A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant.

BACKGROUND: The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. METHODS: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. RESULTS: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. CONCLUSIONS: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids. IMPACT: Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia.

INTRODUCTION: Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown. METHODS AND RESULTS: This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients' vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h. DISCUSSION: Melatonin half-life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.

Natural History of Postnatal Cardiopulmonary Adaptation in Infants Born Extremely Preterm and Risk for Death or Bronchopulmonary Dysplasia.

OBJECTIVE: To study the natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and establish its association with death or bronchopulmonary dysplasia (BPD). STUDY DESIGN: This was a prospective, observational, cohort study of infants born extremely preterm (<29 weeks). Initial echocardiogram was performed at <48 hours of life, followed by serial echocardiograms every 24-48 hours until 14 days of life. Resolution or no resolution of pulmonary hypertension (PH) at 72-96 hours was considered normal or delayed postnatal cardiopulmonary adaptation, respectively. PH between 96 hours and 14 days was defined as subsequent PH. Elevated pulmonary artery pressure throughout the 14 days of life was considered persistent PH. BPD was assessed at 36 weeks of postmenstrual age. RESULTS: Sixty infants were enrolled; 2 died before a sequential echocardiogram could be done at 72-96 hours. Normal and delayed cardiopulmonary adaptation were noted in 26 (45%) and 32 (55%) infants, respectively. Five patterns of postnatal cardiopulmonary adaptation were recognized: normal without subsequent PH (n = 20), normal with subsequent PH (n = 6), delayed adaptation without subsequent PH (n = 6), delayed adaptation with subsequent PH (n = 16), and persistent PH (n = 10). Infants with delayed cardiopulmonary adaptation were of lower gestation and birth weight and required prolonged ventilation and supplemental oxygen (P < .05). On multivariate analysis, the incidence of death or BPD was significantly greater among infants with delayed adaptation (P < .001). CONCLUSION: Infants born extremely preterm have normal or delayed postnatal cardiopulmonary adaptation that can be complicated by subsequent or persistent PH. Delayed cardiopulmonary adaptation is associated independently with death or BPD.

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.

Receipt of palivizumab before birth hospitalization discharge among preterm infants in the United States.

OBJECTIVE: This study aims to determine predischarge palivizumab receipt prevalence among infants ≤ 36 weeks' gestational age. STUDY DESIGN: This retrospective cohort study used hospital discharge records from the Premier Perspective database (Premier Inc., Charlotte, NC) of infants ≤ 36 weeks' gestational age who were discharged home after birth hospitalization during the November-March respiratory syncytial virus (RSV) seasons from 2006 to 2011. Descriptive statistics were performed and logistic regression was employed to identify differences in categorical variables. RESULTS: Among infants ≤ 36 weeks' gestational age discharged home during the RSV seasons, 21.4 to 27.0% had a record of palivizumab receipt before discharge. Among infants ≤ 30 weeks' gestational age, palivizumab receipt was 82.3 to 88.8%. Receipt varied considerably at the hospital level, from 0 to 100%. CONCLUSION: This study improves our understanding of characteristics associated with predischarge palivizumab administration. The identified gaps in recommended care can help inform future implementation of palivizumab and other interventions to help improve the health of high-risk preterm infants in the United States.

Maternal recorded voice played to preterm infants in incubators reduces her own depression, anxiety and stress: a pilot randomized control trial.

OBJECTIVE: To study the effects of playing mother's recorded voice to preterm infants in the NICU on their mothers' mental health as measured by the Depression, Anxiety and Stress Scale -21 (DASS-21) questionnaire. DESIGN/METHODS: This was a pilot single center prospective randomized controlled trial done at a level IV NICU. The trial was registered at clinicaltrials.gov (NCT04559620). Inclusion criteria were mothers of preterm infants with gestational ages between 26wks and 30 weeks. DASS-21 questionnaire was administered to all the enrolled mothers in the first week after birth followed by recording of their voice by the music therapists. In the interventional group, recorded maternal voice was played into the infant incubator between 15 and 21 days of life. A second DASS-21 was administered between 21 and 23 days of life. The Wilcoxon rank-sum test was used to compare DASS-21 scores between the two groups and Wilcoxon signed-rank test was used to compare the pre- and post-intervention DASS-21 scores. RESULTS: Forty eligible mothers were randomized: 20 to the intervention group and 20 to the control group. The baseline maternal and neonatal characteristics were similar between the two groups. There was no significant difference in the DASS-21 scores between the two groups at baseline or after the study intervention. There was no difference in the pre- and post-interventional DASS-21 scores or its individual components in the experimental group. There was a significant decrease in the total DASS-21 score and the anxiety component of DASS-21 between weeks 1 and 4 in the control group. CONCLUSION: In this pilot randomized control study, recorded maternal voice played into preterm infant's incubator did not have any effect on maternal mental health as measured by the DASS-21 questionnaire. Data obtained in this pilot study are useful in future RCTs (Randomized Controlled Trial) to address this important issue.

