Importance:Visual inspection is commonly the first-line screening method for hyperbilirubinemia in neonates cared for at home. However, it is unreliable and may delay treatment. Objective:To assess the clinical outcomes, costs, and user convenience associated with universal transcutaneous bilirubin (TCB) screening for detecting hyperbilirubinemia in a diverse neonatal population cared for at home. Design, Setting, and Participants:This prospective decision analytical model was conducted between July 11, 2021, and June 9, 2023, in 9 midwifery practices across the Netherlands. Neonates (gestational age ≥35 weeks) were eligible if they had their first midwife visit prior to postnatal day 6 and had not yet received phototherapy. Exposure:At each home visit, the midwife first undertook visual inspection and then performed TCB measurements on the neonate's sternum. Bilirubin was measured in blood when indicated by visual inspection and/or elevated TCB reading. Main Outcomes and Measures:The hypothesis was that TCB could replace visual inspection if (1) more neonates requiring treatment for hyperbilirubinemia were detected and (2) fewer heel pricks were needed. The 2 main outcomes were (1) blood bilirubin level greater than the national guideline's treatment threshold and (2) requiring a heel prick for bilirubin quantification. McNemar tests were used for both hypotheses. Cost-effectiveness was assessed using a decision-tree analytic model. Results:Data from 2314 neonates (median [IQR] gestational age, 39 [39-40] weeks; 1172 [50.6%] male) were analyzed. Overall, 78 (3.4%) had a bilirubin level greater than the treatment threshold. Of these, 28 had been identified through TCB screening but missed by visual inspection (absolute risk difference, 28%; 95% CI, 13%-42%; P < .001). Although TCB missed 7 neonates identified through visual inspection, these were all attributable to either misinterpretation of TCB readings by the midwife or structural overestimation of blood bilirubin levels in one hospital laboratory. TCB screening led to 102 additional heel pricks vs visual inspection (244 vs 142; P < .001). Sensitivity analysis showed that when TCB screening was selectively applied only to neonates with any jaundice, additional heel pricks were reduced to 82 (P < .001), with no loss in diagnostic performance. Universal TCB screening saved €15 ($17) per neonate. Conclusions and Relevance:In this decision analytical model study of 2314 (near) full-term neonates, universal TCB screening among neonates cared for at home identified more neonates requiring treatment but required more heel pricks than visual inspection alone. Universal TCB screening was cost-effective compared with visual inspection. The additional required heel pricks decreased by selective TCB screening.

OBJECTIVES Preterm birth and neonatal intensive care unit (NICU) admission are not only extremely stressful for the infant itself but can also impact parental mental health. This Dutch national prospective cohort study aimed to describe the trajectory of parental mental health following preterm birth (<29 weeks of gestation) and identify contributing factors for mothers and fathers separately. METHODS As part of the “Happiness for the Improvement of Premature and Parental Outcome” study, parents completed questionnaires on posttraumatic stress and depressive symptoms at 3 time points up to term-equivalent age. To determine potential contributing factors, additional questionnaires were completed to capture prenatal psychosocial history, family and birth-related factors, postnatal stressors, and protective factors. Data were analyzed using unstructured mixed-effects models and generalized least squares. RESULTS Questionnaires were completed by 217 of 385 families (of 259/446 children). Clinically elevated posttraumatic stress symptoms peaked at term-equivalent age, affecting 35.1% of mothers and 16.4% of fathers. Clinically elevated depressive symptoms peaked at 1 to 2 weeks after birth in mothers (39.5%) and at term-equivalent age in fathers (24.3%). For both parents, prenatal psychosocial history and NICU-related parental stress were significant contributors to parental mental health. More neonatal stress exposure, having fewer children, and perceived social support were additional factors for fathers’ mental health only. CONCLUSIONS These findings illustrate the impact of preterm birth and NICU admission on parental mental health. Identification of shared and parent-specific risk factors is important to identify parents with the highest risk for adverse outcomes and provides opportunities for early interventions.

