To determine (1) the magnitude of clustering of bronchopulmonary dysplasia (36 weeks) or death (the outcome) across centers of the Eunice Kennedy Shriver National Institute of Child and Human Development National Research Network, (2) the infant-level variables associated with the outcome and estimate their clustering, and (3) the center-specific practices associated with the differences and build predictive models.
Data on neonates with a birth weight of <1250 g from the cluster-randomized benchmarking trial were used to determine the magnitude of clustering of the outcome according to alternating logistic regression by using pairwise odds ratio and predictive modeling. Clinical variables associated with the outcome were identified by using multivariate analysis. The magnitude of clustering was then evaluated after correction for infant-level variables. Predictive models were developed by using center-specific and infant-level variables for data from 2001 2004 and projected to 2006.
In 2001–2004, clustering of bronchopulmonary dysplasia/death was significant (pairwise odds ratio: 1.3; P < .001) and increased in 2006 (pairwise odds ratio: 1.6; overall incidence: 52%; range across centers: 32%–74%); center rates were relatively stable over time. Variables that varied according to center and were associated with increased risk of outcome included lower body temperature at NICU admission, use of prophylactic indomethacin, specific drug therapy on day 1, and lack of endotracheal intubation. Center differences remained significant even after correction for clustered variables.
Bronchopulmonary dysplasia/death rates demonstrated moderate clustering according to center. Clinical variables associated with the outcome were also clustered. Center differences after correction of clustered variables indicate presence of as-yet unmeasured center variables.
logistic models; infant; premature; predictive value of tests; clustering
A count of 3 neonatal morbidities (bronchopulmonary dysplasia, brain injury, and severe retinopathy of prematurity) strongly predict the risk of death or neurosensory impairment in extremely low birth weight infants who survive to 36 weeks’ postmenstrual age. Neonatal infection has also been linked with later impairment. We examined whether the addition of infection to the count of 3 neonatal morbidities further improves the prediction of poor outcome.
We studied 944 infants who participated in the Trial of Indomethacin Prophylaxis in Preterms and survived to 36 weeks’ postmenstrual age. Culture-proven sepsis, meningitis, and stage II or III necrotizing enterocolitis were recorded prospectively. We investigated the incremental prognostic importance of neonatal infection by adding terms for the different types of infection to a logistic model that already contained terms for the count of bronchopulmonary dysplasia, brain injury, and severe retinopathy. Poor outcome at 18 months of age was death or survival with 1 or more of the following: cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness.
There were 414 (44%) infants with at least 1 episode of infection or necrotizing enterocolitis. Meningitis and the presence of any type of infection added independent prognostic information to the morbidity-count model. The odds ratio associated with infection or necrotizing enterocolitis in this model was 50% smaller than the odds ratio associated with each count of the other 3 neonatal morbidities. Meningitis was rare and occurred in 22 (2.3%) of 944 infants.
In this cohort of extremely low birth weight infants who survived to 36 weeks’ postmenstrual age, neonatal infection increased the risk of a late death or survival with neurosensory impairment. However, infection was a weaker predictor of poor outcome than bronchopulmonary dysplasia, brain injury, and severe retinopathy.
extremely low birth weight infant; infection; bronchopulmonary dysplasia; brain injury; retinopathy; neurosensory impairment
Inflammation mediated by cytokines may be important in the pathogenesis of bronchopulmonary dysplasia and the competing outcome of death in extremely low birth weight infants.
To develop multi-variable logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at 36w post-menstrual age using clinical and cytokine data from the first 28 days.
1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development had 25 cytokines measured from blood collected within 4 h of birth and on days 3, 7, 14, and 21. Stepwise regression using peak values of the 25 cytokines and 15 clinical variables identified variables associated with BPD/death. Multi-variable logistic regression was done for bronchopulmonary dysplasia/death using variables selected by stepwise regression. Similar analyses were also done using average cytokine values from days 0–21, days 0–3, and from days 14–21.
Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. Combining results from all models, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukins-1β, -6, -8, -10, and interferon-γ and lower concentrations of interleukin-17, RANTES, and tumor necrosis factor-β. Compared to models with only clinical variables, addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.
The overall pattern of cytokines suggests bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T-lymphocytes.
Logistic models; Infant; premature; Predictive value of tests
To evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among ELBW infants.
