Neonatal Risk Factors for Pulmonary Vein Stenosis in Infants Born Preterm with Severe Bronchopulmonary Dysplasia.

OBJECTIVE: To evaluate associations between neonatal risk factors and pulmonary vein stenosis (PVS) among infants born preterm with severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: We performed a case-control study of infants born from 2010 to 2022 at <32 weeks' gestation with sBPD among 46 neonatal intensive care units in the Children's Hospitals Neonatal Consortium. Cases with PVS were matched to controls using epoch of diagnosis (2010-2016; 2017-2022) and hospital. Multivariable logistic regression analyses were utilized to evaluate PVS association with neonatal risk factors. RESULTS: From 10 171 preterm infants with sBPD, we identified 109 cases with PVS and matched those to 327 controls. The prevalence of PVS (1.07%) rose between epochs (0.8% in 2010-2016 to 1.2% in 2017-2022). Relative to controls, infants with PVS were more likely to be <500 g at birth, to be small for gestational age <10th%ile, or have surgical necrotizing enterocolitis, atrial septal defects, or pulmonary hypertension. In multivariable models, these associations persisted, and small for gestational age, surgical necrotizing enterocolitis, atrial septal defects, and pulmonary hypertension were each independently associated with PVS. Among infants on respiratory support at 36 weeks' postmenstrual age, infants with PVS had 4.3-fold higher odds of receiving mechanical ventilation at 36 weeks' postmenstrual age. Infants with PVS also had 3.6-fold higher odds of in-hospital mortality relative to controls. CONCLUSIONS: In a large cohort of preterm infants with sBPD, multiple independent, neonatal risk factors are associated with PVS. These results lay important groundwork for the development of targeted screening to guide the diagnosis and management of PVS in preterm infants with sBPD.

Surgical interventions and short-term outcomes for preterm infants with post-haemorrhagic hydrocephalus: a multicentre cohort study.

OBJECTIVE: To (1) describe differences in types and timing of interventions, (2) report short-term outcomes and (3) describe differences among centres from a large national cohort of preterm infants with post-haemorrhagic hydrocephalus (PHH). DESIGN: Cohort study of the Children's Hospitals Neonatal Database from 2010 to 2022. SETTING: 41 referral neonatal intensive care units (NICUs) in North America. PATIENTS: Infants born before 32 weeks' gestation with PHH defined as acquired hydrocephalus with intraventricular haemorrhage. INTERVENTIONS: (1) No intervention, (2) temporising device (TD) only, (3) initial permanent shunt (PS) and (4) TD followed by PS (TD-PS). MAIN OUTCOME MEASURES: Mortality and meningitis. RESULTS: Of 3883 infants with PHH from 41 centres, 36% had no surgical intervention, 16% had a TD only, 19% had a PS only and 30% had a TD-PS. Of the 46% of infants with TDs, 76% were reservoirs; 66% of infants with TDs required PS placement. The percent of infants with PHH receiving ventricular access device placement differed by centre, ranging from 4% to 79% (p<0.001). Median chronological and postmenstrual age at time of TD placement were similar between infants with only TD and those with TD-PS. Infants with TD-PS were older and larger than those with only PS at time of PS placement. Death before NICU discharge occurred in 12% of infants, usually due to redirection of care. Meningitis occurred in 11% of the cohort. CONCLUSIONS: There was significant intercentre variation in rate of intervention, which may reflect variability in care or referral patterns. Rate of PS placement in infants with TDs was 66%.

Spectrum of Disease in Hospitalized Newborns with Congenital Micrognathia: A Cohort of 3,236 Infants at North American Tertiary-Care Intensive Care Units.

OBJECTIVE: To describe the spectrum of disease and burden of care in infants with congenital micrognathia from a multicenter cohort hospitalized at tertiary care centers. STUDY DESIGN: The Children's Hospitals Neonatal Database was queried from 2010 through 2020 for infants diagnosed with micrognathia. Demographics, presence of genetic syndromes, and cleft status were summarized. Outcomes included death, length of hospitalization, neonatal surgery, and feeding and respiratory support at discharge. RESULTS: Analysis included 3,236 infants with congenital micrognathia. Cleft palate was identified in 1266 (39.1%). A genetic syndrome associated with micrognathia was diagnosed during the neonatal hospitalization in 256 (7.9%). Median (IQR) length of hospitalization was 35 (16, 63) days. Death during the hospitalization (n = 228, 6.8%) was associated with absence of cleft palate (4.4%, P < .001) and maternal Black race (11.6%, P < .001). During the neonatal hospitalization, 1289 (39.7%) underwent surgery to correct airway obstruction and 1059 (32.7%) underwent gastrostomy tube placement. At the time of discharge, 1035 (40.3%) were exclusively feeding orally. There was significant variability between centers related to length of stay and presence of a feeding tube at discharge (P < .001 for both). CONCLUSIONS: Infants hospitalized with congenital micrognathia have a significant burden of disease, commonly receive surgical intervention, and most often require tube feedings at hospital discharge. We identified disparities based on race and among centers. Development of evidence-based guidelines could improve neonatal care.

