Histologic features and decreased lung FOXF1 gene expression in severe bronchopulmonary dysplasia without a genetic diagnosis of alveolar capillary dysplasia.

We report the case of a preterm infant who died at 10 months of age with severe bronchopulmonary dysplasia (sBPD) with refractory pulmonary hypertension and respiratory failure who had striking histologic features compatible with the diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) but without genetic confirmation of the diagnosis. We further demonstrate dramatic reductions in lung FOXF1 and TMEM100 content in sBPD, suggesting common mechanistic links between ACDMPV and sBPD with impaired FOXF1 signaling.

Respiratory support strategies in the management of severe, longstanding bronchopulmonary dysplasia.

Despite efforts to minimize ventilator-induced lung injury, some preterm infants require positive pressure support after 36 weeks' post-menstrual age. Infants with severe BPD typically experience progressive mismatch of ventilation and perfusion, which manifests as respiratory distress, hypoxemia in room air, hypercarbia, and growth failure. Lung compliance varies, but lung resistance generally increases with prolonged exposure to positive pressure ventilation and other sources of inflammation. Serial lung radiographs reveal a heterogeneous pattern, with areas of both hyperinflation and atelectasis; in extreme cases, macrocystic changes may be noted. Efforts to wean the respiratory support are often unsuccessful, and trials of high frequency ventilation, exogenous corticosteroids, and diuretics are common. The incidence of pulmonary hypertension increases with the severity of BPD, as does the mortality rate. Therefore, periodic screening and efforts to mitigate the risk of PH is fundamental to the management of longstanding BPD. Failure of conventional, lung-protective strategies (e.g., high rate/low tidal-volume and/or high frequency ventilation) warrants consideration of ventilatory strategies individualized to the disease physiology. Non-invasive modes of respiratory support may be successful in infants with mild to moderate BPD phenotypes. However, infants with moderate to severe BPD phenotypes often require invasive respiratory support, and pressure-limited or volume-targeted conventional ventilation may be better suited to the physiology than high-frequency ventilation. The consistent provision of adequate support is fundamental to the management of longstanding BPD and is best achieved with a stepwise increase in ventilator support until comfortable spontaneous respirations are achieved. Adequately supported infants typically experience improvements in both oxygenation and ventilation, which, if sustained, may arrest and generally reverses the course of a potentially lethal lung disease. Care should be individualized to address the most likely pulmonary mechanics, including variable lung compliance, elevated airway resistance, and variable airway obstruction.

Use of a Quality Scorecard to Enhance Quality and Safety in Community Hospital Newborn Nurseries.

OBJECTIVE: To implement a quality improvement (QI) scorecard as a tool for enhancing quality and safety efforts in level 1 and 2 community hospital nurseries affiliated with Nationwide Children's Hospital. STUDY DESIGN: A QI scorecard was developed for data collection, analytics, and reporting of neonatal quality metrics and cross-sector collaboration. Newborn characteristics were included for risk stratification, as were clinical and process measures associated with neonatal morbidity and mortality. Quality and safety activities took place in community hospital newborn nurseries in Ohio, and education was provided in both online and in-person collaborations, followed by local team sessions at partner institutions. Baseline (first 12 months) and postbaseline comparisons of clinical and process measures were analyzed by logistic regression, adjusting for potential confounders. RESULTS: In logistic regression models, at least 1 center documented improvements in each of the 4 process measures, and 3 of the 4 centers documented improvements in compliance with glucose checks obtained within 90 minutes of birth among at-risk infants. CONCLUSION: Collaborative QI projects led to improvements in perinatal metrics associated with important outcomes. Formation of a center-driven QI scorecard is feasible and provides community hospitals with a framework for collecting, analyzing, and reporting neonatal QI metrics.

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.

Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia.