This is a retrospective analysis of extremely low birth weight (<1,000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network sites from January 2000 to June 2007. Infants were tracked until death or 18–22 months corrected age. Infants who died between NICU discharge and the 18–22 month follow-up visit were classified as post-NICU discharge mortality. Association of maternal and infant risk factors with post-NICU discharge mortality was determined using logistic regression analysis. A prediction model with six significant predictors was developed and validated.
5,364 infants survived to NICU discharge. 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. Post-NICU discharge mortality rate was 22.3 per 1000 ELBW infants. In the prediction model, African-American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intra-partum antibiotics was associated with decreased risk of post-NICU discharge mortality.
We identified African-American race, unknown medical insurance and prolonged NICU stay as risk factors associated with post-NICU discharge mortality among ELBW infants.
extremely preterm infants; discharge; mortality; predictive model
We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation).
Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity.
Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants.
This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants.
low-birth weight infant; NICUs; treatment; patient outcome assessment
Individuals with Down syndrome (DS) are at increased risk of several morbidities with lifelong health consequences. Little is known about mortality or morbidity risks in early infancy among very-low-birth-weight (VLBW) infants with DS. Our objective was to compare survival and neonatal morbidities between VLBW infants with DS and VLBW infants with other non-DS chromosomal anomalies, other non-chromosomal birth defects, and VLBW infants without major birth defects.
Data were collected prospectively for infants weighing 401-1500 grams born and/or cared for at one of the study centers participating in the NICHD Neonatal Research Network from 1994 through 2008. Risk of death and morbidities including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups.
Infants with DS were at increased risk of death (adjusted relative risk [RR] 2.47, 95% confidence interval [CI] 2.00-3.07), PDA, NEC, LOS, and BPD relative to infants with no birth defects. Decreased risk of death (RR 0.40, 95% CI 0.31-0.52) and increased risks of NEC and LOS were observed when comparing infants with DS to infants with other non-DS chromosomal anomalies. Relative to infants with non-chromosomal birth defects, infants with DS were at increased risk of PDA and NEC.
The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for caretakers in anticipating the need for enhanced surveillance for prevention of these morbidities.
neonatal mortality; neonatal morbidity; preterm infants; Down syndrome; trisomy 21
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
Candida; neonate; mortality; neurodevelopmental impairment
Bronchopulmonary dysplasia (BPD) is the most common serious pulmonary morbidity in premature infants. The score for neonatal acute physiology (SNAP) is a physiologic severity index for neonatal intensive care and correlates well with neonatal mortality and clinical outcomes. The prognostic value of the SNAP score for BPD in preterm infants remains to be clarified. The aim of the study was to determine whether SNAP can predict the development of BPD or death, and to investigate the contribution of SNAP to the predictive accuracy of other potential perinatal risk factors for the adverse outcome in critically ill preterm infants.
We conducted a study in 160 critically ill preterm infants with less than 33 gestational weeks. The original SNAP score was prospectively calculated based on 28 items collected during the first 24 hours of admission. The potential perinatal risk factors were assessed during the first 72 hours of life. Major outcome measures were BPD and mortality before the time of BPD screening.
Of the 160 infants, 17 died and 41 developed BPD. The SNAP score was significantly associated with BPD or death (odds ratio [OR] =1.28; 95% confidence interval [CI], 1.16-1.41; p <0.001), even after adjustment for gestational age (OR =1.27; 95% CI, 1.13-1.41; p <0.001). High SNAP score was an independent predictor of BPD or death (area under the curve [AUC] =0.78; 95% CI, 0.70-0.85; p <0.001), with additional predictive value when combined with other perinatal risk factors. Multivariate regression analysis resulted in a final model, including SNAP, gestational age, apnea of prematurity, patent ductus arteriosus, and surfactant use as independent risk factors, with a higher predictive accuracy compared with individual components (AUC =0.92; 95% CI, 0.87-0.96; p <0.001).
SNAP is associated with adverse outcome of BPD or death. High SNAP scores are predictive of BPD or death in critically ill preterm infants, and add prognostic value to other perinatal risk factors.
Adverse outcome; Bronchopulmonary dysplasia; Critically ill preterm infants; Mortality; Perinatal risk factors; Predictive test; SNAP (the score for neonatal acute physiology)
The purpose of this work was to evaluate therapy for patent ductus arteri-osus as a risk factor for death or neurodevelopmental impairment at 18 to 22 months, bronchopulmonary dysplasia, or necrotizing enterocolitis in extremely low birth weight infants.