Surgical outcome and treatment trends in 1289 infants with micrognathia: a multicenter cohort.

BACKGROUND: Studies of infants with micrognathia, especially Robin Sequence (RS), are limited by its rarity and both phenotypic and diagnostic variability. Most knowledge of this condition is sourced from small, single-institution samples. METHODS: This is a cross-sectional study including infants with micrognathia admitted to 38 Children's Hospital Neonatal Consortium centers from 2010-2020. Predictor variables included demographic data, birth characteristics, cleft and syndrome status. Outcome variables included length of stay (LOS), death, feeding or respiratory support, and secondary airway operations. RESULTS: 1289 infants with micrognathia had a surgery to correct upper airway obstruction. Mean age and weight at operation were 34.8±1.8 weeks and 3515.4±42 grams, respectively. A syndromic diagnosis was made in 150 (11.6%) patients, with Stickler (5.4%) and Treacher Collins Syndromes (2.2%) most common. Operations included: mandibular distraction osteogenesis (MDO), 66.3%; tracheostomy, 25.4%; and tongue-lip adhesion (TLA), 8.3%. Tracheostomy patients had a lower birth weight, head circumference, gestational age, and APGAR scores. MDO patients were less likely to need a second airway operation compared to TLA patients (3.5%vs17.8%,p<0.001). The proportion of infants feeding exclusively orally at hospital discharge differed significantly, from most to least: MDO, TLA, tracheostomy. Hospital LOS was not statistically different for patients that had MDO and TLA, but was longer for those with primary tracheostomy. Mortality was low for all operations (0.5%). CONCLUSION: In this 1289 surgical patient cohort, MDO was associated with shorter hospital stay, improved oral feeding, and lower rates of secondary airway operations. Prospective multi-center studies are necessary to support these conclusions.

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data.

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Variability in antibiotic duration for necrotizing enterocolitis and outcomes in a large multicenter cohort.

OBJECTIVES: To evaluate variability in antibiotic duration for necrotizing enterocolitis (NEC) and associated clinical outcomes. STUDY DESIGN: Five-hundred ninety-one infants with NEC (315 medical; 276 surgical) were included from 22 centers participating in Children's Hospitals Neonatal Consortium (CHNC). Multivariable analyses were used to determine predictors of variability in time to full feeds (TFF) and length of stay (LOS). RESULTS: Median (IQR) antibiotic duration was 12 (9, 17) days for medical and 17 (14, 21) days for surgical NEC. Wide variability in antibiotic use existed both within and among centers. Duration of antibiotic therapy was associated with longer TFF in both medical (OR 1.04, 95% CI [1.01, 1.05], p < 0.001) and surgical NEC (OR 1.02 [1, 1.03] p = 0.046); and with longer LOS in medical (OR 1.03 [1.02, 1.04], p < 0.001) and surgical NEC (OR 1.01 [1.01, 1.02], p = 0.002). CONCLUSION: Antibiotic duration for both medical and surgical NEC remains variable within and among high level NICUs.

A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.

OBJECTIVE: To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. STUDY DESIGN: Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. RESULTS: Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. CONCLUSIONS: Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.

Improving Compliance with a Rounding Checklist through Low- and High-technology Interventions: A Quality Improvement Initiative.