Every clinical decision to start or discontinue phototherapy ultimately depends on a single laboratory value of a total serum bilirubin (TSB) level. Yet that value is neither the biologically most relevant marker of bilirubin neurotoxicity nor necessarily measured with sufficient analytical accuracy. Although TSB remains the most widely used clinically available marker to guide phototherapy, it is an indirect measure of bilirubin neurotoxicity. Unbound bilirubin (UB) levels are considered biologically more relevant, representing the fraction of bilirubin that can cross the blood-brain barrier and potentially cause neurotoxicity. However, UB measurements are not routinely available, technically demanding, and lacks broad standardization for clinical use. The bilirubin-to-albumin (B/A) ratio may provide a pragmatic intermediate marker, as it partly reflects bilirubin-binding capacity, but its clinical value is limited by variability in albumin binding and the influence of illness severity, acidosis, and competing substances. Therefore, despite its limitations, TSB levels remain the practical standard for treatment decisions. But clinically relevant analytical bias remains an important limitation of TSB measurements, emphasizing that the reliability of the assay is as important as the choice of biomarker.

OBJECTIVE:To assess how restricting open-label access to an off-label drug influences consent and trial enrolment in neonatal medicine. DESIGN:Multicentre, quasinatural experiment. SETTING:Seventeen neonatal intensive care units in the Netherlands and Belgium participating in the DOXA-trial, a double-blind, randomised, placebo-controlled study of doxapram in extremely preterm infants. PATIENTS:Infants born before 29 weeks' gestation whose parents were approached for DOXA-trial participation. INTERVENTIONS:Ten centres discontinued open-label doxapram outside the DOXA-trial (intervention centres), while seven continued its use (control centres). MAIN OUTCOME MEASURES:Parental consent rates (proportion of parents who provided written informed consent among those approached) and patient enrolment rates (proportion of infants randomised among those whose parents were approached), compared 12 months before and after the policy change in intervention centres and before and after a corresponding reference point in control centres. The reference point in control centres was defined as the mean discontinuation date across intervention centres RESULTS: Overall consent rates increased from 27.8% to 37.1% after the intervention or reference point (+9.3, 95% CI 3.3 to 15.4, p=0.003). In intervention centres, the consent rates rose from 27.1% to 42.9% (+15.8, 95% CI 8.6 to 23.0, p<0.001) and enrolment rates rose proportionally from 9.9% to 16.6% (+6.7, 95% CI 1.5 to 11.9, p=0.011), whereas in control centres, consent and enrolment rates remained unchanged. CONCLUSION:Restricting open-label access to an off-label investigational drug can substantially increase parental consent and patient enrolment in neonatal RCTs. To promote both ethical recruitment and optimal enrolment, future trials should explicitly discuss equipoise in each contributing unit and align local clinical practices with the trial design prior to initiation.

INTRODUCTION:The Bilistick is a handheld point-of-care device for measuring total bilirubin levels in small blood volumes. We assessed its diagnostic accuracy and user convenience in near-term neonates cared for at home. METHODS:A prospective cohort study was conducted in nine Dutch community midwifery practices. Neonates ≥35 weeks' gestation were eligible if they were at home between postnatal days 2-8 and had not received phototherapy. A Bilistick version 2.0 was used in parallel to laboratory-based bilirubin (LBB) quantification when significant visible jaundice was observed or the transcutaneous bilirubin reading was elevated. RESULTS:A total of 2,314 neonates were included in the study, with 423 blood samples analyzed across 13 laboratories. On 203 occasions, the Bilistick was not used. Among the remaining 220 Bilistick readings, 104 failed, and 2 lacked corresponding LBB results. A Bland-Altman plot of 114 paired measurements of Bilistick and LBB showed a mean difference of +9.7 µmol/L (0.57 mg/dL) with corresponding 95% limits of agreement of -179.7 to +199.2 µmol/L (-10.5 to 11.7 mg/dL). The positive predictive value of a Bilistick reading for having a total serum bilirubin level above the phototherapy threshold was 36.4%. The negative predictive value was 90.1%, sensitivity 60%, and specificity 77.6%. Hemolysis (24%) contributed to overestimations by the Bilistick. Community midwives expressed multiple barriers related to user convenience. CONCLUSION:Diagnostic accuracy of the Bilistick when used in the home setting was limited. Its use was further hindered by a significant proportion of failed readings and low user convenience when operated by midwives.

