Effect of Systemic Hydrocortisone on Brain Abnormalities and Regional Brain Volumes in Ventilator-dependent Infants Born Preterm: Substudy of the SToP-BPD Study.

OBJECTIVE: To evaluate whether a high cumulative dose of systemic hydrocortisone affects brain development compared with placebo when initiated between 7 and 14 days after birth in ventilated infants born preterm. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted in 16 neonatal intensive care units among infants born at <30 weeks of gestation or with a birth weight of <1250 g who were ventilator-dependent in the second week after birth. Three centers performed MRI at term-equivalent age. Brain injury was assessed on MRI using the Kidokoro scoring system and compared between the 2 treatment groups. Both total and regional brain volumes were calculated using an automatic segmentation method and compared using multivariable regression analysis adjusted for baseline variables. RESULTS: From the 3 centers, 78 infants participated in the study and 59 had acceptable MRI scans (hydrocortisone group, n = 31; placebo group, n = 28). Analyses of the median global brain abnormality score of the Kidokoro score showed no difference between the hydrocortisone and placebo groups (median, 7; IQR, 5-9 vs median, 8, IQR, 4-10, respectively; P = .92). In 39 infants, brain tissue volumes were measured, showing no differences in the adjusted mean total brain tissue volumes, at 352 ± 32 mL in the hydrocortisone group and 364 ± 51 mL in the placebo group (P = .80). CONCLUSIONS: Systemic hydrocortisone started in the second week after birth in ventilator-dependent infants born very preterm was not found to be associated with significant differences in brain development compared with placebo treatment. TRIAL REGISTRATION: The SToP-BPD study was registered with the Netherlands Trial Register (NTR2768; registered on 17 February 2011; https://www.trialregister.nl/trial/2640) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010; https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023777-19/NL).

Patient-reported outcomes for congenital diaphragmatic hernia: A qualitative study.

OBJECTIVE: To identify Patient-reported outcomes (PROs) for parents with a lived experience of a prenatal diagnosis of isolated congenital diaphragmatic hernia (CDH). METHOD: Thematic analysis of in-depth interview transcripts. RESULTS: Interviews (n = 26) identified 11 PROs for given time points throughout the CDH trajectory. At the time of diagnosis, acceptable quality of life was selected as relevant PRO to decide whether to continue or terminate the pregnancy. During pregnancy, (neonatal) survival chances and the eligibility for foetal therapy were prominent outcomes with foetal and maternal complications adding distress. After birth, postnatal management options became the next milestone. When survival was deemed likely, post-hospital discharge complications and future care for infant and child became important. In retrospect, impact on family, bonding, parental mental health, and parental satisfaction with care were reported as relevant outcomes. CONCLUSION: PROs are relevant in addition to hard medical outcomes, as they help parents to make decisions suiting their unique needs and personal situation. Given the knowledge inherently related to the parent's perspective, our findings provide relevant directions for clinicians to support parents and their family in facing challenging decisions in healthcare. The outcomes impacting parents are essential to prepare parents for the steep journey ahead.

Ventilation and respiratory outcome in extremely preterm infants: trends in the new millennium.

