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... Show moreFetal 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. Show less
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... Show moreBackground: 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. Show less
Boer, M.C. den; Houtlosser, M.; Witlox, R.S.G.M.; Zanten, H.A. van; Vries, M.C. de; Pas, A.B. te 2022
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... Show moreBackground: 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. Show less
Background: Preterm infants are commonly supported with 5-8 cmH(2)O CPAP. However, animal studies demonstrate that high initial CPAP levels (12-15 cmH(2)O) which are then reduced (termed... Show moreBackground: Preterm infants are commonly supported with 5-8 cmH(2)O CPAP. However, animal studies demonstrate that high initial CPAP levels (12-15 cmH(2)O) 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 cmH(2)O CPAP for the first 10 min after birth. PB-CPAP consisted of 15 cmH(2)O CPAP that was decreased when infants were stabilized (heart rate >= 100 bpm, SpO(2) >= 85%, FiO(2) <= 0.4, spontaneous breathing) to 8 cmH(2)O with steps of ~2/3 cmH(2)O/min. Primary outcomes were feasibility and SpO(2) 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 cmH(2)O n = 20). Protocol deviations in the PB-CPAP group included one infant receiving 3 inflations with 15 cmH(2)O PEEP and two infants in which CPAP levels were decreased faster than described in the study protocol. In the 5-8 cmH(2)O CPAP group, three infants received 4, 10, and 12 cmH(2)O CPAP. During evaluations, caregivers indicated that the current PB-CPAP protocol was difficult to execute. The SpO(2) 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 SpO(2) but increased heart rate and shortened the duration of mask ventilation, which may reflect faster lung aeration. Show less
Objective To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in... Show moreObjective To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in very preterm infants admitted to the neonatal intensive care unit. The original model was developed in the UK and included gestational age, birthweight and gender. Design External validation study in a population-based cohort. Setting Dutch neonatal wards. Population or sample All admitted white, singleton infants born between 23(+0) and 32(+6) weeks of gestation between 1 January 2015 and 31 December 2019. Additionally, the model's performance was assessed in four populations of admitted infants born between 24(+0) and 31(+6) weeks of gestation: white singletons, non-white singletons, all singletons and all multiples. Methods The original model was applied in all five validation sets. Model performance was assessed in terms of calibration and discrimination and, if indicated, it was updated. Main outcome measures Calibration (calibration-in-the-large and calibration slope) and discrimination (c statistic). Results Out of 6092 infants, 5659 (92.9%) survived. The model showed good external validity as indicated by good discrimination (c statistic 0.82, 95% CI 0.79-0.84) and calibration (calibration-in-the-large 0.003, calibration slope 0.92, 95% CI 0.84-1.00). The model also showed good external validity in the other singleton populations, but required a small intercept update in the multiples population. Conclusions A high-quality prognostic model predicting survival in very preterm infants had good external validity in an independent, nationwide cohort. The accurate performance of the model indicates that after impact assessment, implementation of the model in clinical practice in the neonatal intensive care unit could be considered. Tweetable abstract A high-quality model predicting survival in very preterm infants is externally valid in an independent cohort. Show less
Wagner, M.; Boer, M.C. den; Jansen, S.; Groepel, P.; Visser, R.; Witlox, R.S.G.M.; ... ; Pas, A.B. te 2021
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... Show moreObjective 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.Single centre evaluation of the use of eye-tracking glasses during neonatal procedures as an additional tool for outside teaching and video-based reflection. The feasibility and potential benefit during a pandemic is reported. Show less
Introduction: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for... Show moreIntroduction: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP. Methods: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied. Results: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage >= 3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54-0.66) and increased for small for GA (SGA) (1.73, 1.11-2.62), mechanical ventilation >7 days (2.13, 1.35-3.37) and postnatal corticosteroids (2.57, 1.44-4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27-0.50), SGA (OR 5.65 and CI 2.17-14.92), postnatal corticosteroids (OR 3.81 and CI 1.72-8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29-24.48). Conclusion: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline. Show less
