Publications by authors named "Arno van Heijst"

108 Publications

Follow-up after very preterm birth in Europe.

Arch Dis Child Fetal Neonatal Ed 2021 Feb 10. Epub 2021 Feb 10.

Université de Paris, CRESS, Obstetrical Perinatal and Pediatric Epidemiology Research Team, EPOPé, INSERM, INRA, F-75004 Paris, France.

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http://dx.doi.org/10.1136/archdischild-2020-320823DOI Listing
February 2021

Maternal risk associated with the VACTERL association: A case-control study.

Birth Defects Res 2020 11 22;112(18):1495-1504. Epub 2020 Jul 22.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center (Radboudumc), Nijmegen, the Netherlands.

Background: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors.

Methods: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI).

Results: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL.

Conclusion: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.
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http://dx.doi.org/10.1002/bdr2.1773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689936PMC
November 2020

Survival and causes of death in extremely preterm infants in the Netherlands.

Arch Dis Child Fetal Neonatal Ed 2020 11 6. Epub 2020 Nov 6.

Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands.

Objective: In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25 to 24 weeks' gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.

Design: National cohort study, using data from the Netherlands Perinatal Registry.

Patients: The study population included all 3312 stillborn and live born infants with a gestational age (GA) between 24 and 26 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.

Main Outcome Measures: Survival to discharge, as well as cause and timing of death.

Results: After guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks' GA (27%-69%, p<0.001), resulting in increased survival to discharge in 24-week live born infants (13%-34%, p<0.001). Top three causes of in-hospital mortality were necrotising enterocolitis (28%), respiratory distress syndrome (19%) and intraventricular haemorrhage (17%). A significant decrease in cause of death either complicated or caused by respiratory insufficiency was seen over time (34% in 2011-2014 to 23% in 2015-2017, p=0.006).

Conclusions: Implementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks' GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.
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http://dx.doi.org/10.1136/archdischild-2020-318978DOI Listing
November 2020

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

Am J Perinatol 2020 Sep 8. Epub 2020 Sep 8.

Department of Neonatology, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.

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;  = 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  = 0.70; 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..
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http://dx.doi.org/10.1055/s-0040-1715530DOI Listing
September 2020

Increase in treatment of retinopathy of prematurity in the Netherlands from 2010 to 2017.

Acta Ophthalmol 2021 Feb 23;99(1):97-103. Epub 2020 Jul 23.

Leiden University Medical Center, Leiden, Netherlands.

Purpose: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods.

Methods: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared.

Results: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born <25 weeks increased by factor 1.23 and higher oxygen saturation levels were aimed at in most centres. At treatment decision, 59.6% (P1) versus 83.5% (P2) (p = 0.263) infants were classified as Type 1 ROP (ETROP classification). Infants were treated with laser photocoagulation (98 versus 96%) and intravitreal bevacizumab (2 versus 4%). Retreatment was necessary in 10 versus 21 (p = 0.160). Retinal detachment developed in 6 versus 13 infants (p = 0.791) of which 2 versus 6 bilateral (p = 0.599).

Conclusion: In period 2, the number of infants treated according to the ETROP criteria (Type 1) increased, the number of ROP treatments, retinal detachments and retreatments doubled and the absolute number of retinal detachments increased. Neonatal data did not provide a decisive explanation, although changes in neonatal policy were reported.
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http://dx.doi.org/10.1111/aos.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891652PMC
February 2021

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

Eur J Pediatr 2020 Nov 29;179(11):1813-1822. Epub 2020 May 29.

Department of Neonatology, Amalia Children's Hospital, Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.

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.
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http://dx.doi.org/10.1007/s00431-020-03693-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547969PMC
November 2020

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

Pediatr Res 2020 May 15. Epub 2020 May 15.

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1038/s41390-020-0931-5DOI Listing
May 2020

Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia.

Pediatrics 2020 04 5;145(4). Epub 2020 Mar 5.

Intensive Care and Departments of Pediatric Surgery.

Background: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ∼27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables.

Methods: We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule ( = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 ( = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots.

Results: With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities.

Conclusions: In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model's ability to predict mortality in a population of patients with prenatally diagnosed CDH.
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http://dx.doi.org/10.1542/peds.2019-2379DOI Listing
April 2020

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

Blood 2020 06;135(24):2171-2181

Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1182/blood.2019002633DOI Listing
June 2020

Surgical Complications in Children with CDH: A Multivariate Analysis.