Ventilation and respiratory care have substantially changed over the last decades in extremely premature neonates but the impact on respiratory health remains largely unclear. To determine changes in respiratory care and disease frequency in extremely premature infants, a retrospective single-centre cohort study of extremely preterm infants was performed. All infants born alive between 24 + 0 and 27 + 6 weeks of gestation in 2000-2001 (Epoch 1), 2009-2010 (Epoch 2), and 2018-2019 (Epoch 3) were included. The primary outcome of this study was the incidence of bronchopulmonary dysplasia (BPD, diagnosed according to three different criteria) or death. Secondary outcomes included the usage of different ventilation modes, changes in pharmacotherapy, and the incidence of significant extra-pulmonary morbidities. A total of 184 neonates were included of whom 151 survived until 36 weeks of corrected GA (cGA). Oxygen or positive pressure dependence increased over time (26.1%, 41.7%, and 56.1% respectively), with higher adjusted odds in Epoch 3 for the composite outcome "BPD or death" (adjusted odds ratio: 2.55 [95%CI 1.19-5.61]). Severity-based definitions showed increasing trends in survivors only. Time spent on invasive mechanical ventilation was similar throughout the years, but the use of non-invasive ventilation significantly increased in Epoch 3 (32.0 [95%CI 25.0-37.0] vs 27.0 [95%CI 26.0-32.0] vs 53.0 [95%CI 46.0-58.0] days). Moreover, mortality-adjusted rates of severe IVH, NEC, or intestinal perforation and multiple sepsis tended to decrease.   Conclusion: In spite of significant clinical advancements and adherence to novel treatment guidelines in our neonatal intensive care unit, the incidence of BPD increased over time. What is Known: • Rates of BPD are stable or increase in population-based studies. • Extremely preterm infants are particularly susceptible to developing BPD. What is New: • Despite increased use of evidence-based corticosteroid administration and early initiation of caffeine, the incidence of BPD has not decreased over the past decade.  • Increased usage of non-invasive ventilation is associated with an increase of BPD incidence.

What should we tell parents? Congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is characterized by a defect in the muscle dividing the thoracic and abdominal cavities. This leads to herniation of the abdominal organs into the thorax and a disturbance of lung development. Two-thirds of cases are identified by prenatal ultrasound in the second trimester, which should prompt referral to a tertiary center for prognosis assessment and counseling by a multidisciplinary team familiar with this condition. In this review, we summarize evidence on prenatal diagnosis and postnatal management of CDH. There is a focus on information that should be provided to expecting parents during prenatal counseling.

Prenatal diagnosis of congenital diaphragmatic hernia: Parental counselling and support needs.

OBJECTIVE: To define the dimensions of patient-centeredness of prenatal care for parents who had a fetus with isolated congenital diaphragmatic hernia (CDH) by exploring their values, experiences, needs and preferences. METHODS: In-depth interviews with parents who were faced with the prenatal diagnosis of isolated CDH. RESULTS: Interviews (n = 18) identified seven dimensions of patient-centeredness. Parental preferences are respected by unconditional acceptance of parental choices and needs. After diagnosis access to care should occur by swift referral to a specialised centre to prevent parents receiving contradictory information. Information and education help parents to gain some sense of control and cope with the many uncertainties. A multidisciplinary team with a coordinating professional is perceived supportive (coordination and integration), and seamless referral between local and treatment centres reduces parental distress (continuity and transition). Family-centred emotional support helps parents to cope with emotions and distress. Informal support by involvement of family and friends and trusted peer-support is of added value. CONCLUSION: The impact of the uncertainty of outcome in this condition is tremendous and needs to be considered when providing prenatal care. After initial diagnosis, one should avoid speculation about the severity of the condition and outcome, and provide swift referral to a specialist centre expert in managing CDH. Provision of realistic and comprehensive information helps parents cope. Multidisciplinary and continuous support throughout the full trajectory, but also integrated psychosocial support should become standard-of-care.

Pulmonary hypertension in congenital diaphragmatic hernia: Antenatal prediction and impact on neonatal mortality.

OBJECTIVE: To determine the prevalence of pulmonary hypertension (PAH) in left-sided congenital diaphragmatic hernia (CDH); how we could predict it; and how PAH contributed to the model for mortality prediction. STUDY DESIGN: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day (d) 1, 7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio (o/e LHR), liver-herniation, fetoscopic endoluminal tracheal occlusion (FETO), and gestational age (GA) at delivery. The combined effect of pre- and postnatal variables on mortality was modeled by Cox regression. RESULTS: Of the 197 neonates, 56 (28.4%) died. At d1, 67.5% (133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge. At d1, o/e LHR (odds ratio (OR) 0.96) and FETO (OR 2.99) independently correlated to PAH (areas under the curve [AUC]: 0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9; AUC: 0.65). None were significant for PAH at discharge. Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction (p = 0.02), in a model including o/e LHR (HR: 0.94), FETO (HR: 0.35), liver herniation (HR: 16.78), and PAH (HR: 15.95). CONCLUSIONS: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH.