INTRODUCTION: Checklists aid in ensuring consistency and completeness in medical care delivery. However, using an improvement and safety checklist during rounds was variable in our neonatology intensive care unit (NICU), and completion was not tracked sustainably. This quality improvement (QI) initiative's primary aim was to increase compliance with checklist completion from 31% to >75% within 1 year. METHODS: A multidisciplinary QI team identified barriers to checklist completion and implemented a human factors-focused low-technology intervention (redesign of a hard-copy checklist) and later a high-technology clinical decision support tool within the electronic health record. The primary outcome measure was percent compliance with the use of the checklist. Process metrics included the duration of checklist completion. Balancing measures included staff perceptions of work burden and question relevance. RESULTS: Major barriers to checklist utilization were inability to remember, rounding interruptions, and perceived lack of question relevance to patients. Average biweekly checklist compliance improved from 31% before interventions to 80% after interventions. Average checklist completion time decreased from 46 to 11 seconds. Follow-up surveys demonstrated more respondents found questions "completely relevant" (34% pre versus 43% post) but perceived increased work burden (26% pre versus 31% post). CONCLUSIONS: Using QI methodology, human factors-based interventions, and a novel clinical decision support tool, we significantly improved efficiency and checklist compliance and created an automated, sustainable method for monitoring completion and responses. This foundational project provides an infrastructure broadly applicable to QI work in other healthcare settings.

Cerebral Pulsed Arterial Spin Labeling Perfusion Weighted Imaging Predicts Language and Motor Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy.

Rationale and Objectives: To compare cerebral pulsed arterial spin labeling (PASL) perfusion among controls, hypoxic ischemic encephalopathy (HIE) neonates with normal conventional MRI(HIE/MRI⊕), and HIE neonates with abnormal conventional MRI(HIE/MRI⊖). To create a predictive machine learning model of neurodevelopmental outcomes using cerebral PASL perfusion. Materials and Methods: A total of 73 full-term neonates were evaluated. The cerebral perfusion values were compared by permutation test to identify brain regions with significant perfusion changes among 18 controls, 40 HIE/MRI⊖ patients, and 15 HIE/MRI⊕ patients. A machine learning model was developed to predict neurodevelopmental outcomes using the averaged perfusion in those identified brain regions. Results: Significantly decreased PASL perfusion in HIE/MRI⊖ group, when compared with controls, were found in the anterior corona radiata, caudate, superior frontal gyrus, precentral gyrus. Both significantly increased and decreased cerebral perfusion changes were detected in HIE/MRI⊕ group, when compared with HIE/MRI⊖ group. There were no significant perfusion differences in the cerebellum, brainstem and deep structures of thalamus, putamen, and globus pallidus among the three groups. The machine learning model demonstrated significant correlation (p < 0.05) in predicting language(r = 0.48) and motor(r = 0.57) outcomes in HIE/MRI⊖ patients, and predicting language(r = 0.76), and motor(r = 0.53) outcomes in an additional group combining HIE/MRI⊖ and HIE/MRI⊕. Conclusion: Perfusion MRI can play an essential role in detecting HIE regardless of findings on conventional MRI and predicting language and motor outcomes in HIE survivors. The perfusion changes may also reveal important insights into the reperfusion response and intrinsic autoregulatory mechanisms. Our results suggest that perfusion imaging may be a useful adjunct to conventional MRI in the evaluation of HIE in clinical practice.

Use of Point-of-Care Gastric pH Testing to Assess the Efficacy of Acid Suppression Therapy in the Neonatal Intensive Care Unit.

OBJECTIVE: The use of acid suppression therapies in newborns lacks efficacy and is associated with adverse effects. Point-of-care (POC) assessment of gastric aspirate pH may provide an objective, noninvasive measure of gastric acidity in tube fed infants. We conducted the present study to characterize the POC gastric pH levels in gastric tube fed infants before and after initiation of enteral omeprazole or ranitidine. STUDY DESIGN: Retrospective cohort study of infants with gastric aspirate pH levels determined by POC pH strips. Gastric pH levels recorded during 7 days before and 14 days after medication initiation were compared using Wilcoxon's sign-rank tests. RESULTS: Among 307 evaluated infants, 284 (92%) had a median gastric pH level ≥4 in 7 days prior to ranitidine or omeprazole. In 14 days after medication initiation, the median gastric pH of infants with pretreatment median gastric pH < 4 increased to 4.5 and 5 (p < 0.01) in the ranitidine and omeprazole groups, respectively. There was no change in infants with pretreatment median gastric pH ≥4. CONCLUSION: Among infants receiving gastric tube feedings and enteral omeprazole or ranitidine, only those with a pretreatment gastric pH level <4 demonstrated a significant increase in gastric pH. Validation of our findings against esophageal pH multichannel intraluminal impedance testing is needed.

