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.

An Infant with High-Output Heart Failure and Pulmonary Hypertension Resulting from a Giant Cutaneous Hemangioma.

We present the clinical course of an 8-month-old infant with a giant cutaneous hemangioma resulting in high-output heart failure and pulmonary hypertension. The lesion was successfully embolized and excised, with rapid resolution of heart failure and improvement in pulmonary hypertension.

The association between pulmonary vascular disease and respiratory improvement in infants with type I severe bronchopulmonary dysplasia.

OBJECTIVE: To describe the association between echocardiographic measures of pulmonary vascular disease and time to respiratory improvement among infants with Type I severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: We measured the pulmonary artery acceleration time indexed to the right ventricular ejection time (PAAT/RVET) and right ventricular free wall longitudinal strain (RVFWLS) at 34-41 weeks' postmenstrual age. Cox-proportional hazards models were used to estimate the relationship between the PAAT/RVET, RVFWLS, and the outcome: days from 36 weeks' postmenstrual age to room-air or discharge with oxygen (≤0.5 L/min). RESULT: For 102 infants, the mean PAAT/RVET and RVFWLS were 0.27 ± 0.06 and -22.63 ± 4.23%. An abnormal measurement was associated with an increased time to achieve the outcome (PAAT/RVET: 51v24, p < 0.0001; RVFWLS; 62v38, p = 0.0006). A normal PAAT/RVET was independently associated with a shorter time to outcome (aHR = 2.04, 1.11-3.76, p = 0.02). CONCLUSION: The PAAT/RVET may aid in anticipating timing of discharge in patients with type I severe BPD.

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.

Qualitative indications for tracheostomy and chronic mechanical ventilation in patients with severe bronchopulmonary dysplasia.

BACKGROUND: The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE: To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN: We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS: The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight <10th %ile at 44 weeks PMA. CONCLUSIONS: Understanding the range of indications utilized by high level NICUs around the country to pursue a tracheostomy in an infant with sBPD is one step toward standardizing consensus indications for tracheostomy in the future.

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.

The Pulmonary Circulation in the Single Ventricle Patient.

In recent decades, survival of children with complex congenital heart disease has improved considerably. Specifically, children with a variety of congenital heart defects resulting in 'single ventricle' physiology can now undergo palliative surgery that allows survival beyond the neonatal period, and in many cases into adulthood, despite having a single functional ventricular pumping chamber supplying both the pulmonary and systemic circulation. Our growing understanding of the functionally univentricular heart has resulted in freedom from Fontan failure of >50% at 25 years post-Fontan. Yet there is still a fair amount of knowledge to be gained, specifically as it relates to the pulmonary circulation in this group of patients. Knowledge gaps relate not only to the pulmonary circulation after Fontan operation, but also at each stage of the single ventricle surgical palliation, including the native physiology prior to any intervention. The pulmonary circulation is affected by multiple issues related to the single ventricle, including specific details of the anatomy unique to each patient, any intervention(s) undertaken, and potential complications such as aortopulmonary collaterals, protein losing enteropathy, plastic bronchitis, venovenous collaterals, pulmonary arteriovenous fistulae, ventricular dysfunction, pulmonary venous stenosis, and more. This chapter will review the current knowledge with regard to the pulmonary circulation in the single ventricle patient, primarily after the Fontan operation. Additionally, it is our hope to help the practitioner assess the pulmonary circulation in the single ventricle patient; we will also discuss the evidence behind and approach to treatment strategies in order to optimize the pulmonary circulation in this complex group of patients.

Cord Blood Biomarkers of Placental Maternal Vascular Underperfusion Predict Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

OBJECTIVE: To assess whether cord blood biomarkers associated with placental maternal vascular underperfusion (MVU) are predictive of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). STUDY DESIGN: Premature infants enrolled in a longitudinal cohort study were randomly sampled from 4 gestational age strata (n?=?190, range 23-36 weeks). Fifteen factors from a human angiogenesis panel were measured in cord blood using multiplex immunoassay. Multivariate linear regression was used to compare biomarker levels according to placental histologic MVU, taking into account acute/chronic inflammation and fetal vascular pathology. Biomarkers associated with MVU were further evaluated in the subgroup of extremely low gestational age infants (gestational age ? 28 weeks; n?=?48), and measured by enzyme-linked immunoassay in an additional 39 infants to determine associations with BPD (defined using the National Institutes of Health workshop criteria) and PH (identified by echocardiogram at 36 weeks of gestation). RESULTS: Cord blood placental growth factor (PIGF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor-A were decreased with MVU (P?