Very preterm neonates admitted to the neonatal intensive care unit (NICU) face daily stressors that activate their hypothalamic–pituitary–adrenal (HPA) axis, triggering cortisol release and potentially affecting their outcomes. We examined the relationship between NICU stressors, urinary cortisol levels, and short-term outcomes in very preterm neonates. This study was part of a multicenter cohort study (HIPPO) including 446 neonates (gestational age < 29 weeks) across all Dutch NICUs. Data on daily stress exposure for the first 28 days and outcomes were prospectively collected, along with urine samples on postnatal days 8 (T1) and 28 (T2) to determine cortisol levels as markers of the stress response. Urinary samples were available for 391 (88

BackgroundNeonatal jaundice is a very common condition in the first week of life requiring timely recognition of the small subset of neonates at risk of developing severe neonatal hyperbilirubinemia (SNH). Total serum bilirubin, as quantified through blood testing, remains the gold standard for diagnosis, whereas screening based on visual inspection has been proven unreliable in identifying which jaundiced neonates require total serum bilirubin. Picterus Jaundice Pro (JP) is a mobile health app developed for use by health care professionals and parents to screen for imminent SNH. However, parental user experiences with Picterus JP remain largely unexplored. ObjectiveThis study aimed to evaluate the usability and user-friendliness of Picterus JP when used and evaluated by parents. MethodsBetween August 2023 and January 2025, we conducted a prospective mixed methods study at 3 maternity care settings: the maternity wards of 2 hospitals in the Netherlands and 1 hospital in Israel. Parents were invited to participate if their infant was near term born (gestational age of ≥35 weeks) and at least 12 hours old but still in the first week of life. Parents used Picterus JP once according to the manufacturer’s instructions. Immediately afterward, usability was evaluated using the validated mHealth App Usability Questionnaire, an instrument measured on a 7-point Likert scale ranging from 1 (“strongly disagree”) to 7 (“strongly agree”), and open-ended questions. A subset of parents and nurses participated in semistructured interviews and focus groups. ResultsIn total, 123 parents completed the questionnaire. The median mHealth App Usability Questionnaire score was 6 (IQR 5-7) out of 7. A total of 87.7% (100/114) of the parents indicated that they would use Picterus JP at home. Parents reported that they found the app easy, quick, and convenient, although 55.8% (67/120) reported a failure on the first try. Some parents struggled to find or interpret the instructions, but most of those who tried again (79/105, 75.2%) obtained a bilirubin estimate. Additionally, 12 nurses from 2 participating maternity wards provided their observations on parents’ use of Picterus JP in 2 focus groups. Thematic analysis of all combined data identified 3 themes that were considered important for the usability of Picterus JP: intention to use Picterus JP, infant well-being, and instruction and guidance. ConclusionsParents rated Picterus JP highly in terms of usability despite encountering difficulties during initial use. Technical improvements and more proactive guidance seem important to support successful parental use. Nonetheless, both parents and nurses were positive about the potential of Picterus JP for home screening for SNH.

