De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops.

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.

Record, reflect and refine: using video review as an initiative to improve neonatal care.

BACKGROUND: The goal of every medical team is to provide optimal care for their patients. We aimed to use video review (VR) sessions to identify and address areas for improvement in neonatal care. METHODS: For nine months, neonatal procedures (stabilization at birth, intubations and sterile line insertions) were video recorded and reviewed with the neonatal care providers. Action research was used to identify and address areas for improvement which were categorized as (1) protocol/equipment adjustments, (2) input for research, (3) aspects of variety, or (4) development of educational material or training programs. RESULTS: Eighteen VR sessions were organized with a mean(SD) of 17(5) staff members participating. In total, 120 areas for improvement were identified and addressed, of which 84/120 (70%) were categorized as aspects of variety, 20/120 (17%) as development of educational material or training programs, 10/120 (8%) as protocol/equipment adjustments, and 6/120 (5%) as input for research. The areas for improvement were grouped in themes per category, including sterility, technique, equipment, communication, teamwork, parents' perspective and ventilation. CONCLUSION: Our study showed that regularly organized VR empowered healthcare providers to identify and address a large variety of areas for improvement, contributing to continuous learning and improvement processes. IMPACT: Video review empowered healthcare providers to identify areas for improvement in neonatal care Video review gave providers the opportunity to address identified areas for improvement, either by enhancing the application of external evidence (i.e. guidelines), learning from individual clinical expertise or strengthening resilience and teamwork Embedding regularly organized video review sessions allowed for continuous monitoring of care by providers, which can be beneficial for creating ongoing learning and improvement processes The structured pathways, supporting implementation of changes that were proposed based on the video review sessions, could help other centers make use of the potential video review has to offer.

Minimising alarm pressure on a single room NICU through automated withdrawal of resolved alarms.

AIM: In 2017, the Leiden University Medical Centre implemented a secondary alarm system using handheld devices to ensure accurate patient monitoring on the single room NICU. Initially, alarms remained active on the handheld devices until one of the caregivers in the alarm chain accepted the alarm. In 2020, a bidirectional communication protocol (BCP) was implemented, enabling automated withdrawal of resolved alarms. The aim of this study was to evaluate the effect of this implementation on the alarm duration and pressure. METHODS: Data of all alarms of the secondary alarm chain in the 90 days before and after the implementation were analysed and compared between both periods. RESULTS: Following the implementation of the BCP, 60% of the alarms were withdrawn before the designated nurse responded. Despite a significant higher total number of alarms, the median alarm duration decreased from 9 (7-14) to 6 (4-10) s, the acceptance rate of the designated nurse increased from 93% to 95% and the median time of alarm sounding per phone per hour significantly decreased from 71 (51-101) to 51 (35-69) s following implementation of the BCP. CONCLUSION: This study showed that automated withdrawal of resolved alarms significantly reduces alarm duration and pressure on a NICU.

Putting genome-wide sequencing in neonates into perspective.

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

Correction: Putting genome-wide sequencing in neonates into perspective.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Long-Term Neurodevelopmental and Respiratory Outcome after Intrauterine Therapy for Fetal Thoracic Abnormalities.

INTRODUCTION: The aim of this study is to evaluate long-term neurodevelopmental and respiratory outcome after fetal therapy for fetal pleural effusion, congenital cystic adenomatoid malformation, and bronchopulmonary sequestration. METHODS: Children ≥18 months of age underwent an assessment of neurologic, motor, and cognitive development. Medical records were reviewed to determine respiratory outcome. Behavioral outcome was assessed using the Child Behavioral Checklist. RESULTS: Between 2001 and 2016, 63 fetuses with fetal hydrops secondary to thoracic abnormalities were treated at our center. Overall perinatal survival was 64% (40/63). Twenty-six children were included for follow-up (median age 55 months). Severe neurodevelopmental impairment (NDI) was detected in 15% (4/26). Three out of 4 children with severe NDI had associated causes contributing to the impairment. Overall adverse outcome, including perinatal mortality or NDI, was 55% (27/49). Fifteen percent (4/26) had severe respiratory sequelae. Parents did not report more behavioral problems than Dutch norms. DISCUSSION: Our results suggest that severe NDI in this specific high-risk cohort occurs in 15%, which is above the range of the incidence of NDI reported in case series treated with other fetal therapies (5-10%). Large multicenter studies and an international web-based registry are warranted to prospectively gather outcome data at fixed time points.

Caffeine to improve breathing effort of preterm infants at birth: a randomized controlled trial.