Utility of echocardiography in predicting mortality in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). STUDY DESIGN: Infants with sBPD in the Children's Hospitals Neonatal Database who had echocardiograms 34-44 weeks' postmenstrual age (PMA) were included. SP and RVSP were categorized normal, abnormal (flattened/bowed SP or RVSP > 40 mmHg) or missing. RESULTS: Of 1157 infants, 115 infants (10%) died. Abnormal SP or RVSP increased mortality (SP 19% vs. 8% normal/missing, RVSP 20% vs. 9% normal/missing, both p < 0.01) in unadjusted and multivariable models, adjusted for significant covariates (SP OR 1.9, 95% CI 1.2-3.0; RVSP OR 2.2, 95% CI 1.1-4.7). Abnormal parameters had high specificity (SP 82%; RVSP 94%), and negative predictive value (SP 94%, NPV 91%) for mortality. CONCLUSIONS: Abnormal SP or RVSP is independently associated with mortality in sBPD infants. Negative predictive values distinguish infants most likely to survive.

The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year.

OBJECTIVES: To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. STUDY DESIGN: This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Children's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. RESULTS: Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30-124 vs 41 IQR 17-74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4-7.0 vs 0.8 IQR 0.3-3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18-1.63, P < .001). CONCLUSIONS: Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

Tracheobronchomalacia Is Associated with Increased Morbidity in Bronchopulmonary Dysplasia.

RATIONALE: Tracheobronchomalacia is a common comorbidity in neonates with bronchopulmonary dysplasia. However, the effect of tracheobronchomalacia on the clinical course of bronchopulmonary dysplasia is not well-understood. OBJECTIVE: We sought to assess the impact of tracheobronchomalacia on outcomes in neonates with bronchopulmonary dysplasia in a large, multi-center cohort. METHODS: We preformed a cohort study of 974 neonates with bronchopulmonary dysplasia admitted to 27 neonatal intensive care units participating in the Children's Hospital Neonatal Database who had undergone bronchoscopy. In hospital morbidity for neonates with bronchopulmonary dysplasia and tracheobronchomalacia (N=353, 36.2%) was compared to those without tracheobronchomalacia (N=621, 63.8%) using mixed-effects multivariate regression. RESULTS: Neonates with tracheobronchomalacia and bronchopulmonary dysplasia had more comorbidities, such as gastroesophageal reflux (OR=1.65, 95%CI 1.23- 2.29, P=0.001) and pneumonia (OR=1.68, 95%CI 1.21-2.33, P=0.002) and more commonly required surgeries such as tracheostomy (OR=1.55, 95%CI 1.15-2.11, P=0.005) and gastrostomy (OR=1.38, 95%CI 1.03-1.85, P=0.03) compared with those without tracheobronchomalacia. Neonates with tracheobronchomalacia were hospitalitized (118 ± 93 vs 105 ± 83 days, P=0.02) and ventilated (83.1 ± 91.1 vs 67.2 ± 71.9 days, P=0.003) longer than those without tracheobronchomalacia. Upon discharge, neonates with tracheobronchomalacia and BPD were more likely to be mechanically ventilated (OR=1.37, 95CI 1.01-1.87 P=0.045) and possibly less likely to receive oral nutrition (OR=0.69, 95%CI 0.47-1.01, P=0.058). CONCLUSIONS: Tracheobronchomalacia is common in neonates with bronchopulmonary dysplasia who undergo bronchoscopy and is associated with longer and more complicated hospitalizations.

The Association between Positive Tracheal Aspirate Cultures and Adverse Pulmonary Outcomes in Preterm Infants with Severe Bronchopulmonary Dysplasia.

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use.

Global alignment of immunization safety assessment in pregnancy - The GAIA project.

Immunization in pregnancy provides a promising contribution to globally reducing neonatal and under-five childhood mortality and morbidity. Thorough assessment of benefits and risks for the primarily healthy pregnant women and their unborn babies is required. The GAIA project was formed in response to the call of the World Health Organization for a globally concerted approach to actively monitor the safety of vaccines and immunization in pregnancy programs. GAIA aims to improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMIC. In the first year of the project, a large and functional network of experts was created. The first outputs include a guidance document for clinical trials of immunization in pregnancy, a basic data collection guide, ten case definitions of key obstetric and neonatal health outcomes, an ontology of key terms and a map of pertinent disease codes. The GAIA Network is designed as an open and growing forum for professionals sharing the GAIA vision and aim. Based on the initial achievements, tools and services are developed to support investigators and strengthen immunization in pregnancy programs with specific focus on LMIC.