We studied infants in the National Institute of Child Health and Human Development Neonatal Research Network Generic Data Base born between 2000 and 2004 at 23 to 28 weeks’ gestation and at <1000-g birth weight with patent ductus arteriosus. Patent ductus arteriosus therapy was evaluated as a risk factor for outcomes in bivariable and multivariable analyses.
Treatment for subjects with patent ductus arteriosus (n = 2838) included 403 receiving supportive treatment only, 1525 treated with indomethacin only, 775 with indomethacin followed by secondary surgical closure, and 135 treated with primary surgery. Patients who received supportive therapy for patent ductus arteriosus did not differ from subjects treated with indomethacin only for any of the outcomes of interest. Compared with indomethacin treatment only, patients undergoing primary or secondary surgery were smaller and more premature. When compared with indomethacin alone, primary surgery was associated with increased adjusted odds for neurodevelopmental impairment and bronchopulmonary dysplasia in multivariable logistic regression. Secondary surgical closure was associated with increased odds for neurodevelopmental impairment and increased adjusted odds for bronchopulmonary dysplasia but decreased adjusted odds for death. Risk of necrotizing enterocolitis did not differ among treatments. Indomethacin prophylaxis did not significantly modify these results.
Our results suggest that infants treated with primary or secondary surgery for patent ductus arteriosus may be at increased risk for poor short- and long-term outcomes compared with those treated with indomethacin. Prophylaxis with indomethacin in the first 24 hours of life did not modify the subsequent outcomes of patent ductus arteriosus therapy.
patent ductus arteriosus; bronchopulmonary dysplasia; necrotizing enterocolitis; neurodevelopmental impairment; therapy ductus arteriosus
BACKGROUND AND OBJECTIVE:
The Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) antenatal consent study demonstrated that mothers of infants enrolled in the SUPPORT trial had significantly different demographics and exposure to antenatal steroids compared with mothers of eligible, but not enrolled infants. The objective of this analysis was to compare the outcomes of bronchopulmonary dysplasia, severe retinopathy of prematurity, severe intraventricular hemorrhage or periventricular leukomalacia (IVH/PVL), death, and death/severe IVH/PVL for infants enrolled in SUPPORT in comparison with eligible, but not enrolled infants.
Perinatal characteristics and neonatal outcomes were compared for enrolled and eligible but not enrolled infants in bivariate analyses. Models were created to test the effect of enrollment in SUPPORT on outcomes, controlling for perinatal characteristics.
There were 1316 infants enrolled in SUPPORT; 3053 infants were eligible, but not enrolled. In unadjusted analyses, enrolled infants had significantly lower rates of death before discharge, severe IVH/PVL, death/severe IVH/PVL (all < 0.001), and bronchopulmonary dysplasia (P = .003) in comparison with eligible, but not enrolled infants. The rate of severe retinopathy of prematurity was not significantly different. After adjustment for perinatal factors, enrollment in the trial was not a significant predictor of any of the tested clinical outcomes.
The results of this analysis demonstrate significant outcome differences between enrolled and eligible but not enrolled infants in a trial using antenatal consent, which were likely due to enrollment bias resulting from the antenatal consent process. Additional research and regulatory review need to be conducted to ensure that large moderate-risk trials that require antenatal consent can be conducted in such a way as to ensure the generalizability of results.
antenatal steroids; clinical research/trials; informed consent; neonatal
We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO2 response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO2 of 39±50 mm Hg versus a mean decrease of 11±15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.
Nitric oxide; pulmonary hypoplasia; oligohydramnios; PPROM; bronchopulmonary dysplasia
Extremely low birth weight infants often require rehospitalization during infancy. Our objective was to identify at the time of discharge which extremely low birth weight infants are at higher risk for rehospitalization.
Data from extremely low birth weight infants in Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers from 2002–2005 were analyzed. The primary outcome was rehospitalization by the 18- to 22-month follow-up, and secondary outcome was rehospitalization for respiratory causes in the first year. Using variables and odds ratios identified by stepwise logistic regression, scoring systems were developed with scores proportional to odds ratios. Classification and regression-tree analysis was performed by recursive partitioning and automatic selection of optimal cutoff points of variables.