BackgroundCaffeine promotes spontaneous breathing by antagonizing adenosine. We assessed the direct effect of caffeine on respiratory effort in preterm infants at birth.MethodsThirty infants of 24-30 weeks of gestation were randomized for receiving caffeine directly after birth in the delivery room (caffeine DR group) or later in the neonatal intensive care unit (control group). Primary outcome was respiratory effort, expressed as minute volume, tidal volumes, respiratory rate, rate of rise to maximum tidal volume, and recruitment breaths at 7-9 min after birth.ResultsAfter correction for gestational age, minute volumes ((mean±SD; 189±74 vs. 162±70 ml/kg/min; P<0.05) and tidal volumes ((median (interquartile range (IQR)) 5.2 (3.9-6.4) vs. 4.4 (3.0-5.6) ml/kg) were significantly greater in the caffeine DR group. Although respiratory rates were similar ((mean±SD) 35±10 vs. 33±10), RoR increased significantly ((median (IQR) 14.3 (11.2-19.8) vs. 11.2 (7.9-15.2) ml/kg/s), and more recruitment breaths were observed (13 vs. 9%).ConclusionCaffeine increases respiratory effort in preterm infants at birth, but the effect on clinical outcomes needs further investigation.

Clinical and molecular characterization of an infant with a tandem duplication and deletion of 19p13.

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.

Using the providers' perspective on video review of neonatal procedures to create a roadmap: a qualitative study.

OBJECTIVE: To examine the providers' perceptions and experiences on implementation of video review (VR) of procedures in the neonatal intensive care unit (NICU). DESIGN: Qualitative study using semi-structured interviews with neonatal care providers about their experiences with VR. Interviews were audio-recorded, transcribed and thematically analysed using the data analysis software Atlas.ti V.22.2. SETTING: Providers working in the NICU of the Leiden University Medical Center were interviewed during implementation of VR. RESULTS: In total, 28 NICU staff members were interviewed. The interviewed providers appreciated VR and valued the focus on a safe learning environment. Five overarching themes were identified: (1) added value: providers reported that VR is a powerful tool for reflection on daily practice and serves as a magnifying glass on practice, provides a helicopter view and VR with nursing and medical staff together led to new insights and was seen as highly valuable; (2) preconditions and considerations: the existing culture of trust on the NICU positively influenced providers' perception; (3) adjustment: it was recommended to first let providers attend a VR session, before being recorded; (4) experiences with VR: suggestions were made by the providers regarding the preparation and organisation of VR and the role of the chair; (5) embedding VR: providers considered how to embed VR on the long-term while maintaining a safe learning environment and provided suggestions for expanding. CONCLUSION: Neonatal care providers appreciated the use of VR and provided viewpoints on how to implement VR successfully, which were used to develop a roadmap with recommendations.

Quality improvement initiative: implementing and redefining video review of real-time neonatal procedures using action research.

Video review (VR) of procedures in the medical environment can be used to drive quality improvement. However, first it has to be implemented in a safe and effective way. Our primary objective was to (re)define a guideline for implementing interprofessional VR in a neonatal intensive care unit (NICU). Our secondary objective was to determine the rate of acceptance by providers attending VR. For 9 months, VR sessions were evaluated with a study group, consisting of different stakeholders. A questionnaire was embedded at the end of each session to obtain feedback from providers on the session and on the safe learning environment. In consensus meetings, success factors and preconditions were identified and divided into different factors that influenced the rate of adoption of VR. The number of providers who recorded procedures and attended VR sessions was determined. A total of 18 VR sessions could be organised, with an equal distribution of medical and nursing staff. After the 9-month period, 101/125 (81%) of all providers working on the NICU attended at least 1 session and 80/125 (64%) of all providers recorded their performance of a procedure at least 1 time. In total, 179/297 (61%) providers completed the questionnaire. Almost all providers (99%) reported to have a positive opinion about the review sessions. Preconditions and success factors related to implementation were identified and addressed, including improving the pathway for obtaining consent, preparation of VR, defining the role of the chair during the session and building a safe learning environment. Different strategies were developed to ensure findings from sessions were used for quality improvement. VR was successfully implemented on our NICU and we redefined our guideline with various preconditions and success factors. The adjusted guideline can be helpful for implementation of VR in emergency care settings.

[Apgar score: time to "call it"?] / De apgarscore: tijd om af te schaffen?

Virginia Apgar designed the apgar score during a breakfast with colleagues in response to a discussion about the need to evaluate newborns at birth. She scribbled down the score on a piece of paper and the score has been indispensable ever since, not just for reflecting the clinical condition and to indicate whether intervention was needed, but also to predict outcome. The reliability and validity have been often questioned, also in a recent study. Is it time to "call it" and send the score on retirement?