OBJECTIVE: To test the hypothesis that elevated respiratory severity indices will identify patients with severe bronchopulmonary dysplasia (BPD) at the greatest risk for adverse in-hospital outcomes. STUDY DESIGN: This was a retrospective cohort study. A modified respiratory severity score (mean airway pressure × fraction of inspired oxygen) and a modified pulmonary score (respiratory support score × fraction of inspired oxygen + sum of medication scores) were calculated in a consecutive cohort of patients ≥36 weeks of postmenstrual age with severe BPD admitted to a referral center between 2010 and 2018. The association between each score and the primary composite outcome of death/prolonged length of stay (>75th percentile for cohort) was assessed using area under the receiver operator characteristic curve (AUROC) analysis and logistic regression. Death and the composite outcome death/tracheostomy were analyzed as secondary outcomes. RESULTS: In 303 patients, elevated scores were significantly associated with increased adjusted odds of death/prolonged length of stay: aOR 1.5 (95% CI 1.3-1.7) for the modified respiratory severity score and aOR 11.5 (95% CI 5.5-24.1) for the modified pulmonary score. The modified pulmonary score had slightly better discrimination of death/prolonged length of stay when compared with the modified respiratory severity score, AUROC 0.90 (95% CI 0.85-0.94) vs 0.88 (95% CI 0.84-0.93), P = .03. AUROCs for death and death/tracheostomy did not differ significantly when comparing the modified respiratory severity score with the modified pulmonary score. CONCLUSIONS: In our referral center, the modified respiratory severity score or the modified pulmonary score identified patients with established severe BPD at the greatest risk for death/prolonged length of stay, death, and death/tracheostomy.

Association of time of first corticosteroid treatment with bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: To evaluate the association between the time of first systemic corticosteroid initiation and bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: A multi-center retrospective cohort study from January 2010 to December 2016 using the Children's Hospitals Neonatal Database and Pediatric Health Information System database was conducted. The study population included preterm infants <32 weeks' gestation treated with systemic corticosteroids after 7 days of age and before 34 weeks' postmenstrual age. Stepwise multivariable logistic regression was used to assess the association between timing of corticosteroid initiation and the development of Grade 2 or 3 BPD as defined by the 2019 Neonatal Research Network criteria. RESULTS: We identified 598 corticosteroid-treated infants (median gestational age 25 weeks, median birth weight 760 g). Of these, 47% (280 of 598) were first treated at 8-21 days, 25% (148 of 598) were first treated at 22-35 days, 14% (86 of 598) were first treated at 36-49 days, and 14% (84 of 598) were first treated at >50 days. Infants first treated at 36-49 days (aOR 2.0, 95% CI 1.1-3.7) and >50 days (aOR 1.9, 95% CI 1.04-3.3) had higher independent odds of developing Grade 2 or 3 BPD when compared to infants treated at 8-21 days after adjusting for birth characteristics, admission characteristics, center, and co-morbidities. CONCLUSIONS: Among preterm infants treated with systemic corticosteroids in routine clinical practice, later initiation of treatment was associated with a higher likelihood to develop Grade 2 or 3 BPD when compared to earlier treatment.

In-hospital outcomes of late referrals for established bronchopulmonary dysplasia.

OBJECTIVE: To determine the in-hospital outcomes for patients with established bronchopulmonary dysplasia (BPD) referred late for severe disease. STUDY DESIGN: Retrospective cohort study of patients with established BPD referred to our center after 36 weeks PMA. RESULT: Among 71 patients with BPD referred to our center after 36 weeks PMA between 2010 and 2018, the median PMA was 47 weeks (IQR, 42, 53) and the median respiratory severity score was 8.1 (IQR 4.5, 11.0) on admission. Survival in this cohort was 92%. Most survivors were discharged home without the need for positive pressure respiratory support (77%) or pulmonary vasodilators (89%). For survivors, we observed a significant improvement in median z-scores for length (-6.7 vs -3.3, p < 0.0001) between admission and discharge. CONCLUSION: Despite presenting relatively late with a high degree of illness severity, nearly all patients in this cohort survived to hospital discharge with improvement in comorbidities.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

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.