Retinopathy of prematurity (ROP) is a leading cause of preventable blindness in preterm infants, with a disproportionate burden in low- and middle-income countries. Screening criteria from high-income settings may not be directly applicable in these contexts. We developed and validated two pragmatic risk-based screening models using multicenter Indonesian neonatal data: Model A (FiO₂-based) and Model B (SpO₂-based). Significant predictors included intrauterine growth restriction, oxygen exposure, exchange transfusion, and socioeconomic status. Internal validation showed moderate discrimination (AUC 0.719–0.732) with sensitivities of 77–86% and specificities of 44–58%. The bedside operational score form is presented for clinical use. External validation in 163 infants (gestational age 25–37 weeks, birth weight 600–2000 g) confirmed robust performance, with the combined rule (positive if either model was positive) achieving a sensitivity 84%, a specificity 81%, positive predictive value 76%, and negative predictive value 87%. The pre-test probability of ROP was 0.42, increasing to 0.76 after a positive screen and decreasing to 0.13 after a negative result. These findings support the use of locally validated risk-based scores as a practical complement to gestational age and birth weight criteria, optimizing ROP case finding in resource-limited settings.

This study aims to quantify stress exposure related to clinical stressors in preterm infants during NICU admission and identify risk factors for high stress exposure. In this national cohort study, preterm infants (gestational age < 29 weeks) were prospectively followed during the first 28 days of their admission to one of the 10 NICUs in the Netherlands. The NeO-stress score, consisting of 38 clinical stressors graded with a severity index, was applied to describe stress exposure. We assessed the impact of infant characteristics at birth and postnatal age on NeO-stress scores using linear mixed modelling. In total, 446 infants were included with a median gestational age of 27+2 weeks (IQR 26+2–28+2). The median NeO-stress score per day was 61 (IQR 39–87) and highest (74, IQR 52–101) on the day of admission. Nasal/oral (37

Undiagnosed severe neonatal jaundice, caused by hyperbilirubinemia, can lead to irreversible brain damage. The Picterus® Jaundice Pro application (Picterus JP) is a mobile health app developed for use by healthcare professionals and parents to screen for neonatal hyperbilirubinemia. Yet, parental experiences with the Picterus JP remain largely unexplored. To evaluate the usability and user-friendliness of Picterus JP when used and evaluated by parents. Between August 2023 and January 2025, we conducted a prospective mixed-methods study at three maternity care settings: the maternity wards of two hospitals in the Netherlands and one hospital in Israel. Parents were invited to participate if their infant was term-born, at least 12 hours old, but still in the first week of life. Parents used Picterus JP once according to the manufacturer’s instructions. Immediately afterwards, usability was evaluated using the validated mHealth App Usability Questionnaire (MAUQ) and open-ended questions. A subset of parents and nurses participated in semi-structured interviews and focus groups. : In total, 123 participants completed the questionnaire. The median [IQR] MAUQ-score was 6 [5-7] out of 7. Ninety-seven (88%) parents indicated they would use Picterus JP at home. Parents reported they found the app easy, quick and convenient, although sixty-seven (56%) reported a failure on the first try. Some parents struggled to find or interpret the instructions, but most (75%) who tried again obtained a bilirubin estimate. The thematic analysis identified three themes that were considered important for the usability of Picterus JP: intention to use Picterus JP, infant wellbeing and instruction and guidance. Parents rated Picterus JP highly in terms of usability, despite encountering difficulties during initial use. Technical improvements and more proactive guidance seem important to support successful parental use. Nonetheless, both parents and nurses are positive about the Picterus JP potential for home screening of severe neonatal jaundice. N/A This study was registered in PaNaMa (ID 10763), the internal research registry of the University Medical Center Groningen (UMCG). Formal trial registration in a WHO-recognized trial registry was not required because the study did not fall under the Dutch Medical Research Involving Human Subjects Act (WMO).

Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range. Sixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Background: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. Methods: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. Results: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. Conclusions: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36–41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

AimsLittle is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment.MethodsNeonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed‐effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range.ResultsSixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1‐compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment.ConclusionResults of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model‐informed precision dosing.