Video recording emergency care and video-reflection to improve patient care; a narrative review and case-study of a neonatal intensive care unit.

As the complexity of emergency care increases, current research methods to improve care are often unable to capture all aspects of everyday clinical practice. Video recordings can visualize clinical care in an objective way. They can be used as a tool to assess care and to reflect on care with the caregivers themselves. Although the use of video recordings to reflect on medical interventions (video-reflection) has increased over the years, it is still not used on a regular basis. However, video-reflection proved to be of educational value and can improve teams' management and performance. It has a positive effect on guideline adherence, documentation, clinical care and teamwork. Recordings can also be used for video-reflexivity. Here, caregivers review recordings together to reflect on their everyday practice from new perspectives with regard to context and conduct in general. Although video-reflection in emergency care has proven to be valuable, certain preconditions have to be met and obstacles need to be overcome. These include gaining trust of the caregivers, having a proper consent-procedure, maintaining confidentiality and adequate use of technical equipment. To implement the lessons learned from video-reflection in a sustainable way and to continuously improve care, it should be integrated in regular simulation training or education. This narrative review will describe the development of video recording in emergency care and how video-reflection can improve patient care and safety in new ways. On our own department, the NICU at the LUMC, video-reflection has already been implemented and we want to further expand this. We will describe the use of video-reflection in our own unit. Based on the results of this narrative review we will propose options for future research to increase the value of video-reflection.

Comparing Descriptive Statistics for Retrospective Studies From One-per-Minute and One-per-Second Data.

Background: Large amounts of data are collected in neonatal intensive care units, which could be used for research. It is unclear whether these data, usually sampled at a lower frequency, are sufficient for retrospective studies. We investigated what to expect when using one-per-minute data for descriptive statistics. Methods: One-per-second inspiratory oxygen and saturation were processed to one-per-minute data and compared, on average, standard deviation, target range time, hypoxia, days of supplemental oxygen, and missing signal. Results: Outcomes calculated from data recordings (one-per-minute = 92, one-per-second = 92) showed very little to no difference. Sub analyses of recordings under 100 and 200 h showed no difference. Conclusion: In our study, descriptive statistics of one-per-minute data were comparable to one-per-second and could be used for retrospective analyses. Comparable routinely collected one-per-minute data could be used to develop algorithms or find associations, retrospectively.

Consent for Delivery Room Studies: What Can Be Learned from Perceptions of Parents.

BACKGROUND: Obtaining ethically valid consent to participate in delivery room (DR) studies from parents facing an imminent premature birth can be challenging. This study aims to provide insight into parental experiences with and perceptions of consent for DR studies. METHODS: Semistructured interviews were conducted with parents of very and extreme preterm infants. Interviews were audio-recorded, transcribed, and analyzed using the qualitative data analysis software Atlas. ti V.8.4. RESULTS: Twenty-five parents were interviewed. Despite being in an emotional and stressful situation, most parents considered being approached for DR studies as valuable. According to parents, this was mostly due to appropriate timing and communication, compassion, and investigators not being obtrusive. Interviewed parents generally decided to accept or decline study participation based on perceived risk. Parents differed widely in how risk of specific study interventions was perceived, but agreed on the fact that parental consent is needed for DR studies that involve risk. There was no consensus among parents on deferred consent for DR studies running at our NICU. However, parents considered deferred consent appropriate for observational studies. Furthermore, it became clear that parental misunderstanding of various aspects of DR studies, including aims, the concept of randomization, and risk associated with specific interventions, was common. CONCLUSIONS: Insight into parental perceptions of consent for DR studies allowed us to determine areas where the validity of parental consent can be improved. Further research on parental perspectives for consent for DR studies will allow us to establish consent procedures that are considered both valid and valuable.

Video-based reflection on neonatal interventions during COVID-19 using eye-tracking glasses: an observational study.