Clinical phenotypes and management concepts for severe, established bronchopulmonary dysplasia.

With advances in care, the bronchopulmonary dysplasia phenotypes have evolved, so that infants who would have died in previous eras are now surviving with significant pulmonary and neurologic morbidities. The spectrum of bronchopulmonary dysplasia phenotypes is broad, however, ranging from very mild to very severe disease, and management strategies used in previous eras of care may not be appropriate for the most severe phenotypes. The pathophysiology depends largely on the gestational age at birth, but disease progression and long-term outcome depends on the net sum of antenatal, perinatal and postnatal exposures. There is no single management strategy for the wide spectrum of clinical presentations of BPD; care must be individualized. Regardless of the phenotype, the support apparatus should match the disease physiology. Here we describe an interdisciplinary approach to management in terms of achieving clinical stability and progress along a continuum, from diagnosis at 36 weeks of corrected gestational age to convalescence. The clinical trajectory depends on the balance of factors related to support of respiration, healing of the lungs, and return of organ growth and development. The overall treatment strategy should optimize positive influences that lead to a pro-growth state, while minimizing exposures that interfere with lung growth and development. This is best achieved by use of a multi-disciplinary team, with feedback loops that inform clinical decision-making regarding respiratory stability, tolerance for cares and activities, the clinical response to changes in the care plan, and progress in growth and development.

Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age.

INTRODUCTION: Few studies have examined the relationship between birth plurality and neurocognitive function among children born extremely preterm. STUDY DESIGN: We compared rates of Z-scores ≤-2 on 18 tests of neurocognitive function and academic achievement at age 10 years in 245 children arising from twin pregnancies, 55 from triplet pregnancies, and 6 from a septuplet pregnancy to that of 568 singletons, all of whom were born before the 28th week of gestation. RESULTS: In total, 874 children were evaluated at the age of 10 years. After adjusting for confounders, children of multifetal pregnancies performed significantly better on one of six subtests of executive function than their singleton peers. Performance was similar on all other assessments of intelligence, language, academic achievement, processing speed, visual perception, and fine motor skills. CONCLUSION: We found no evidence that children born of multifetal pregnancies had worse scores than their singleton peers on assessments of neurocognitive and academic function.

The use of inhaled corticosteroids in chronically ventilated preterm infants.

Bronchopulmonary dysplasia (BPD) is the most usual reason for preterm infants to require chronic mechanical ventilation. Inflammation is a key factor underlying the lung injury leading to the development of BPD, and the rationale for use of corticosteroids in the management of ventilator-dependent preterm infants is based on their anti-inflammatory effects. Because systemic corticosteroids are associated with significant adverse effects in preterm infants, attention has turned to the use of inhaled corticosteroids (ICS) as a potentially safer therapy for BPD. The aim of this review is to discuss what is known about the efficacy and safety of ICS in chronically ventilated preterm infants. However, this has been a challenge since there is a paucity of high-grade evidence for the use of ICS in these patients. Thus, there is a real need for well-powered randomized controlled trials examining short- and long-term outcomes of ICS use in this population.

Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.

BACKGROUND: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). METHODS: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. RESULTS: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. CONCLUSION: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.

Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns.

INTRODUCTION: Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns. METHODS: We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile. RESULTS: The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile. CONCLUSIONS: Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability.

Lenticulostriate vasculopathy in extremely low gestational age newborns: Inter-rater variability of cranial ultrasound readings, antecedents and postnatal characteristics.