Factors that affect the postnatal increase in superior mesenteric artery blood flow velocity in very low birth weight preterm infants.

OBJECTIVE: To identify factors related to the postnatal increase in superior mesenteric artery blood flow velocity (SMA BFV). STUDY DESIGN: SMA BFV was measured in 35 infants (birth weight 1047±246 g) on day of life (DOL) 1, 3, 5, 7 10 and 14. Latent curve modeling (LCM) was used to measure the longitudinal change in BFV for each subject, and the correlation between changes in BFV and baseline values. Non-parametric correlations were calculated between BFV and variables previously reported to be related to SMA BFV. RESULTS: There was significant variability in SMA BFV on DOL 1, a significant increase from DOL 1-14, and significant variability in the postnatal increase. Infants with higher enteral feeding volumes had greater increases, while infants receiving positive pressure ventilation or hyperalimentation had lower increases. CONCLUSIONS: Several clinical factors affect the postnatal increase in SMA BFV. The use of LCM is useful in longitudinal studies of very low birth weight (VLBW) infants, who are clinically and demographically heterogeneous.

Severity and Cost of RSV Hospitalization Among US Preterm Infants Following the 2014 American Academy of Pediatrics Policy Change.

The American Academy of Pediatrics (AAP) Committee on Infectious Diseases (COID) periodically publishes recommendations for respiratory syncytial virus (RSV) immunoprophylaxis (IP) use in pediatric patients considered to be at highest risk for severe RSV infection. In 2014, for the first time, the AAP COID stopped recommending the use of RSV IP for otherwise healthy infants born at 29 weeks' gestational age (wGA) or later, stating that RSV hospitalization (RSVH) rates in this population are similar to those of term infants. Subsequently, epidemiological studies in the US at national and regional levels provided evidence of the impact of the policy change in 29-34 wGA infants. The results of these studies demonstrated a significant decrease in IP use after 2014 that was associated with an increased rate of RSVH in 29-34 wGA infants and an increase in morbidities. RSVH-related morbidities included pediatric intensive care unit (ICU) admissions, an increased need for mechanical ventilation, and an increase in the length of stay. After the change in recommendations, the costs of RSVH also rose among 29-34 wGA infants. The severity of the illness and expenses associated with RSVH were generally higher among 29-34 wGA infants of younger chronologic age compared with older preterm infants. Overall, these studies underscore that 29-34 wGA infants continue to be a high-risk pediatric population that could benefit from the protection provided by RSV IP. On the basis of these data, in 2018, the National Perinatal Association developed guidelines that recommended RSV IP for all ≤ 32 wGA infants and 32-35 wGA infants with additional risk factors. Re-evaluation of the AAP COID policy is warranted in light of these observations.

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. Objectives: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. Design, Setting, and Participants: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. Interventions: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. Main Outcomes and Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. Results: A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). Conclusions and Relevance: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

Duration of significant patent ductus arteriosus and bronchopulmonary dysplasia in extremely preterm infants.

OBJECTIVE: To demonstrate the association between the duration of significant patent ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD) in extremely preterm infants. METHODS: All extremely preterm infants (<29 weeks) treated in our Neonatal Intensive Care Unit from January 2013 to March 2016 were included if their PDA status was confirmed at <7 days of life. Infants with genetic syndromes, complex congenital anomalies and insignificant PDAs were excluded. Total duration of significant PDA was estimated by reviewing serial echocardiograms. Significant PDA was diagnosed using our scoring system that was based upon echocardiographic parameters and clinical status of the infants. Study cohort was divided into four groups based on the duration of significant PDA. Group A-No PDA, Group B-PDA <1-week, Group C- PDA 1-2 weeks, and Group D-PDA >2 weeks. ANOVA and multivariate analysis were performed to compare the groups. RESULTS: There were 147 infants with no PDA (Group A), 50, 35, and 41 infants were enrolled in Groups B, C, and D, respectively. There were no differences in maternal and neonatal variables among groups except for the following: maternal smoking, chorioamnionitis, antenatal indomethacin, gestation, birth weight, mode of delivery and incidence of death or BPD. Logistic regression analysis showed that longer duration of significant PDA was associated with higher risk for death or BPD (adjusted OR 1.37, 95% CI 1.03-1.82). CONCLUSION: Longer duration of significant PDA is associated with the higher risk for BPD/death in extremely preterm infants.

Does the initial surgery for necrotizing enterocolitis matter? Comparative outcomes for laparotomy vs. peritoneal drain as initial surgery for necrotizing enterocolitis in infants <1000 g birth weight.