A total of 3787 infants were evaluated (mean ± SD birth weight: 787 ± 136 g; gestational age: 26 ± 2 weeks; 48% male, 42% black). Forty-five percent of the infants were rehospitalized by 18 to 22 months; 14.7% were rehospitalized for respiratory causes in the first year. Both regression models (area under the curve: 0.63) and classification and regression-tree models (mean misclassification rate: 40%–42%) were moderately accurate. Predictors for the primary outcome by regression were shunt surgery for hydrocephalus, hospital stay of >120 days for pulmonary reasons, necrotizing enterocolitis stage II or higher or spontaneous gastrointestinal perforation, higher fraction of inspired oxygen at 36 weeks, and male gender. By classification and regression-tree analysis, infants with hospital stays of >120 days for pulmonary reasons had a 66% rehospitalization rate compared with 42% without such a stay.
The scoring systems and classification and regression-tree analysis models identified infants at higher risk of rehospitalization and might assist planning for care after discharge.
logistic models; infant; premature; predictive value of tests
Postnatal corticosteroids have been used for prevention and treatment of neonatal chronic lung disease (CLD) (also know as bronchopulmonary dysplasia), a significant cause of mortality and morbidity in preterm infants. As both dexamethasone and hydrocortisone administration within the first seven days of life is associated with an increased risk of cerebral palsy, early postnatal corticosteroid therapy is not recommended to prevent CLD. After seven days of life, dexamethasone has been shown to decrease the rate of CLD at 36 weeks’ postmenstrual age with less impact on neurodevelopmental outcome. No trials have examined whether the benefits of corticosteroids outweigh the adverse effects for infants at high risk of, or with, severe CLD. While routine dexamethasone therapy of all ventilated infants is not recommended, clinicians may consider a short course of low-dose dexamethasone for individual infants at high risk of or with severe CLD. There is no evidence that hydrocortisone is an effective or safe alternative to dexamethasone and little evidence to support routine use of inhaled corticosteroids for prevention or treatment. Inhaled corticosteroids may be considered as an alternative to dexamethasone for treating individual infants with severe CLD. This revision replaces a statement published jointly with the American Academy of Pediatrics in 2002.
Bronchopulmonary dysplasia; Chronic lung disease; Dexamethasone; Postnatal corticosteroids; Preterm infants
This article discusses how research in the past 5 years into management strategies influencing respiratory outcomes has changed (or not changed) the author's clinical practice. Changes include using inhaled nitric oxide but no longer systemic pulmonary vasodilators in term born infants with pulmonary hypertension. Use of postnatal steroids is now restricted to systemic administration in infants with severe respiratory failure and who are ventilator dependent beyond 2 weeks of age. Infants with bronchopulmonary dysplasia, unless they have pulmonary hypertension, are maintained at oxygen saturation levels of 90–92% rather than ⩾95%. Supine sleeping is instituted in prematurely born infants without contraindications several weeks prior to neonatal discharge to reinforce to parents the importance of supine sleeping their baby at home. Further research is required to identify the optimal respiratory support strategy, particularly for very immature infants.
Diminished lung function appears to be a risk factor for respiratory syncytial virus (RSV) infection/bronchiolitis in term born infants.
To determine if diminished lung function prior to neonatal unit discharge was associated with subsequent symptomatic RSV lower respiratory tract infection (LRTI) and respiratory morbidity in prematurely born infants.
Of 39 infants in a tertiary neonatal intensive care unit (median gestational age 28 weeks, range 23–31), 20 had bronchopulmonary dysplasia. Lung function (compliance and resistance of the respiratory system (Crs and Rrs) and functional residual capacity (FRC)) was measured on the neonatal unit at 36 weeks postmenstrual age (PMA). Following neonatal unit discharge, nasopharyngeal aspirates were obtained on every occasion, at home or in hospital, an infant had an LRTI. RSV was identified by immunofluorescence and/or culture.
The 15 infants who suffered a symptomatic RSV LRTI had a higher mean Rrs and suffered more wheeze at follow up than the rest of the cohort. Regression analysis showed that a high Rrs was significantly associated with a symptomatic RSV LRTI; significant factors for cough were a high Rrs and a symptomatic RSV LRTI, and for wheeze were a high Rrs.
