrease in cardiac output with minimal change in CBVI and ACVI. With shunt closure, these results reversed. After progressive hemorrhage, cardiac output and all volumes decreased significantly, except for ACVI. Following repetitive volume resuscitation, cardiac output increased and all hemodynamic volumes increased significantly. Correlations between changes in COufp and changes in hemodynamic volumes (ACVI 0.83; CBVI 0.84 and TEDVI 0.78 respectively) were (slightly) better than between changes in COufp and changes in heart rate (0.44) and central venous pressure (0.7). Changes in hemodynamic volumes using TPUD were as expected under different conditions. Hemodynamic volumetry using TPUD might be a promising technique that has the potential to improve the assessment and interpretation of the hemodynamic status in critically ill newborns and children.