OBJECTIVE: The aim of this study was to determine the experience with, and the feasibility of, point-of-view video recordings using eye-tracking glasses for training and reviewing neonatal interventions during the COVID-19 pandemic. DESIGN: Observational prospective single-centre study. SETTING: Neonatal intensive care unit at the Leiden University Medical Center. PARTICIPANTS: All local neonatal healthcare providers. INTERVENTION: There were two groups of participants: proceduralists, who wore eye-tracking glasses during procedures, and observers who later watched the procedures as part of a video-based reflection. MAIN OUTCOME MEASURES: The primary outcome was the feasibility of, and the proceduralists and observers' experience with, the point-of-view eye-tracking videos as an additional tool for bedside teaching and video-based reflection. RESULTS: We conducted 12 point-of-view recordings on 10 different patients (median gestational age of 30.9±3.5 weeks and weight of 1764 g) undergoing neonatal intubation (n=5), minimally invasive surfactant therapy (n=5) and umbilical line insertion (n=2). We conducted nine video-based observations with a total of 88 observers. The use of point-of-view recordings was perceived as feasible. Observers further reported the point-of-view recordings to be an educational benefit for them and a potentially instructional tool during COVID-19. CONCLUSION: We proved the practicability of eye-tracking glasses for point-of-view recordings of neonatal procedures and videos for observation, educational sessions and logistics considerations, especially with the COVID-19 pandemic distancing measures reducing bedside teaching opportunities.

Comparison of two devices for automated oxygen control in preterm infants: a randomised crossover trial.

OBJECTIVE: To compare the effect of two different automated oxygen control devices on target range (TR) time and occurrence of hypoxaemic and hyperoxaemic episodes. DESIGN: Randomised cross-over study. SETTING: Tertiary level neonatal unit in the Netherlands. PATIENTS: Preterm infants (n=15) born between 24+0 and 29+6 days of gestation, receiving invasive or non-invasive respiratory support with oxygen saturation (SpO2) TR of 91%-95%. Median gestational age 26 weeks and 4 days (IQR 25 weeks 3 days-27 weeks 6 days) and postnatal age 19 (IQR 17-24) days. INTERVENTIONS: Inspired oxygen concentration was titrated by the OxyGenie controller (SLE6000 ventilator) and the CLiO2 controller (AVEA ventilator) for 24 hours each, in a random sequence, with the respiratory support mode kept constant. MAIN OUTCOME MEASURES: Time spent within set SpO2 TR (91%-95% with supplemental oxygen and 91%-100% without supplemental oxygen). RESULTS: Time spent within the SpO2 TR was higher during OxyGenie control (80.2 (72.6-82.4)% vs 68.5 (56.7-79.3)%, p<0.005). Less time was spent above TR while in supplemental oxygen (6.3 (5.1-9.9)% vs 15.9 (11.5-30.7)%, p<0.005) but more time spent below TR during OxyGenie control (14.7 (11.8%-17.2%) vs 9.3 (8.2-12.6)%, p<0.05). There was no significant difference in time with SpO2 <80% (0.5 (0.1-1.0)% vs 0.2 (0.1-0.4)%, p=0.061). Long-lasting SpO2 deviations occurred less frequently during OxyGenie control. CONCLUSIONS: The OxyGenie control algorithm was more effective in keeping the oxygen saturation within TR and preventing hyperoxaemia and equally effective in preventing hypoxaemia (SpO2 <80%), although at the cost of a small increase in mild hypoxaemia. TRIAL REGISTRY NUMBER: NCT03877198.

Prenatal interventions for fetal lung lesions.

The widespread availability of high resolution ultrasound equipment and almost universal routine anatomy scanning in all pregnant women in the developed world has lead to increased detection of abnormalities in the fetal thorax. Already in the 1980s, large pleural effusions and significant macrocystic lesions in the fetus were easily detected on ultrasound. However, smaller lung tumours were often missed. Nowadays, fetal medicine centres receive many referrals for evaluation of fetal lung lesions, of which the most common are congenital cystic adenomatoid malformation and bronchopulmonary sequestration. Almost invariably, both the parents and the referring physicians experience anxiety after detection of large lung masses in the fetus. However, the vast majority of the currently detected fetal lung lesions have an excellent prognosis without the need for prenatal intervention. In the small group of fetuses in which the prognosis is poor, almost exclusively those with concomitant fetal hydrops and cardiac failure, several options for fetal therapy exist, often with a more than 50% survival rate. Indications, techniques, complications and outcomes of these interventions will be described in this review.

Automated oxygen control in preterm infants, how does it work and what to expect: a narrative review.