World J Surg 2020 06;44(6):2042-2048

Department of Pediatric Surgery, Radboudumc-Amalia Children's Hospital, Route 618, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1007/s00268-020-05387-4DOI Listing
June 2020

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

Eur J Pediatr 2020 Jun 22;179(6):855-863. Epub 2020 Jan 22.

Department of Surgery, Division of Pediatric Surgery, Radboudumc-Amalia Children's Hospital, Route 618, PO box 9101, 6500, Nijmegen, HB, Netherlands.

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.
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http://dx.doi.org/10.1007/s00431-020-03576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220865PMC
June 2020

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

Scand J Med Sci Sports 2020 Apr 15;30(4):662-671. Epub 2019 Dec 15.

Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1111/sms.13604DOI Listing
April 2020

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia.

BMJ Open 2019 11 5;9(11):e032122. Epub 2019 Nov 5.

Department of Intensive care and Pediatric Surgery, Erasmus University Rotterdam, Rotterdam, The Netherlands.

Introduction: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking.

Methods And Analysis: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses.

Ethics And Dissemination: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained.

Trial Registration Number: NTR6982; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-032122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858099PMC
November 2019

Validation of an Assessment Instrument for Pediatric Basic Life Support.

Pediatr Emerg Care 2019 Jul 15. Epub 2019 Jul 15.

Pediatrics, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, the Netherlands.

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.
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http://dx.doi.org/10.1097/PEC.0000000000001899DOI Listing
July 2019

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

Dev Cogn Neurosci 2019 08 27;38:100678. Epub 2019 Jun 27.

Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital, 3015 CN Rotterdam, the Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 CN Rotterdam, the Netherlands. Electronic address:

In a nationwide randomized controlled trial, white matter microstructure was assessed before and immediately after Cogmed Working-Memory Training (CWMT) in school-age neonatal critical illness survivors. Eligible participants were survivors (8-12 years) with an IQ ≥ 80 and a z-score of ≤ -1.5 on (working)memory test at first assessment. Diffusion Tensor Imaging was used to assess white matter microstructure. Associations between any training-induced changes and improved neuropsychological outcome immediately and one year post-CWMT were evaluated as well. The trial was conducted between October 2014-June 2017 at Erasmus MC-Sophia, Rotterdam, Netherlands. Researchers involved were blinded to group allocation. Participants were randomized to CWMT(n = 14) or no-intervention(n = 20). All children completed the CWMT. Global fractional anisotropy(FA) increased significantly post-CWMT compared to no-intervention(estimated-coefficient = .007, p = .015). Increased FA(estimated coefficient = .009, p = .033) and decreased mean diffusivity(estimated-coefficient = -.010, p = .018) were found in the left superior longitudinal fasciculus(SFL) post-CWMT compared no-intervention. Children after CWMT who improved with >1SD on verbal working-memory had significantly higher FA in the left SLF post-CWMT(n = 6; improvement = .408 ± .01) than children without this improvement post-CWMT(n = 6; no-improvement = .384 ± .02), F(1,12) = 6.22, p = .041, η = .47. No other structure-function relationships were found post-CWMT. Our findings demonstrate that white matter microstructure and associated cognitive outcomes are malleable by CWMT in survivors of neonatal critical illness.
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http://dx.doi.org/10.1016/j.dcn.2019.100678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969347PMC
August 2019

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

Neonatology 2019 28;116(2):154-162. Epub 2019 Jun 28.

Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance.

Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines.

Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs.

Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam.

Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.
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http://dx.doi.org/10.1159/000499330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878731PMC
May 2020

Development of Nationwide Recommendations to Support Prenatal Counseling in Extreme Prematurity.

Pediatrics 2019 06;143(6)

Departments of Neonatology and Pediatrics and.

Objectives: To develop a nationwide, evidence-based framework to support prenatal counseling in extreme prematurity, focusing on organization, decision-making, content, and style aspects.

Methods: A nationwide multicenter RAND-modified Delphi method study was performed between November 2016 and December 2017 in the Netherlands. Firstly, recommendations were extracted from literature and previous studies. Secondly, an expert panel ( = 21) with experienced parents, obstetricians, and neonatologists rated the recommendations on importance for inclusion in the framework. Thirdly, ratings were discussed in a consensus meeting. The final set of recommendations was approved and transformed into a framework.

