Variation in follow-up for children born very preterm in Europe.

BACKGROUND: Children born very preterm (<32 weeks of gestation) face high risks of neurodevelopmental and health difficulties compared with children born at term. Follow-up after discharge from the neonatal intensive care unit is essential to ensure early detection and intervention, but data on policy approaches are sparse. METHODS: We investigated the characteristics of follow-up policy and programmes in 11 European countries from 2011 to 2022 using healthcare informant questionnaires and the published/grey literature. We further explored how one aspect of follow-up, its recommended duration, may be reflected in the percent of parents reporting that their children are receiving follow-up services at 5 years of age in these countries using data from an area-based cohort of very preterm births in 2011/12 (N = 3635). RESULTS: Between 2011/12 and 22, the number of countries with follow-up policies or programmes increased from 6 to 11. The policies and programmes were heterogeneous in eligibility criteria, duration and content. In countries that recommended longer follow-up, parent-reported follow-up rates at 5 years of age were higher, especially among the highest risk children, born <28 weeks' gestation or with birthweight <1000 g: between 42.1% and 70.1%, vs. <20% in most countries without recommendations. CONCLUSIONS: Large variations exist in follow-up policies and programmes for children born very preterm in Europe; differences in recommended duration translate into cross-country disparities in reported follow-up at 5 years of age.

Glomerular filtration rate in critically ill neonates and children: creatinine-based estimations versus iohexol-based measurements.

BACKGROUND: Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods. METHODS: In this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values). RESULTS: One hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11-40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38-51%). eGFR equations significantly overestimated mGFR (60-71 versus 41 ml/min/1.73 m2, p < 0.001-0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%). CONCLUSION: Iohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Prediction of movement difficulties at 5 years from parent report at 2 years in children born extremely preterm.

AIM: To assess the predictive validity of parent-reported gross motor impairment (GMI) at age 2 years to detect significant movement difficulties at age 5 years in children born extremely preterm. METHOD: Data were from 556 children (270 males, 286 females) born at less than 28 weeks' gestation in 2011 to 2012 in 10 European countries. Parent report of moderate/severe GMI was defined as walking unsteadily or unable to walk unassisted at 2 years corrected age. Examiners assessed significant movement difficulties (score ≤ 5th centile on the Movement Assessment Battery for Children, Second Edition) and diagnoses of cerebral palsy (CP) were collected by parent report at 5 years chronological age. RESULTS: At 2 years, 66 (11.9%) children had moderate/severe GMI. At 5 years, 212 (38.1%) had significant movement difficulties. Parent reports of GMI at age 2 years accurately classified CP at age 5 years in 91.0% to 93.2% of children. Classification of moderate/severe GMI at age 2 years had high specificity (96.2%; 95% confidence interval 93.6-98.0) and positive predictive value (80.3%; 68.7-89.1) for significant movement difficulties at age 5 years. However, 74.5% of children with significant movement difficulties at 5 years were not identified with moderate/severe GMI at age 2 years, resulting in low sensitivity (25.1%; 19.4-31.5). INTERPRETATION: This questionnaire may be used to identify children born extremely preterm who at age 2 years have a diagnosis of CP or movement difficulties that are likely to have a significant impact on their functional outcomes at age 5 years.

High Healthcare Use at Age 5 Years in a European Cohort of Children Born Very Preterm.

OBJECTIVES: To describe parent-reported healthcare service use at age 5 years in children born very preterm and investigate whether perinatal and social factors and the use of very preterm follow-up services are associated with high service use. STUDY DESIGN: We used data from an area-based cohort of births at <32 weeks of gestation from 11 European countries, collected from birth records and parental questionnaires at 5 years of age. Using the published literature, we defined high use of outpatient/inpatient care (≥4 sick visits to general practitioners, pediatricians, or nurses, ≥3 emergency room visits, or ≥1 overnight hospitalization) and specialist care (≥2 different specialists or ≥3 visits). We also categorized countries as having either a high or a low rate of children using very preterm follow-up services at age 5 years. RESULTS: Overall, 43% of children had high outpatient/inpatient care use and 48% had high specialist care use during the previous year. Perinatal factors were associated with high outpatient/inpatient and specialist care use, with a more significant association with specialist services. Associations with intermediate parental educational level and unemployment were stronger for outpatient/inpatient services. Living in a country with higher rates of very preterm follow-up service use was associated with lower use of outpatient/inpatient services. CONCLUSIONS: Children born very preterm had high healthcare service use at age 5 years, with different patterns for outpatient/inpatient and specialist care by perinatal and social factors. Longer follow-up of children born very preterm may improve care coordination and help avoid undesirable health service use.

MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.

Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1. The index case died as an infant from progressive and severe pneumonia caused by Pseudomonas aeruginosa and poor wound healing. The younger sibling was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. In addition to the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as a transcriptional coregulator. Degranulation was enhanced upon suboptimal neutrophil activation, whereas production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis or bacterial killing was found. Also, monocyte-derived macrophages showed intact phagocytosis, and lymphocyte counts and proliferative capacity were normal. Nonhematopoietic primary fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and F-actin content, most likely as a result of compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as the most prominent features.

Motor-related health care for 5-year-old children born extremely preterm with movement impairments.

AIM: To (1) determine the proportion of 5-year-old children born extremely preterm (EPT) with movement difficulties including cerebral palsy (CP) and the proportion of these children receiving motor-related health care (MRHC), and (2) describe factors associated with receiving MRHC. METHOD: Children born before 28 weeks' gestation in 2011 to 2012 in 11 European countries were assessed with the Movement Assessment Battery for Children, Second Edition (MABC-2) at 5 years of age. Information on family characteristics, child health including CP diagnosis, and health care use were collected using parent-report questionnaires. MRHC was defined as visits in the previous year with health care providers (physical and occupational therapists) specialized in assessing/treating motor problems. We analysed receipt of MRHC and associated factors among children at risk of movement difficulties (MABC-2 score 6th-15th centiles), with significant movement difficulties (SMD; ≤5th centile) or with CP. RESULTS: Of 807 children assessed at 5 years 7 months (SD 4 months; 4 years 7 months-7 years 1 month), 412 were males (51.1%), 170 (21.1%) were at risk of movement difficulties, 201 (24.9%) had SMD, and 92 (11.4%) had CP. Those who received MRHC comprised 89.1% of children with CP, 42.8% with SMD, and 25.9% at risk of movement difficulties. MRHC for children with SMD varied from 23.3% to 66.7% between countries. Children were more likely to receive MRHC if they had other developmental problems or socioemotional, conduct, or attention difficulties. INTERPRETATION: Efforts are needed to increase MRHC for 5-year-old children born EPT with movement difficulties. WHAT THIS PAPER ADDS: Children born extremely preterm without cerebral palsy frequently experienced motor difficulties. Most of these children were not receiving motor-related health care (MRHC). Large geographical differences throughout Europe were observed in receipt of MRHC. Socioemotional problems were related to MRHC use.

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..

Fast detection of FOXF1 variants in patients with alveolar capillary dysplasia with misalignment of pulmonary veins using targeted sequencing.

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal congenital lung disorder associated with heterozygous variants in the FOXF1 gene or its regulatory region. Patients with ACD/MPV unnecessarily undergo invasive and expensive treatments while awaiting a diagnosis. The aim of this study was to reduce the time to diagnose ACD/MPV by developing a targeted next-generation sequencing (NGS) panel that detects FOXF1 variants. METHODS: A FOXF1-targeted NGS panel was developed for detection of mutations and large genomic alterations and used for retrospective testing of ACD/MPV patients and controls. Results were confirmed with Sanger sequencing and SNP array analysis. RESULTS: Each amplicon of the FOXF1-targeted NGS panel was efficiently sequenced using DNA isolated from blood or cell lines of 15 ACD/MPV patients and 8 controls. Moreover, testing of ACD/MPV patients revealed six novel and six previously described pathogenic or likely pathogenic FOXF1 alterations. CONCLUSION: We successfully designed a fast and reliable targeted genetic test to detect variants in the FOXF1 gene and its regulatory region in one run. This relatively noninvasive test potentially prevents unnecessary suffering for patients and reduces the use of futile and expensive treatments like extra-corporeal membrane oxygenation. IMPACT: FOXF1-targeted NGS potentially prevents ACD/MPV patients from unnecessary suffering and expensive treatments. FOXF1-targeted NGS potentially reduces the number of misdiagnosis in ACD/MPV patients. Retrospective testing of ACD/MPV patients using FOXF1-targeted NGS revealed six novel pathogenic or likely pathogenic variants.

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.

Surgical Complications in Children with CDH: A Multivariate Analysis.