Palliative care approaches to neonates with chronic respiratory failure.

Neonates with chronic respiratory failure have uncertain prognosis and can face significant treatment burden. As the trajectory of the illness becomes more concerning, consultation with a pediatric palliative service should be considered, especially as therapeutic options shift from standard to "innovative." Benefits include as follows: supporting emotionally conflicted providers and parents, maintaining transparency in determination of goals, and balancing medical progress with each individual patient's and family's best interests.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Placental Villous Vascularity Is Decreased in Premature Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

The development of pulmonary hypertension (PH) is a serious complication of bronchopulmonary dysplasia (BPD) among infants born at extremely low gestational ages. Bronchopulmonary dysplasia-associated PH is characterized by persistent pulmonary vasoconstriction, progressive right heart dysfunction, and an increased risk of death. We have shown previously that certain placental vascular lesions are associated with BPD-associated PH. Further evaluation of the villous and vascular morphometry of these placentas is warranted. Using digital image analysis (DIA), we compared villous and vascular morphometric parameters of placentas from infants with and without BPD-associated PH. We conducted a case-control study of placentas from 14 infants born at ≤28 weeks' gestational age (GA). Cases with PH (N=7) and non-PH controls (N=7) were identified using echocardiogram screening at 36 weeks' corrected GA. Central parenchymal sections from each placenta were stained for CD31. Digital image analysis was used to measure vessel and villous capillary number, perimeter, diameter, and area. Mean villous vascularity (number of vessels per villus) was calculated for each patient. Mean vessel and villous number as well as area were similar between the two groups. Villous vascularity was decreased in placentas from infants who ultimately had PH disease compared to non-PH controls (5.5±1.0 vs 7.1±1.6; P<0.05). Placental villous vascularity is decreased in infants with BPD-associated PH. Further studies should assess whether placental morphometric markers may allow clinicians to better predict BPD and provide earlier and more targeted management.

Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus.

OBJECTIVE: To test the hypothesis that infants who are just being introduced to enteral feedings will advance to full enteral nutrition at a faster rate if they receive "trophic" (15 mL/kg/d) enteral feedings while receiving indomethacin or ibuprofen treatment for patent ductus arteriosus. STUDY DESIGN: Infants were eligible for the study if they were 23(1/7)-30(6/7) weeks' gestation, weighed 401-1250 g at birth, received maximum enteral volumes ≤60 mL/kg/d, and were about to be treated with indomethacin or ibuprofen. A standardized "feeding advance regimen" and guidelines for managing feeding intolerance were followed at each site (N = 13). RESULTS: Infants (N = 177, 26.3 ± 1.9 weeks' mean ± SD gestation) were randomized at 6.5 ± 3.9 days to receive "trophic" feeds ("feeding" group, n = 81: indomethacin 80%, ibuprofen 20%) or no feeds ("fasting [nil per os]" group, n = 96: indomethacin 75%, ibuprofen 25%) during the drug administration period. Maximum daily enteral volumes before study entry were 14 ± 15 mL/kg/d. After drug treatment, infants randomized to the "feeding" arm required fewer days to reach the study's feeding volume end point (120 mL/kg/d). Although the enteral feeding end point was reached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the 2 groups. There were no differences between the 2 groups in the incidence of infection, necrotizing enterocolitis, spontaneous intestinal perforation, or other neonatal morbidities. CONCLUSION: Infants required less time to reach the feeding volume end point if they were given "trophic" enteral feedings when they received indomethacin or ibuprofen treatments.

Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents.

The perinatal transition from fetal to extrauterine life requires a dramatic change in the circulatory pattern as the organ of gas exchange switches from the placenta to the lungs. Pulmonary hypertension can occur during early newborn life, and present as early respiratory failure or as a complication of more chronic diseases, such as bronchopulmonary dysplasia. The most effective pharmacotherapeutic strategies for infants with persistent pulmonary hypertension of the newborn are directed at selective reduction of pulmonary vascular resistance. This article discusses currently available therapies for pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness.