Prematurely born infants, who had a symptomatic RSV LRTI and/or respiratory morbidity at follow up, had worse lung function prior to neonatal unit discharge.
respiratory syncytial virus; lung function; prematurity; cough; wheeze
Background. An abnormally high incidence (44%) of bronchopulmonary dysplasia with variations in rates among cities was observed in Colombia among premature infants. Objective. To identify risk factors that could explain the observed high incidence and regional variations of bronchopulmonary dysplasia. Study Design. A case-control study was designed for testing the hypothesis that differences in the disease rates were not explained by differences in city-of-birth specific population characteristics or by differences in respiratory management practices in the first 7 days of life, among cities. Results. Multivariate analysis showed that premature rupture of membranes, exposure to mechanical ventilation after received nasal CPAP, no surfactant exposure, use of rescue surfactant (instead of early surfactant), PDA, sepsis and the median daily FIO2, were associated with a higher risk of dysplasia. Significant differences between cases and controls were found among cities. Models exploring for associations between city of birth and dysplasia showed that being born in the highest altitude city (Bogotá) was associated with a higher risk of dysplasia (OR 1.82 95% CI 1.31–2.53). Conclusions. Bronchopulmonary dysplasia was manly explained by traditional risk factors. Findings suggest that altitude may play an important role in the development of this disease. Prenatal steroids did not appear to be protective at high altitude.
Recent progress in neonatal medicine has enabled survival of many extremely low-birth-weight infants. Prenatal steroids, surfactants, and non-invasive ventilation have helped reduce the incidence of the classical form of bronchopulmonary dysplasia characterized by marked fibrosis and emphysema. However, a new form of bronchopulmonary dysplasia marked by arrest of alveolarization remains a complication in the postnatal course of extremely low-birth-weight infants. To better understand this challenging complication, detailed alveolarization mechanisms should be delineated. Proper alveolarization involves the temporal and spatial coordination of a number of cells, mediators, and genes. Cross-talk between the mesenchyme and the epithelium through soluble and diffusible factors are key processes of alveolarization. Lung interstitial cells derived from the mesenchyme play a crucial role in alveolarization. Peak alveolar formation coincides with intense lung interstitial cell proliferation. Myofibroblasts are essential for secondary septation, a critical process of alveolarization, and localize to the front lines of alveologenesis. The differentiation and migration of myofibroblasts are strictly controlled by various mediators and genes. Disruption of this finely controlled mechanism leads to abnormal alveolarization. Since arrest in alveolarization is a hallmark of a new form of bronchopulmonary dysplasia, knowledge regarding the role of lung interstitial cells during alveolarization and their control mechanism will enable us to find more specific therapeutic strategies for bronchopulmonary dysplasia. In this review, the role of lung interstitial cells during alveolarization and control mechanisms of their differentiation and migration will be discussed.
Bronchopulmonary dysplasia; Myofibroblast; Lung development
Rationale: Apelin, a potent vasodilator and angiogenic factor, may be a novel therapeutic agent in neonatal chronic lung disease, including bronchopulmonary dysplasia.
Objectives: To determine the beneficial effect of apelin in neonatal rats with hyperoxia-induced lung injury, a model for premature infants with bronchopulmonary dysplasia.
Methods: The cardiopulmonary effects of apelin treatment (62 μg/kg/d) were studied in neonatal rats by exposure to 100% oxygen, using two treatment strategies: early concurrent treatment during continuous exposure to hyperoxia for 10 days and late treatment and recovery in which treatment was started on Day 6 after hyperoxic injury for 9 days and continued during the 9-day recovery period. We investigated in both models the role of the nitric oxide–cyclic guanosine monophosphate (cGMP) pathway in apelin treatment by specific inhibition of the nitric oxide synthase activity with Nω-nitro-l-arginine methyl ester (l-NAME, 25 mg/kg/d).
Measurements and Main Results: Parameters investigated include survival, lung and heart histopathology, pulmonary fibrin deposition and inflammation, alveolar vascular leakage, lung cGMP levels, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Prophylactic treatment with apelin improved alveolarization and angiogenesis, increased lung cGMP levels, and reduced pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy. These beneficial effects were completely absent in the presence of l-NAME. In the injury-recovery model apelin also improved alveolarization and angiogenesis, reduced arteriolar wall thickness, and attenuated right ventricular hypertrophy.