Although lenticulostriate vasculopathy (LSV) was first detected on a cranial ultrasound nearly 30 years ago, its clinical implications and significance remain unknown. The objective of this study was to evaluate the inter-rater reliability of cranial ultrasound readings of LSV, and to explore relationships with potential antecedents and developmental correlates in extremely low gestational age newborns. Of the 1506 infants enrolled during the years 2002-2004, 1450 had at least one set of ultrasound scans evaluated for LSV and 939 had all three sets. To evaluate the inter-rater agreement for identifying LSV, we compared readings from two independent radiologists on days 1-4, 5-14, and on or after day 15. We then evaluated the relationships between LSV and maternal, antenatal, and postnatal characteristics. Our results showed that kappa values were 0.18, 0.33, and 0.36 on days 1-4, days 5-14, and day 15 or greater. Infants who were identified as LSV positive by two readers had higher Score for Neonatal Acute Physiology-II (an illness severity indicator), higher rates of tracheal infection and bacteremia, lower partial pressure of arterial oxygen and pH levels on 2 of the first 3 postnatal days, and they were more likely to have a lower psycho-motor development index at age 2 years. Positive agreement on the presence of LSV was low, as was the kappa value, an index of inter-rater reliability. Infants with high illness severity scores and their correlates were at increased risk of developing LSV, while those who develop LSV appear to be at increased risk of motor dysfunction.

Antecedents of perinatal cerebral white matter damage with and without intraventricular hemorrhage in very preterm newborns.

BACKGROUND: Isolated periventricular leukomalacia, defined as periventricular leukomalacia unaccompanied by intraventricular hemorrhage, is reportedly increased in newborns with systemic hypotension and in infants who received treatment for systemic hypotension or a patent ductus arteriosus. METHODS: This study sought to determine if the risk profile of one or more hypoechoic lesions unaccompanied by intraventricular hemorrhage, our surrogate for isolated periventricular leukomalacia, differs from that of one or more hypoechoic lesions preceded or accompanied by intraventricular hemorrhage. We compared extremely preterm infants (i.e., gestation 23-27 weeks) with each of these entities to 885 extremely preterm infants who had neither an isolated hypoechoic lesion nor a hypoechoic lesion preceded or accompanied by intraventricular hemorrhage. RESULTS: The risk of a hypoechoic lesion with intraventricular hemorrhage (N = 61) was associated with gestation <25 weeks, high Score for Acute Neonatal Physiology, early recurrent or prolonged acidemia, analgesic exposure, and mechanical ventilation 1 week after birth. CONCLUSIONS: In this large, multicenter sample of extremely low gestational age newborns, the risk profile of a hypoechoic lesion unaccompanied by intraventricular hemorrhage differed from that of a hypoechoic lesion with intraventricular hemorrhage. This suggests that hypoechoic lesions accompanied or preceded by intraventricular hemorrhage (our surrogate for periventricular hemorrhagic infarction) may have a different causal pathway than hypoechoic lesions without intraventricular hemorrhage, our surrogate for periventricular leukomalacia.

Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns.

OBJECTIVES: To evaluate in extremely low gestational age newborns, relationships between indicators of hypotension during the first 24 postnatal hours and developmental delay at 24 months of age. METHODS: The 945 infants in this prospective study were born at <28 weeks, were assessed for three indicators of hypotension in the first 24 postnatal hours, and were evaluated with the Bayley Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 24 months corrected age. Indicators of hypotension included: (1) mean arterial pressure in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile for the difference between the lowest and highest mean arterial pressure. Logistic regression was used to evaluate relationships between hypotension and developmental outcomes, adjusting for potential confounders. RESULTS: 78% of infants in this cohort received volume expansion or vasopressor; all who received a vasopressor were treated with volume expansion. 26% had an MDI <70 and 32% had a PDI <70. Low MDI and PDI were associated with low gestational age, which in turn, was associated with receipt of vasopressor treatment. Blood pressure in the lowest quartile for gestational age was associated with vasopressor treatment and labile blood pressure. After adjusting for potential confounders, none of the indicators of hypotension were associated with MDI <70 or PDI <70. CONCLUSIONS: In this large cohort of extremely low gestational age newborns, we found little evidence that early postnatal hypotension indicators are associated with developmental delay at 24 months corrected gestational age.