INTRODUCTION: Several medical and surgical improvements in the treatment of congenital diaphragmatic hernia (CDH) patients have led to a higher survival rate. However, some of these improvements also lead to an increased morbidity rate. This study aims to determine the contribution different medical and surgical treatments have had on the development of surgical complications. METHOD: All CDH patients treated in a single centre between 2000 and 2015 were retrospectively evaluated. Multivariate logistic regression was used to estimate the independent effects of several treatment options that could influence the surgical outcome by adjustment for multiple risk factors. RESULTS: Sixty of the 197 surgically repaired CDH patients had surgical complications. There were more haemorrhagic complications in the ECMO compared to non-ECMO group (27% vs. 2%, p < 0.001). The use of inhaled nitric oxide was also significantly related to haemorrhage (OR = 13.0 (95% CI 1.1-159)). After adjustment for other risk factors, chylothorax was neither significantly associated with ECMO treatment (OR = 1.6 (95% CI 0.5-5.2) nor with patch repair (OR = 2.1: 95% CI 0.7-6.1). A recurrence occurred more often in patients with pulmonary hypertension (OR = 10.0 (95% CI 1.5-65.8) and after treatment with an abdominal patch (OR = 11.3: 95% CI 1.5-84.4). CONCLUSION: ECMO treatment and the inhalation of nitric oxide are used in the most severe CDH patients but are associated with a higher risk on surgical haemorrhage. The recurrence rate is associated with both the use of an abdominal patch and the presence of pulmonary hypertension, regardless of medical treatment.

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.

Congenital diaphragmatic eventration and hernia sac compared to CDH with true defects: a retrospective cohort study.

Congenital diaphragmatic eventration (CDE) and congenital diaphragmatic hernia (CDH) with or without hernia sac are three different types of congenital diaphragmatic malformations, which this study evaluates. All surgically treated patients with CDE or Bochdalek type CDH between 2000 and 2016 were included in this retrospective analysis. Demographics, CDH-characteristics, treatment, and clinical outcome were evaluated. In total, 200 patients were included. Patients with an eventration or hernia sac had no significant differences and were compared as patients without a true defect to patients with a true defect. The 1-year survival of patients with a true defect was significantly lower than patients with no true defect (76% versus 97%, p = 0.001). CDH with no true defect had significantly better short-term outcomes than CDH with true defect requiring patch repair. However, at 30 days, they more often required oxygen supplementation (46% versus 26%, p = 0.03) and had a higher recurrence rate (8% versus 0%, p = 0.006) (three eventration and two hernia sac patients). Conclusion: Patients without a true defect seem to have a more similar clinical outcome than CDH patients with a true defect, with a better survival. However, the recurrence rate and duration of oxygen supplementation at 30 days are higher than CDH patients with a true defect.What is Known:• Congenital diaphragmatic hernia with or without hernia sac and congenital diaphragmatic eventration (incomplete muscularization) are often treated similarly.• Patients with hernia sac and eventration are thought to have a relatively good outcome, but exact numbers are not described.What is New:• Congenital diaphragmatic eventration and patients with hernia sac seem to have a more similar clinical outcome than Bochdalek type CDH with a true defect.• Patients without a true defect (eventration or hernia sac) have a high recurrence rate.

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.

Low breastfeeding continuation to 6 months for very preterm infants: A European multiregional cohort study.

Breastfeeding confers multiple benefits for the health and development of very preterm infants, but there is scarce information on the duration of breastfeeding after discharge from the neonatal intensive care unit (NICU). We used data from the Effective Perinatal Intensive Care in Europe population-based cohort of births below 32 weeks of gestation in 11 European countries in 2011-2012 to investigate breastfeeding continuation until 6 months. Clinical and sociodemographic characteristics were collected from obstetric and neonatal medical records as well as parental questionnaires at 2 years of corrected age. Among 3,217 ever-breastfed infants, 34% were breastfeeding at 6 months of age (range across countries from 25% to 56%); younger and less educated mothers were more likely to stop before 6 months (adjusted relative risk [aRR] <25 years: 0.68, 95% CI [0.53, 0.88], vs. 25-34 years; lower secondary: 0.58, 95% CI [0.45, 0.76] vs. postgraduate education). Multiple birth, bronchopulmonary dysplasia (BPD), and several neonatal transfers reduced the probability of continuation but not low gestational age, fetal growth restriction, congenital anomalies, or severe neonatal morbidities. Among infants breastfeeding at discharge, mixed versus exclusive breast milk feeding at discharge was associated with stopping before 6 months: aRR = 0.60, 95% CI [0.48, 0.74]. Low breastfeeding continuation rates in this high-risk population call for more support to breastfeeding mothers during and after the neonatal hospitalization, especially for families with low socio-economic status, multiples, and infants with BPD. Promotion of exclusive breastfeeding in the NICU may constitute a lever for improving breastfeeding continuation after discharge.

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.