BACKGROUND: Automated oxygen control systems are finding their way into contemporary ventilators for preterm infants, each with its own algorithm, strategy and effect. OBJECTIVE: To provide guidance to clinicians seeking to comprehend automated oxygen control and possibly introduce this technology in their practice. METHOD: A narrative review of the commercially available devices using different algorithms incorporating rule-based, proportional-integral-derivative and adaptive concepts are described and explained. An overview of how they work and, if available, the clinical effect is given. RESULTS: All algorithms have shown a beneficial effect on the proportion of time that oxygen saturation is within target range, and a decrease in hyperoxia and severe hypoxia. Automated oxygen control may also reduce the workload for bedside staff. There is concern that such devices could mask clinical deterioration, however this has not been reported to date. CONCLUSIONS: So far, trials involving different algorithms are heterogenous in design and no head-to-head comparisons have been made, making it difficult to differentiate which algorithm is most effective and what clinicians can expect from algorithms under certain conditions.

Feasibility and Effect of Physiological-Based CPAP in Preterm Infants at Birth.

Background: Preterm infants are commonly supported with 5-8 cmH2O CPAP. However, animal studies demonstrate that high initial CPAP levels (12-15 cmH2O) which are then reduced (termed physiological based (PB)-CPAP), improve lung aeration without adversely affecting cardiovascular function. We investigated the feasibility of PB-CPAP and the effect in preterm infants at birth. Methods: Preterm infants (24-30 weeks gestation) were randomized to PB-CPAP or 5-8 cmH2O CPAP for the first 10 min after birth. PB-CPAP consisted of 15 cmH2O CPAP that was decreased when infants were stabilized (heart rate ≥100 bpm, SpO2 ≥85%, FiO2 ≤ 0.4, spontaneous breathing) to 8 cmH2O with steps of ~2/3 cmH2O/min. Primary outcomes were feasibility and SpO2 in the first 5 min after birth. Secondary outcomes included physiological and breathing parameters and short-term neonatal outcomes. Planned enrollment was 42 infants. Results: The trial was stopped after enrolling 31 infants due to a low inclusion rate and recent changes in the local resuscitation guideline that conflict with the study protocol. Measurements were available for analysis in 28 infants (PB-CPAP n = 8, 5-8 cmH2O n = 20). Protocol deviations in the PB-CPAP group included one infant receiving 3 inflations with 15 cmH2O PEEP and two infants in which CPAP levels were decreased faster than described in the study protocol. In the 5-8 cmH2O CPAP group, three infants received 4, 10, and 12 cmH2O CPAP. During evaluations, caregivers indicated that the current PB-CPAP protocol was difficult to execute. The SpO2 in the first 5 min after birth was not different [61 (49-70) vs. 64 (47-74), p = 0.973]. However, infants receiving PB-CPAP achieved higher heart rates [121 (111-130) vs. 97 (82-119) bpm, p = 0.016] and duration of mask ventilation was shorter [0:42 (0:34-2:22) vs. 2:58 (1:36-6:03) min, p = 0.020]. Infants in the PB-CPAP group required 6:36 (5:49-11:03) min to stabilize, compared to 9:57 (6:58-15:06) min in the 5-8 cmH2O CPAP group (p = 0.256). There were no differences in short-term outcomes. Conclusion: Stabilization of preterm infants with PB-CPAP is feasible but tailoring CPAP appeared challenging. PB-CPAP did not lead to higher SpO2 but increased heart rate and shortened the duration of mask ventilation, which may reflect faster lung aeration.

Reviewing recordings of neonatal resuscitation with parents.

BACKGROUND: Recording of neonatal resuscitation, including video and respiratory parameters, was implemented for research and quality purposes at the neonatal intensive care unit (NICU) of the Leiden University Medical Center, and parents were offered to review the recording of their infant together with a neonatal care provider. We aimed to provide insight in parental experiences with reviewing the recording of the neonatal resuscitation of their premature infant. METHODS: This study combined participant observations during parental review of recordings with retrospective qualitative interviews with parents. RESULTS: Parental review of recordings of neonatal resuscitation was observed on 20 occasions, reviewing recordings of 31 children (12 singletons, 8 twins and 1 triplet), of whom 4 died during admission. Median (range) gestational age at birth was 27+5 (24+5-30+3) weeks. Subsequently, 25 parents (13 mothers and 12 fathers) were interviewed.Parents reported many positive experiences, with special emphasis on the value for getting hold of the start of their infant's life and coping with the trauma of neonatal resuscitation. Reviewing recordings of neonatal resuscitation frequently resulted in appreciation for the child, the father and the medical team. Timing and set-up of the review contributed to positive experiences. Parents considered screenshots/copies of the recording of the resuscitation of their infant as valuable keepsakes of their NICU story and reported that having the screenshots/video comforted them, especially when their child died during admission. CONCLUSION: Parents consider reviewing recordings of neonatal resuscitation as valuable. These positive parental experiences could allay concerns about sharing recordings of neonatal resuscitation with parents.