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

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

Characterization of Esophageal Motility in Infants With Congenital Diaphragmatic Hernia Using High-resolution Manometry.

OBJECTIVES: The aim of the study was to characterize esophageal motility and esophagogastric junction (EGJ) function in infants who underwent repair of an isolated congenital diaphragmatic hernia (iCDH). METHODS: High-resolution manometry with impedance was used to investigate esophageal motility and EGJ function after diaphragmatic repair in 12 infants with iCDH (11 left-sided; 9 patch repair). They had esophageal motility studies during neonatal admission (n = 12), at 6 months (n = 10) and at 12 months of life (n = 7). Swallows were analyzed using conventional esophageal pressure topography and pressure flow analysis and were compared with 11 healthy preterm born infants at near-term age. RESULTS: Esophageal peristaltic motor patterns in patients with iCDH were comparable to controls. EGJ end-expiratory pressure was higher in patients with patch repair compared with controls (P = 0.050) and those without patch (P = 0.009). The difference between inspiratory and expiratory pressures at the EGJ was lower in patients with iCDH with patch (P = 0.045) compared to patients without. Patients with iCDH with patch showed increased Pressure Flow Index, resistance of bolus flow at the EGJ, compared with controls (P = 0.043). CONCLUSIONS: Normal esophageal wave patterns are present in the investigated patients with iCDH. EGJ end-expiratory pressure seems lower in patients with iCDH without patch suggesting a decreased EGJ barrier function hence increased vulnerability to gastroesophageal reflux. Patch repair appears to increase end-expiratory pressure at the EGJ above that of controls suggesting that patch surgery tightens the EGJ, thereby increasing flow resistance. This is in line with the increased Pressure Flow Index. In infants with a patch, the inspiration-expiration pressure difference is lower, reflecting diminished activity of the crural diaphragm.

Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration: Netherlands National Trial Register Identifier: NTR2768.

Pericardio-Amniotic Shunting for Incomplete Pentalogy of Cantrell.

A 27-year-old woman, gravida 2, para 0, presented with an incomplete Pentalogy of Cantrell with an omphalocele, diaphragmatic hernia, and a pericardial defect at 32 weeks' gestation. A large pericardial effusion compressed the lungs and had led to a reduced lung growth with an observed-to-expected total lung volume of 28% as measured by MRI. The effusion disappeared completely after the insertion of a pericardio-amniotic shunt at 33 weeks. After birth, the newborn showed no signs of pulmonary hypoplasia and underwent a surgical correction of the defect. Protracted wound healing and a difficult withdrawal from opioids complicated the neonatal period. The child was discharged on postnatal day 105 in good condition. This case demonstrates that in case of Pentalogy of Cantrell with large pericardial effusion, the perinatal outcome might be improved by pericardio-amniotic shunting.

Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracleal occlusion era: a single-center study.

OBJECTIVE: To correlate prenatal indicators of pulmonary hypoplasia with neonatal lung function and pulmonary hypertension (PHT) in isolated congenital diaphragmatic hernia (iCDH). MATERIALS AND METHODS: Prospective single-center study on 40 fetuses with iCDH either expectantly managed (n = 13) or undergoing tracheal occlusion (n = 27). Prenatal predictors included observed/expected lung-head ratio (O/E LHR), observed/expected total fetal lung volume, fetal pulmonary reactivity to maternal O2 administration (Δpulsatility index, ΔPI) and liver-to-thorax ratio (LiTR) as measured in the second and third trimesters. Postnatal outcome measures included survival until discharge, best oxygenation index (OI) and alveolar-arterial oxygen gradient [D(A-a)O2] in the first 24 h of life and the occurrence of PHT in the first 28 days of life. RESULTS: Median gestational age (GA) at evaluations was 27.2 and 34.3 weeks. GA at delivery was 36.0 weeks, and overall survival was 55%. In the second trimester, measurement of lung size, LiTR and pulmonary reactivity were significantly related to survival and the best OI and D(A-a)O2.The occurrence of PHT was better predicted by ΔPI and LiTR. CONCLUSIONS: O/E LHR, LiTR and vascular reactivity correlate with ventilatory parameters in the first 24 h of life. Occurrence of PHT at ≥28 days was best predicted by LiTR and ΔPI, but not by lung size.