Results: A total of 101 recommendations on organization, decision-making, content, and style were included in the framework, including tools to support personalization. The most important recommendations regarding organization were to have both parents involved in the counseling with both the neonatologist and obstetrician. The shared decision-making model was recommended for deciding between active support and comfort care. Main recommendations regarding content of conversation were explanation of treatment options, information on survival, risk of permanent consequences, impossibility to predict an individual course, possibility for multiple future decision moments, and a discussion on parental values and standards. It was considered important to avoid jargon, check understanding, and provide a summary. The expert panel, patient organization, and national professional associations (gynecology and pediatrics) approved the framework.

Conclusions: A nationwide, evidence-based framework for prenatal counseling in extreme prematurity was developed. It contains recommendations and tools for personalization in the domains of organization, decision-making, content, and style of prenatal counseling.
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http://dx.doi.org/10.1542/peds.2018-3253DOI Listing
June 2019

Prenatal counseling in extreme prematurity - Insight into preferences from experienced parents.

Patient Educ Couns 2019 08 23;102(8):1541-1549. Epub 2019 Mar 23.

Scientific Institute for Quality of Care, Radboud university medical center, Nijmegen, the Netherlands.

Objective: In-depth analysis of parental preferences in prenatal counseling in extreme prematurity.

Methods: A nationwide qualitative interview study among experienced parents of extremely premature babies born at 24 - 24 weeks of gestation. Semi-structured interviews were held until saturation, transcribed and qualitatively analyzed to search for parental counseling preferences.

Results: Thirteen parents were included, most parents decided on active care. Organisation: Parents wanted counseling as soon as possible, and for various reasons they wanted more than one conversation. Supportive material to help visualize complex information was suggested to be helpful, preferably with adjustable levels of detail. An empathetic, honest style with commitment of the counselor was regarded important.

Content: Understandable statistics should be used for those who want it. Parents needed different information with respect to the decision-making as opposed to being prepared for future situations. Decision-making: The preferred share of parents' and doctors' input in decision-making varied among parents and among situations. Parents expressed that their roles were to take responsibility for and protect their infant.

Conclusions: Various parental preferences for prenatal counseling were found.

Practice Implications: Common parental preferences for the organisation, content and decision-making elements can provide a starting point for personalized prenatal counseling.
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http://dx.doi.org/10.1016/j.pec.2019.03.016DOI Listing
August 2019

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

PLoS One 2019 14;14(2):e0211910. Epub 2019 Feb 14.

Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.

Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.

Study Design: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.

Results: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia.

Conclusions: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.

Trial Registration: www.trialregister.nl NTR2529.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211910PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375702PMC
November 2019

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.

JAMA 2019 01;321(4):354-363

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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.
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http://dx.doi.org/10.1001/jama.2018.21443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439762PMC
January 2019

Uncontrolled maternal chronic respiratory diseases in pregnancy: A new potential risk factor suggested to be associated with anorectal malformations in offspring.

Birth Defects Res 2019 01 19;111(2):62-69. Epub 2018 Dec 19.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands.

Background: Chronic respiratory diseases and use of antiasthmatic medication during pregnancy may both play a role in the etiology of congenital anorectal malformations (ARM). However, it is unclear, whether the medication use or the underlying condition would be responsible. Therefore, our aim was to unravel the role of maternal chronic respiratory diseases from that of antiasthmatic medication in the etiology of ARM.

Methods: We obtained 412 ARM patients and 2,137 population-based controls from the Dutch AGORA data- and biobank. We used maternal questionnaires and follow-up telephone interviews to obtain information on chronic respiratory diseases, antiasthmatic medication use, and potential confounders. Multivariable logistic regression analyses were performed to estimate odds ratios (ORs) with 95% confidence intervals (95% CI).

Results: We observed higher risk estimates among women with chronic respiratory diseases with and without medication use (1.4 [0.8-2.7] and 2.0 [0.8-5.0]), both in comparison to women without a chronic respiratory disease and without medication use. Furthermore, increased ORs of ARM were found for women using rescue medication (2.4 [0.8-7.3]) or a combination of maintenance and rescue medication (2.5 [0.9-6.7]). In addition, increased risk estimates were observed for women having nonallergic triggers (2.5 [1.0-6.3]) or experiencing exacerbations during the periconceptional period (3.5 [1.4-8.6]).

Conclusions: Although the 95% CIs of most associations include the null value, the risk estimates all point towards an association between uncontrolled chronic respiratory disease, instead of antiasthmatic medication use, with ARM in offspring. Further in-depth studies towards mechanisms of this newly identified risk factor are warranted.
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http://dx.doi.org/10.1002/bdr2.1429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380291PMC
January 2019

Appraisal of a scoring instrument for training and testing neonatal intubation skills.