Conclusions: Apelin reduces pulmonary inflammation, fibrin deposition, and right ventricular hypertrophy, and partially restores alveolarization in rat pups with neonatal hyperoxic lung injury via a nitric oxide synthase–dependent mechanism.
alveolarization; bronchopulmonary dysplasia; nitric oxide synthase inhibition; lung inflammation; right ventricular hypertrophy
There are limited data to inform the choice between early treatment
with continuous positive airway pressure (CPAP) and early surfactant
treatment as the initial support for extremely-low-birth-weight infants.
We performed a randomized, multicenter trial, with a 2-by-2 factorial
design, involving infants who were born between 24 weeks 0 days and 27 weeks
6 days of gestation. Infants were randomly assigned to intubation and
surfactant treatment (within 1 hour after birth) or to CPAP treatment
initiated in the delivery room, with subsequent use of a protocol-driven
limited ventilation strategy. Infants were also randomly assigned to one of
two target ranges of oxygen saturation. The primary outcome was death or
bronchopulmonary dysplasia as defined by the requirement for supplemental
oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in
neonates who were receiving less than 30% oxygen).
A total of 1316 infants were enrolled in the study. The rates of the
primary outcome did not differ significantly between the CPAP group and the
surfactant group (47.8% and 51.0%, respectively; relative
risk with CPAP, 0.95; 95% confidence interval [CI],
0.85 to 1.05) after adjustment for gestational age, center, and familial
clustering. The results were similar when bronchopulmonary dysplasia was
defined according to the need for any supplemental oxygen at 36 weeks (rates
of primary outcome, 48.7% and 54.1%, respectively; relative
risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received
CPAP treatment, as compared with infants who received surfactant treatment,
less frequently required intubation or postnatal corticosteroids for
bronchopulmonary dysplasia (P<0.001), required fewer days of
mechanical ventilation (P = 0.03), and were more likely to be alive
and free from the need for mechanical ventilation by day 7 (P =
0.01). The rates of other adverse neonatal outcomes did not differ
significantly between the two groups.
The results of this study support consideration of CPAP as an
alternative to intubation and surfactant in preterm infants.
(ClinicalTrials.gov number, NCT00233324.)
This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).
Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.
Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤ 12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.
Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
extremely low gestation; very low birth weight; morbidity; death
To compare continuous positive airway pressure (CPAP) vs. traditional mechanical ventilation (MV) at 24 h of age as predictors of neurodevelopmental (ND) outcomes in extremely low birth weight (ELBW) infants at 18-22 mo corrected gestational age (CGA).
Infants ≤ 1000g birth weight born from January 2000 through December 2006 at two hospitals at the Cincinnati site of the National Institute of Child Health and Human Development Neonatal Research Network were evaluated comparing CPAP (N = 198) vs. MV (N = 109). Primary outcomes included the Bayley Score of Infant Development Version II (BSID-II), presence of deafness, blindness, cerebral palsy, bronchopulmonary dysplasia and death.
Ventilatory groups were similar in gender, rates of preterm prolonged rupture of membranes, antepartum hemorrhage, use of antenatal antibiotics, steroids, and tocolytics. Infants receiving CPAP weighed more, were older, were more likely to be non-Caucasian and from a singleton pregnancy. Infants receiving CPAP had better BSID-II scores, and lower rates of BPD and death.
After adjusting for acuity differences, ventilatory strategy at 24 h of age independently predicts long-term neurodevelopmental outcome in ELBW infants.
We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999–2001 (epoch 1) and 2002–2004 (epoch 2).
PATIENTS AND METHODS:
We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes.
Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86–2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91–1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98–2.04]; P = .07).
Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.
extremely preterm; neurodevelopmental; outcome; cerebral palsy; Bayley Scales of Infant Development II
Pulmonary inflammation is associated with the development of bronchopulmonary dysplasia in premature infants. We have previously shown that perinatal pulmonary expression of human IL-1β is sufficient to cause a lung disease similar to bronchopulmonary dysplasia, characterized by inflammation, impaired alveolarization, poor postnatal growth, and increased mortality in infant mice. The αvβ6 integrin plays a critical role in regulating inflammation in the adult lung. To study the role of the β6 integrin subunit in neonatal inflammatory lung disease, we compared the pulmonary development in IL-1β–expressing infant mice with wild-type or null β6 integrin loci. Absence of the β6 integrin subunit decreased the mortality and improved the postnatal growth of IL-1β–expressing pups. The disrupted alveolar development of IL-1β–expressing mice was improved by β6 integrin deficiency. IL-1β–expressing β6−/− pups had shorter alveolar chord length and thinner alveolar walls than IL-1β–expressing β6+/+ pups. In addition, the absence of the β6 integrin subunit reduced IL-1β–induced neutrophil and macrophage infiltration into the alveolar spaces. β6 integrin subunit deficiency suppressed inflammation and goblet cell hyperplasia in the airways and alleviated airway remodeling in IL-1β–expressing mice. The expression of the chemoattractant proteins, keratinocyte-derived chemokine, macrophage-inflammatory protein–2, calgranulin A, and calgranulin B, of osteopontin, and of the chitinase-like lectins, Ym1 and Ym2, was lower in IL-1β–expressing β6−/− than in IL-1β–expressing β6+/+ mice. We conclude that absence of the β6 integrin subunit protects the infant murine lung against IL-1β–induced inflammation and injury.