Tracheomalacia and tracheomegaly in infants and children with congenital diaphragmatic hernia managed with and without fetoscopic endoluminal tracheal occlusion (FETO): a multicentre, retrospective cohort study.

BACKGROUND: Temporary fetoscopic endoluminal tracheal occlusion (FETO) promotes lung growth and increases survival in selected fetuses with congenital diaphragmatic hernia (CDH). FETO is performed percutaneously by inserting into the trachea a balloon designed for vascular occlusion. However, reports on the potential postnatal side-effects of the balloon are scarce. This study aimed to evaluate the prevalence of tracheomalacia in infants with CDH managed with and without FETO and other consequences related to the use of the balloon. METHODS: In this multicentre, retrospective cohort study, we included infants who were live born with CDH, either with FETO or without, who were managed postnatally at four centres (UZ Leuven, Leuven, Belgium; Antoine Béclère, Clamart, France; BCNatal, Barcelona, Spain; and HCor-Heart Hospital, São Paulo, Brazil) between April 5, 2002, and June 2, 2021. We primarily assessed the prevalence of all (symptomatic and asymptomatic) tracheomalacia as reported in medical records among infants with and without FETO. Secondarily we assessed the prevalence of symptomatic tracheomalacia and its resolution as reported in medical records, and compared tracheal diameters as measured on postnatal x-rays. Crude and adjusted risk ratios (aRRs) and 95% CIs were calculated via modified Poisson regression models with robust error variances for potential association between FETO and tracheomalacia. Variables included in the adjusted model were the side of the hernia, observed-to-expected lung-to-head ratio, and gestational age at birth. Crude and adjusted mean differences and 95% CIs were calculated via linear regression models to assess the presence and magnitude of association between FETO and tracheal diameters. In infants who had undergone FETO we also assessed the localisation of balloon remnants on x-rays, and the methods used for reversal of occlusion and potential complications associated with balloon remnants as documented in clinical records. Finally we investigated whether the presence of balloon remnants was influenced by the interval between balloon removal and delivery. FINDINGS: 505 neonates were included in the study, of whom 287 had undergone FETO and 218 had not. Tracheomalacia was reported in 18 (6%) infants who had undergone FETO and in three (1%) who had not (aRR 6·17 [95% CI 1·83-20·75]; p=0·0030). Tracheomalacia was first reported in the FETO group at a median of 5·0 months (IQR 0·8-13·0). Symptomatic tracheomalacia was reported in 13 (5%) infants who had undergone FETO, which resolved in ten (77%) children by 55·0 months (IQR 14·0-83·0). On average, infants who had undergone FETO had a 31·3% wider trachea (with FETO tracheal diameter 7·43 mm [SD 1·24], without FETO tracheal diameter 5·10 mm [SD 0·84]; crude mean difference 2·32 [95% CI 2·11-2·54]; p<0·0001; adjusted mean difference 2·62 [95% CI 2·35-2·89]; p<0·0001). At birth, the metallic component was visible within the body in 75 (37%) of 205 infants with available thoraco-abdominal x-rays: it was located in the gastrointestinal tract in 60 (80%) and in the lung in 15 (20%). No side-effects were reported for any of the infants during follow-up. The metallic component was more likely to be in the lung than either outside the body or the gastrointestinal tract when the interval between occlusion reversal and birth was less than 24 h. INTERPRETATION: Although FETO was associated with an increased tracheal diameter and an increased probability of tracheomalacia, symptomatic tracheomalacia typically resolved over time. There is a higher risk of retention of metallic balloon components if reversal of the occlusion occurs less than 24 h before delivery. Finally, there were no reported side-effects of the metallic component of the balloon persisting in the body during follow-up. Longer-term follow-up is needed to ensure that no tracheal problems arise later in life. FUNDING: None.

Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan.

BACKGROUND: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial). DESIGN: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved. TRIAL REGISTRATION: ClinicalTrials.gov NCT04373902 (registered April 2020).

Red Blood Cell Transfusion in European Neonatal Intensive Care Units, 2022 to 2023.

Importance: Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown. Objective: To describe neonatal RBC transfusion practice in Europe. Design, Setting, and Participants: This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation. Exposure: Admission to the NICU. Main Outcomes and Measures: Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion. Results: A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration. Conclusions and Relevance: In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Short-term pulmonary and systemic effects of hydrocortisone initiated 7-14 days after birth in ventilated very preterm infants: a secondary analysis of a randomised controlled trial.

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 cmH2O (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. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR2768; https://www.trialregister.nl/trial/2640) and European Union Clinical Trials Register (EudraCT, 2010-023777-19).

Effect of systemic hydrocortisone in ventilated preterm infants on parent-reported behavioural outcomes at 2 years' corrected age: follow-up of a randomised clinical trial.

OBJECTIVE: To report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). 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: Parent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 1½-5). RESULTS: Parents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). CONCLUSION: This study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. TRIAL REGISTRATION NUMBER: NTR2768; EudraCT 2010-023777-19.

Impact of COVID-19 on viral respiratory infection epidemiology in young children: A single-center analysis.

Background: The COVID-19 pandemic impacts different health aspects. Concomitant with the adoption of non-pharmaceutical interventions (NPIs) to reduce the spread of SARS-CoV-2, global surveillance studies reported a reduction in occurrence of respiratory pathogens like influenza A and B virus (IAV & IBV) and respiratory syncytial virus (RSV). We hypothesized to observe this collateral benefit on viral respiratory infection epidemiology in young children. Methods: Respiratory samples of children aged below 6 years, presenting at the outpatient clinic, emergency department, or pediatric infectious diseases department of the University Hospitals Leuven, between April 2017 and April 2021 were retrospectively analyzed. The occurrence (positivity rate), and seasonal patterns of viral respiratory infections were described. Chi-squared or Fisher's exact test (and Bonferroni correction) were used to explore differences in occurrence between 2020-2021 and previous 12-month (April to April) periods. Results: We included 3020 samples (453 respiratory panels, 2567 single SARS-CoV-2 PCR tests). IAV and IBV were not detected from March and January 2020, respectively. For IAV, positivity rate in 2020-2021 (0%, n = 0) was significantly different from 2018-2019 (12.4%, n = 17) (p < 0.001) and 2019-2020 (15.4%, n = 19) (p < 0.001). IBV positivity rate in 2020-2021 (0%, n = 0) was not significantly different from previous periods. RSV occurrence was significantly lower in 2020-2021 (3.2%, n = 3), compared to 2017-2018 (15.0%, n = 15) (p = 0.006), 2018-2019 (16.1%, n = 22) (p = 0.002) and 2019-2020 (22.8%, n = 28) (p < 0.001). The RSV (winter) peak was absent and presented later (March-April 2021). Positivity rate of parainfluenza virus 3 (PIV-3) was significantly higher in 2020-2021 (11.8%, n = 11) than 2017-2018 (1%, n = 1) (p = 0.002). PIV-3 was absent from April 2020 to January 2021, whereas no clear seasonal pattern was distinguished the other years. For the other viruses tested, no significant differences in occurrence were observed between 2020-2021 and previous periods. From March 2020 onwards, 20 cases (0.7%) of SARS-CoV-2 were identified. Conclusion: These findings reinforce the hypothesis of NPIs impacting the epidemiology of influenza viruses and RSV in young children. Compared to previous periods, no IAV and IBV cases were observed in the 2020-2021 study period, and the RSV peak occurred later. Since the pandemic is still ongoing, continuation of epidemiological surveillance, even on a larger scale, is indicated.