Arch Dis Child Fetal Neonatal Ed 2019 Sep 1;104(5):F521-F527. Epub 2018 Dec 1.

Department of Neonatology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.

Objective: To determine the validity, reliability, feasibility and applicability of a neonatal intubation scoring instrument.

Design: Prospective observational study.

Setting: Simulation-based research and training centre (Center for Advanced Pediatric and Perinatal Education), California, USA.

Subjects: Forty clinicians qualified for neonatal intubation.

Interventions: Videotaped elective intubations on a neonatal patient simulator were scored by two independent raters. One rater scored the intubations twice. We scored the preparation of equipment and premedication, intubation performance, tube position/fixation, communication, number of attempts, duration and successfulness of the procedure.

Main Outcome Measures: Intraclass correlation coefficients (ICC) were calculated for intrarater and inter-rater reliability. Kappa coefficients for individual items and mean kappa coefficients for all items combined were calculated. Construct validity was assessed with one-way analysis of variance using the hypothesis that experienced clinicians score higher than less experienced clinicians. The approximate time to score one intubation and the instrument's applicability in another setting were evaluated.

Results: ICCs for intrarater and inter-rater reliability were 0.99 (95% CI 0.98 to 0.99) and 0.89 (95% CI 0.35 to 0.96), and mean kappa coefficients were 0.93 (95% CI 0.85 to 1.01) and 0.71 (95% CI 0.56 to 0.92), respectively. There were no differences between the more and less experienced clinicians regarding preparation, performance, communication and total scores. The experienced group scored higher only on tube position/fixation (p0.02). Scoring one intubation took approximately 15 min. Our instrument, developed in The Netherlands, could be readily applied in the USA.

Conclusions: Our scoring instrument for simulated neonatal intubations appears to be reliable, feasible and applicable in another centre. Construct validity could not be established.
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http://dx.doi.org/10.1136/archdischild-2018-315221DOI Listing
September 2019

Duration and Time Trends in Hospital Stay for Very Preterm Infants Differ Across European Regions.

Pediatr Crit Care Med 2018 Dec;19(12):1153-1161

Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes University, Paris, France.

Objectives: To compare duration and changes over time in length of hospital stay for very preterm and extremely preterm infants in 10 European regions.

Design: Two area-based cohort studies from the same regions in 2003 and 2011/2012.

Setting: Ten regions from nine European countries.

Patients: Infants born between 22 + 0 and 31 + 6 weeks of gestational age and surviving to discharge (Models of Organising Access to Intensive Care for Very Preterm Births cohort in 2003, n = 4,011 and Effective Perinatal Intensive Care in Europe cohort in 2011/2012, n = 4,336).

Interventions: Observational study, no intervention.

Measurements And Main Results: Maternal and infant characteristics were abstracted from medical records using a common protocol and length of stay until discharge was adjusted for case-mix using negative binomial regression. Mean length of stay was 63.6 days in 2003 and varied from 52.4 to 76.5 days across regions. In 2011/2012, mean length of stay was 63.1 days, with a narrower regional range (54.0-70.1). Low gestational age, small for gestational age, low 5-minute Apgar score, surfactant administration, any surgery, and severe neonatal morbidities increased length of stay. Infant characteristics explained some of the differences between regions and over time, but large variations remained after adjustment. In 2011/2012, mean adjusted length of stay ranged from less than 54 days in the Northern region of the United Kingdom and Wielkopolska, Poland to over 67 days in the Ile-de-France region of France and the Eastern region of the Netherlands. No systematic decrease in very preterm length of stay was observed over time after adjustment for patient case-mix.

Conclusions: A better understanding of the discharge criteria and care practices that contribute to the wide differences in very preterm length of stay across European regions could inform policies to optimize discharge decisions in terms of infant outcomes and health system costs.
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http://dx.doi.org/10.1097/PCC.0000000000001756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282674PMC
December 2018

Memory deficits following neonatal critical illness: a common neurodevelopmental pathway.

Lancet Child Adolesc Health 2018 04 10;2(4):281-289. Epub 2018 Jan 10.

Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands. Electronic address:

Over the past decade, evidence has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and academic problems. These difficulties are manifest even when intelligence is within the normal range. In this Review, we propose a common neurodevelopmental pathway following neonatal critical illness by showing that survivors of preterm birth, congenital heart disease, and severe respiratory failure share an increased risk of long-term memory deficits and associated hippocampal alterations. Rather than a consequence of underlying diagnosis, we suggest that this shared vulnerability is probably related to common conditions associated with neonatal critical illness, including hypoxia, neuroinflammation, stress, exposure to anaesthetics, or a complex interplay of these factors at different postconceptional ages. Future work should be aimed at improvement of early identification of patients at risk and evaluation of intervention modalities, such as exercise or cognitive training.
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http://dx.doi.org/10.1016/S2352-4642(17)30180-3DOI Listing
April 2018

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

Matern Child Nutr 2019 01 23;15(1):e12657. Epub 2018 Aug 23.