Importance:Quantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification.Objective:To systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification.Data Sources:A systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022.Study Selection:Studies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.Data Extraction and Synthesis:Data extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome.Main Outcomes and Measures:The main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications.Results:Ten studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of -14 μmol/L, with pooled 95% CBs of -106 to 78 μmol/L. For the Bilistick, the pooled mean difference was -17 μmol/L (95% CBs, -114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB.Conclusions and Relevance:Despite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T->MIC) (for efficacy purposes and 100% T->4xMIC and 100% T->5xMIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T->MIC during hypothermia (33.7 degrees C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T->MIC during normothermia (36.7 degrees C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T->4xMIC and 100% T->5xMIC are desired.

Objective Observational studies in preterm infants suggest that systemic hydrocortisone improves pulmonary condition but may also lead to systemic adverse effects. We report the short-term pulmonary and systemic effects of hydrocortisone initiated in the second week. Design Randomised placebo-controlled trial. Setting Dutch and Belgian neonatal intensive care units. Patients Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. Intervention Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). Main outcome measures Data on extubation, ventilator settings, glucose levels, and blood pressure were recorded daily and analysed during the first 7 days of treatment using linear mixed-effects models. Results Infants in the hydrocortisone group (24.3%) failed extubation less often compared with placebo (38.6%, crude risk difference: -14.3% (95% CI: -23.4% to -4.8%)). The estimated difference in daily rate of change between hydrocortisone and placebo was -0.42 cmH(2)O (95% CI: -0.48 to -0.36) for mean airway pressure, -0.02 (95% CI: -0.02 to -0.01) for fraction of inspired oxygen, -0.37 (95% CI: -0.44 to -0.30) for respiratory index, 0.14 mmol/L (95% CI: 0.08 to 0.21) for blood glucose levels and 0.83 mm Hg (95% CI: 0.58 to 1.09) for mean blood pressure. Conclusions Systemic hydrocortisone initiated between 7 and 14 days after birth in ventilated preterm infants improves pulmonary condition, thereby facilitating weaning and extubation from invasive ventilation. The effects of hydrocortisone on blood glucose levels and blood pressure were mild and of limited clinical relevance.

Importance Quantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification. Objective To systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification. Data Sources A systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022. Study Selection Studies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome. Main Outcomes and Measures The main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications. Results Ten studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of −14 μmol/L, with pooled 95% CBs of −106 to 78 μmol/L. For the Bilistick, the pooled mean difference was −17 μmol/L (95% CBs, −114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB. Conclusions and Relevance Despite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

Abstract Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

BACKGROUND AND OBJECTIVES:To provide support to parents of critically ill children, it is important that physicians adequately respond to parents' emotions. In this study, we investigated emotions expressed by parents, physicians' responses to these expressions, and parents' emotions after the physicians' responses in conversations in which crucial decisions regarding the child's life-sustaining treatment had to be made.METHODS:Forty-nine audio-recorded conversations between parents of 12 critically ill children and physicians working in the neonatal and pediatric intensive care units of 3 Dutch university medical centers were coded and analyzed by using a qualitative inductive approach.RESULTS:Forty-six physicians and 22 parents of 12 children participated. In all 49 conversations, parents expressed a broad range of emotions, often intertwining, including anxiety, anger, devotion, grief, relief, hope, and guilt. Both implicit and explicit expressions of anxiety were prevalent. Physicians predominantly responded to parental emotions with cognition-oriented approaches, thereby limiting opportunities for parents. This appeared to intensify parents' expressions of anger and protectiveness, although their anxiety remained under the surface. In response to more tangible emotional expressions, for instance, grief when the child's death was imminent, physicians provided parents helpful support in both affect- and cognition-oriented ways.CONCLUSIONS:Our findings illustrate the diversity of emotions expressed by parents during end-of-life conversations. Moreover, they offer insight into the more and less helpful ways in which physicians may respond to these emotions. More training is needed to help physicians in recognizing parents' emotions, particularly implicit expressions of anxiety, and to choose helpful combinations of responses.