Congenital cystic adenomatoid malformations of the lung: a retrospective study of diagnosis, treatment strategy and postoperative morbidity in surgically treated patients.

OBJECTIVES: The purpose of this study was to evaluate the diagnosis of, clinical signs of and strategy for congenital cystic adenomatoid malformations (CCAM). METHODS: In this retrospective study, patients who had thoracic surgery for CCAM lesions at the University Hospitals of Leuven from July 1993 to July 2016 were identified. Data on diagnosis, prenatal ultrasound findings, clinical signs, lesion site, CCAM type, associated anomalies, imaging, surgical approach and postoperative morbidity were reviewed. The Fisher exact and Mann-Whitney tests were used as appropriate. RESULTS: A total of 55 patients were identified with CCAM. In 65% (n = 36/55), CCAM was detected on prenatal ultrasound scans. Prenatal symptoms due to hydrops or mass effect were present in 22% (n = 8/36), 6 of whom eventually needed prenatal intervention (thoracoamniotic shunting or intrauterine puncture). Elective surgery was performed in 40% of patients (n = 22/55); others developed clinical signs that indicated the need for semi-urgent surgery, with clinical signs of pulmonary infection and respiratory distress being the most common. Most patients had a single lobectomy via a minithoracotomy. Postoperative complications and length of stay were significantly higher in patients with CCAM with preoperative clinical signs. CONCLUSIONS: Surgery in asymptomatic patients with CCAM can be performed safely with few postoperative complications and can be planned at a young age in patients with a high risk of developing clinical signs later in life.

Physiological-based cord clamping versus immediate cord clamping for infants born with a congenital diaphragmatic hernia (PinC): study protocol for a multicentre, randomised controlled trial.

INTRODUCTION: Pulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period in these infants might contribute to the development of pulmonary hypertension after birth-in particular umbilical cord clamping before lung aeration. An ovine model of diaphragmatic hernia demonstrated that cord clamping after lung aeration, called physiological-based cord clamping (PBCC), avoided the initial high pressures in the lung vasculature while maintaining adequate blood flow, thereby avoiding vascular remodelling and aggravation of pulmonary hypertension. We aim to investigate if the implementation of PBCC in the perinatal stabilisation period of infants born with a CDH could reduce the incidence of pulmonary hypertension in the first 24 hours after birth. METHODS AND ANALYSIS: We will perform a multicentre, randomised controlled trial in infants with an isolated left-sided CDH, born at ≥35.0 weeks. Before birth, infants will be randomised to either PBCC or immediate cord clamping, stratified by treatment centre and severity of pulmonary hypoplasia on antenatal ultrasound. PBCC will be performed using a purpose-built resuscitation trolley. Cord clamping will be performed when the infant is considered respiratory stable, defined as a heart rate >100 bpm, preductal oxygen saturation >85%, while using a fraction of inspired oxygen of <0.5. The primary outcome is pulmonary hypertension diagnosed in the first 24 hours after birth, based on clinical and echocardiographic parameters. Secondary outcomes include neonatal as well as maternal outcomes. ETHICS AND DISSEMINATION: Central ethical approval was obtained from the Medical Ethical Committee of the Erasmus MC, Rotterdam, The Netherlands (METC 2019-0414). Local ethical approval will be obtained by submitting the protocol to the regulatory bodies and local institutional review boards. TRIAL REGISTRATION NUMBER: NCT04373902.