Boer, M.C. den; Houtlosser, M.; Witlox, R.S.G.M.; Stap, R. van der; Vries, M.C. de; Lopriore, E.; Pas, A.B. te 2021
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... Show moreBackground 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. Show less
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... Show moreObjective 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 (SpO(2)) TR of 91%-95%. Median gestational age 26 weeks and 4 days (IQR 25 weeks 3days-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 SpO(2) TR (91%-95% with supplemental oxygen and 91%-100% without supplemental oxygen).Results Time spent within the SpO(2) 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 SpO(2) <80% (0.5 (0.1-1.0)% vs 0.2 (0.1-0.4)%, p=0.061). Long-lasting SpO(2) 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 (SpO(2) <80%), although at the cost of a small increase in mild hypoxaemia. Show less
Beek, P.E. van; Groenendaal, F.; Broeders, L.; Dijk, P.H.; Dijkman, K.P.; Dungen, F.A.M. van den; ... ; Andriessen, P. 2021
Objective In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25(+0) to 24(+0) weeks' gestation in 2010. This study aimed to evaluate the impact... Show moreObjective In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25(+0) to 24(+0) 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(0/7) and 26(6/7) 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. Show less
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... Show moreBackground 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. Show less
Boer, M.C. den; Martherus, T.; Houtlosser, M.; Root, L.; Witlox, R.S.G.M.; Pas, A.B. te 2020
Video and physiological parameter recording of neonatal stabilization was implemented at the Neonatal Intensive Care Unit (NICU) of the Leiden University Medical Center. In order to improve... Show moreVideo and physiological parameter recording of neonatal stabilization was implemented at the Neonatal Intensive Care Unit (NICU) of the Leiden University Medical Center. In order to improve documentation and the quality of care provided during neonatal transition, we implemented weekly plenary audits reviewing recordings of neonatal stabilization in 2014. In audits, provided care is reviewed, discussing, among others, mask technique, compliance to the prevailing local guideline, and clinical decision making and alternative treatment options. In this perspective, we argue that auditing neonatal stabilization is a valuable tool to improve patient safety and the quality of care provided during neonatal stabilization. We, therefore, report lessons learned and areas for improvement that could be identified and addressed during audits conducted at our NICU. Important areas for improvement were guideline compliance, documentation, the usage of medical devices, the conduct of delivery room studies, and clinical decision making. By reporting our experiences, we hope to encourage other NICUs to also implement regular audit meetings, fitting to their improvement needs. Show less
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... Show morePurpose 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. Show less
Witlox, R.S.G.M.; Lopriore, E.; Rijken, M.; Klumper, F.J.C.M.; Oepkes, D.; Klink, J.M.M. van 2019
Fetal thoracic abnormalities such as congenital cystic adenomatoid malformation of the lung (CCAM), bronchopulmonary sequestration (BPS) and fetal pleural effusions (FPE) can lead to fetal hydrops... Show moreFetal thoracic abnormalities such as congenital cystic adenomatoid malformation of the lung (CCAM), bronchopulmonary sequestration (BPS) and fetal pleural effusions (FPE) can lead to fetal hydrops due to their space occupying effect. In these cases the risk of fetal demise is very high when left untreated. Different treatment modalities are available to reduce the intrathoracic pressure either by directly reducing the mass of the lesion (e.g. by laser coagulation of the feeding vessel of BPS) or by shunt placement in FPE or macrocystic CCAM. These treatments reduce perinatal mortality. Infants born after fetal therapy are at increased risk of neonatal morbidity and mortality. The rates of respiratory failure at birth and postnatal demise are highest in the group treated for CCAM with hydrops. In patients with BPS and hydrops the rates of neonatal morbidity and demise are lower. The postnatal course of hydropic fetuses treated with thoracoamniotic shunt for isolated hydrothorax is often complicated by respiratory failure and persistent pleural effusions. Neonatal survival is good provided delivery occurs at or after 32 weeks’ gestation. In these groups of patients severe neurodevelopmental impairment (NDI) at long-term follow-up was detected in 15% of cases. Show less