INSERM UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes University, Paris, 75014, France.

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.
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http://dx.doi.org/10.1111/mcn.12657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199087PMC
January 2019

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

BMC Pediatr 2018 08 4;18(1):262. Epub 2018 Aug 4.

Department of Paediatrics, Division of Neonatology, Radboud university medical centre Nijmegen, Radboud Institute for Health Sciences, Amalia Children's Hospital, Internal postal code 804, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, The Netherlands.

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 .
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http://dx.doi.org/10.1186/s12887-018-1215-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090763PMC
August 2018

Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects.

Pulm Circ 2018 Jul-Sep;8(3):2045894018795143. Epub 2018 Jul 30.

2 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. Since its first description, significant achievements in research have led to a better understanding of the underlying molecular mechanism of ACD/MPV and genetic studies have identified associations with genomic alterations in the locus of the transcription factor FOXF1. This in turn has increased the awareness among clinicians resulting in over 200 cases reported so far, including genotyping of patients in most recent reports. Collectively, this promoted a better stratification of the patient group, leading to new perspectives in research on the pathogenesis. Here, we provide an overview of the clinical aspects of ACD/MPV, including guidance for clinicians, and review the ongoing research into the complex molecular mechanism causing this severe lung disorder.
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http://dx.doi.org/10.1177/2045894018795143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108021PMC
July 2018

Various experiences and preferences of Dutch parents in prenatal counseling in extreme prematurity.

Patient Educ Couns 2018 12 4;101(12):2179-2185. Epub 2018 Jul 4.

Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Department of Pediatrics, Nijmegen, The Netherlands.

Objective: To investigate experienced and preferred prenatal counseling among parents of extremely premature babies.

Methods: A Dutch nationwide, multicenter, cross-sectional study using an online survey. Surveys were sent to all parents of extremely premature babies born between 2010 and 2013 at 24-24 weeks of gestation.

Results: Sixty-one out of 229 surveys were returned. A minority (14%) had no counseling conversation. Conversations were done more often by neonatologists (90%) than by obstetricians (39%) and in 37% by both these experts. Supportive material was rarely used (19%). Mortality (92%) and short-term morbidity (88%) were discussed the most, and more frequently than long-term morbidity (65%), practical items (63%) and delivery mode (52%). Most decisions on active care or palliative comfort care were perceived as decisions by doctor and parents together (61%). 80% felt they were involved in decision-making. The preferred way of involvement in decision-making varied among parents.

Conclusion: The vast majority of parents were counseled: mostly by neonatologists, and mainly about mortality and short-term morbidity. Parents wanted to be involved in the decision-making process but differed on the preferred extent of involvement. Practice implications Understanding of shared decision-making may contribute to meet the various preferences of parents.
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http://dx.doi.org/10.1016/j.pec.2018.07.003DOI Listing
December 2018

Improving Long-Term Outcomes After Extracorporeal Membrane Oxygenation: From Observational Follow-Up Programs Toward Risk Stratification.

Front Pediatr 2018 26;6:177. Epub 2018 Jun 26.

Department of Neonatology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.

Since the introduction of extracorporeal membrane oxygenation (ECMO), more neonates and children with cardiorespiratory failure survive. Interest has therefore shifted from reduction of mortality toward evaluation of long-term outcomes and prevention of morbidity. This review addresses the changes in ECMO population and the ECMO-treatment that may affect long-term outcomes, the diagnostic modalities to evaluate neurological morbidities and their contributions to prognostication of long-term outcomes. Most follow-up data have only become available from observational follow-up programs in neonatal ECMO-survivors. The main topics are discussed in this review. Recommendations for long-term follow up depend on the presence of neurological comorbidity, the nature and extent of the underlying disease, and the indication for ECMO. Follow up should preferably be offered as standard of care, and in an interdisciplinary, structured and standardized way. This permits evaluation of outcome data and effect of interventions. We propose a standardized approach and recommend that multiple domains should be evaluated during long-term follow up of neonates and children who needed extracorporeal life support.
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http://dx.doi.org/10.3389/fped.2018.00177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036288PMC
June 2018