Differential patterns of 27 cord blood immune biomarkers across gestational age.

OBJECTIVES: Inflammation has been associated with preterm delivery and adverse neonatal outcomes such as cerebral palsy and chronic lung disease. However, no study to date has simultaneously examined a wide range of inflammatory mediators and their relationship to gestational age. We sought to describe the distribution of immune biomarkers in cord blood across gestational age and to investigate the association between biomarker level patterns and preterm birth. PATIENTS AND METHODS: As part of a large-scale molecular epidemiological study of preterm birth conducted at Boston Medical Center, this study analyzed both clinical and biomarker data from 927 births. Twenty-seven biomarkers were simultaneously quantified by immunoassay. The associations between the quartiles of 27 biomarkers and 3 gestational groups (< or =32, 33-36, and > or =37 weeks) were analyzed. Biomarkers found to be significant were further analyzed for dose-response correlation with preterm birth by logistic regression, adjusted for pertinent demographic and clinical factors. RESULTS: The 27 biomarkers could be classified into 1 of 3 groups: (1) biomarkers increased in preterm birth (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, monocyte chemoattractant protein 1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, soluble IL-6 receptor alpha, tumor necrosis factor alpha, soluble tumor necrosis factor receptor I, and TREM-1 [triggering receptor expressed on myeloid cells 1]); (2) biomarkers decreased in preterm birth (brain-derived neurotrophic factor, IL-1beta, IL-18, matrix metalloproteinase 9, and neurotrophin 3); and (3) biomarkers not associated with preterm birth (IL-6, IL-12, IL-17, granulocyte/macrophage colony-stimulating factor, interferon gamma, macrophage migration inhibitory factor, neurotrophin 4, RANTES [regulated on activation, normal T-cell expressed and secreted], transforming growth factor beta, and tumor necrosis factor beta). CONCLUSIONS: Biomarkers have different directions of association with prematurity; for significant biomarkers, the strength of association increases with biomarker concentration. Our results provide important information that could be used to guide additional studies aimed at determining mechanisms that contribute to preterm birth.

Inhaled NO in the experimental setting.

Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. More than a decade of intensive laboratory and clinical investigation has culminated in the current role for inhaled NO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Not surprisingly, this potent and successful therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment. In addition, there remains intense interest in possible new applications for newborns, as well as strategies that may enhance its efficacy. This review describes several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, and reviews our current knowledge about the role of iNO in other conditions such as congenital diaphragmatic hernia and congenital heart disease. In addition, laboratory and clinical studies addressing a potential role for iNO as a therapeutic modality for the preterm infant are reviewed.

Use of inhaled nitric oxide in the preterm infant.

PURPOSE OF REVIEW: Inhaled nitric oxide is established therapy for term infants with hypoxemic respiratory failure. Laboratory studies demonstrate that inhaled nitric oxide improves lung function and morphology in animal models of bronchopulmonary dysplasia, creating a rationale for clinical studies in premature infants. Four large multicenter randomized trials have now completed enrollment, and one trial has reported neurodevelopmental outcomes at 18-22 months. The purpose of this review is to summarize the results of the most recent preclinical studies and clinical trials. RECENT FINDINGS: In 2006, short-term outcomes from two large multicenter randomized trials were published. These studies differed in their target population and study design. Early use of inhaled nitric oxide was associated with a decrease in brain injury, and decreased chronic lung disease in infants over 1000 g. Inhaled nitric oxide use in older infants (7-21 days) was associated with decreased chronic lung disease, particularly if started early. SUMMARY: Neurodevelopmental outcomes after discharge are still needed from three large multicenter randomized trials. These results will help confirm the long-term implications of the benefits reported in the two most recent trials.

Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide.

We report the use of inhaled prostacyclin (PGI(2)) in 4 neonates with persistent pulmonary hypertension and hypoxemia refractory to inhaled nitric oxide. Oxygenation rapidly improved after inhalation of PGI(2) in all infants. The condition of one infant subsequently deteriorated, and alveolar capillary dysplasia was found at autopsy. The surviving infants were discharged with normal oxygen saturations in room air.