IL-1; chemokine; inflammation; lung development; chronic lung disease
Despite notable advances in neonatal care, bronchopulmonary dysplasia (BPD) remains an important complication of preterm birth, frequently resulting in prolonged hospital stay and long-term morbidity.
A historical cohort study of all preterm infants (gestational age younger than 37 weeks) admitted to the Montreal Children’s Hospital (Montreal, Quebec) between January 1, 1980, and December 31, 1992, was conducted. Information collected included demographic data, maternal and perinatal history, and main neonatal outcomes. Independent risk factors associated with BPD were identified by univariate analysis using one-way ANOVA, t tests or Mantel-Haenszel χ2 testing. Severity of disease was studied using an ordinal multinomial logistic regression model.
In total, 1192 preterm infants were admitted, of whom 551 developed respiratory distress syndrome and 322 developed BPD. For each additional week of prematurity, the risk of developing BPD increased by 54% (adjusted OR 1.54/week [95% CI 1.45 to 1.64]). For each point subtracted on the 1 min Apgar score, the risk of developing BPD was increased by 16% (OR 1.16 [95% CI 1.1 to 1.3]). BPD was also associated with the presence of patent ductus arteriosus (OR 3.5 [95% CI 2.1 to 6.0]), pneumothorax in the first 48 h (OR 9.4 [95% CI 3.6 to 24.8]) or neonatal pneumonia/sepsis in the neonatal period (OR 1.9 [95% CI 1.1 to 3.2]). Severity of BPD was associated with gestational age, 1 min Apgar score, very low birth weight and the presence of neonatal pneumonia/sepsis.
Factors associated with BPD following a preterm birth were the degree of prematurity, birth weight, Apgar score at 1 min, and the presence of patent ductus arteriosus, pneumothorax or neonatal pneumonia/sepsis.
Bronchopulmonary dysplasia; Infant; Newborn; Premature; Respiratory distress syndrome
AIM—To evaluate the relative importance of
biochemical markers of antioxidant status, gestational age, and
parameters of neonatal care in the clinical outcome of premature infants.
METHOD—A prospective, observational, longitudinal
study of the association between these factors was conducted. Blood was
collected from an in situ arterial line within two hours of birth and
at intervals thereafter, when blood was drawn for routine clinical purposes. Outcome was assessed as death, or survival with or without bronchopulmonary dysplasia (BPD). One hundred and forty four babies of
22 to 39 weeks of gestation, who required intensive care at the Jessop
Hospital for Women, between January 1993 and April 1994, were recruited.
RESULTS—Low gestational age at birth was the
most important predictor of mortality and the development of BPD.
Having corrected for gestational age, low plasma antioxidant activity
at birth was an independent risk factor for mortality. Plasma vitamin C
at birth was significantly higher in the babies who died compared with
those with a good outcome, but this effect was not sustained after
correcting for gestational age. Repeated measures of Analysis of
Variance revealed a postnatal increase in antioxidant activity, caeruloplasmin, retinol, cholesterol corrected α tocopherol, and red
blood cell superoxide dismutase (SOD) activity. Vitamin C, on the other
hand, declined in all groups after birth. Logistic regression analysis
revealed that the greater the number of packed cell transfusions
received during intensive care, and the higher the concentration of
vitamin C on the second day of life, the greater the risk of developing BPD.
CONCLUSIONS—After correcting for the
effect of gestational age, low plasma antioxidant activity at birth
was an independent risk factor for mortality. Frequent blood cell
transfusions over the first week of life are associated with an
increased risk of developing BPD. This association may be causal.