PURPOSE: Quantify short-term outcomes associated with initial surgery [laparotomy (LAP) vs. peritoneal drain (PD)] for necrotizing enterocolitis (NEC) in extremely-low-birth-weight (ELBW) infants. METHODS: Using the Children's Hospitals Neonatal Database, we identified ELBW infants <32 weeks' gestation with surgical NEC (sNEC). Unadjusted and multivariable regression analyses were used to estimate the associations between LAP (or PD) and death/short bowel syndrome (SBS) and length of stay (LOS). RESULTS: LAP was the more common initial procedure for sNEC (n = 359/528, 68%). Infants receiving LAP were older and heavier. Initial procedure was unrelated to death/SBS in both bivariate (LAP: 43% vs PD: 46%, p = 0.573) and multivariable analyses (OR = 0.89, 95% CI = 0.57, 1.38, p = 0.6). LAP was inversely related to mortality (29% vs. 41%, p < 0.007) in bivariate analysis, but not significant in multivariable analysis accounting for markers of preoperative illness severity. However, the association between LAP and SBS (14% vs. 5%, p = 0.012) remained significant in multivariable analyses (adjusted OR = 2.25, p = 0.039). LOS among survivors was unrelated to the first surgical procedure in multivariable analysis. CONCLUSION: ELBW infants who undergo LAP as the initial operative procedure for sNEC may be at higher risk for SBS without a clear in-hospital survival advantage or shorter hospitalization. LEVEL OF EVIDENCE: Level II.

Clinico-pathologic conference: persistent tachypnea in a 5-week-old boy.

The patient was a 5-week-old male admitted with tachypnea and increased respiratory: distress. Mother noted increased cough and increased work of breathing. There was no fever, congestion, or nasal discharge. Prior to presenting to the emergency room, he was given a bronchodilator nebulizer treatment at home with no improvement. Two weeks prior to the current admission, he was hospitalized in the pediatric intensive care unit for approximately two weeks for similar complaints. Physical examination on the current admission was significant for minimal nasal flaring and mild subcostal retractions, with intermittent oxygen requirement. Infectious workup was negative.

A National Survey of Neonatologists: Barriers and Prerequisites to Introduce Point-of-Care Ultrasound in Neonatal ICUs.

Point-of-care (POC) ultrasound refers to the use of portable imaging. Although POC ultrasound is widely available to the neonatologists in Australia and Europe, neonatologists in the United States report limited availability. Our objective was to seek the US neonatologists' perception of barriers and prerequisites in adopting POC ultrasound in neonatal intensive care units. An online survey link was sent via e-mail to 3000 neonatologists included in the database maintained by the American Academy of Pediatrics. Survey results (n = 574) were reported as percentage of total responses. Personal experience requiring an urgent sonography in managing cardiac tamponade or pleural effusion was reported by 78% respondents. However, emergent ultrasound (≤10 min) was not available in 80% of the neonatal intensive care units. We compared the responses based on years of clinical experience (>20 vs <20 years), with 272 (48%) neonatologist reporting more than 20 years of experience. Similarly, results from neonatal fellowship programs were compared with nonteaching/teaching hospitals, with 288 (50%) replies from neonatology fellowship programs. Compared with senior neonatologists, respondents with less than 20 years of clinical experience consider POC ultrasound enhances safety and accuracy of clinical procedures (87% vs 82%) and favor adopting POC ultrasound in clinical practice (92% vs 84%). There were no differences in opinion from neonatology fellowship programs compared with the nonteaching/teaching hospitals. Lack of training guidelines, inadequate support from local radiology department, and legal concerns were reported as the top 3 primary barriers in adopting POC ultrasound. If these barriers could be resolved, 89% respondents were inclined to adopt POC ultrasound in clinical practice.

The association of type of surgical closure on length of stay among infants with gastroschisis born≥34 weeks' gestation.

BACKGROUND/PURPOSE: The optimal surgical approach in infants with gastroschisis (GS) is unknown. The purpose of this study was to estimate the association between staged closure and length of stay (LOS) in infants with GS. DESIGN/METHODS: We used the Children's Hospital Neonatal Database to identify surviving infants with GS born ≥34 weeks' gestation referred to participating NICUs. Infants with complex GS, bowel atresia, or referred after 2 days of age were excluded. The primary outcome was LOS; multivariable linear regression was used to quantify the relationship between staged closure and LOS. RESULTS: Among 442 eligible infants, staged closure occurred in 68.1% and was associated with an increased median LOS relative to odds ration (OR):primary closure (37 vs. 28 days, p<0.001). This association persisted in the multivariable equation (ß=1.35, 95% CI: 1.21, 1.52, p<0.001) after adjusting for the presence of necrotizing enterocolitis, short bowel syndrome, and central-line associated bloodstream infections. CONCLUSIONS: In this large, multicenter cohort of infants with GS, staged closure was independently associated with increased LOS. These data can be used to enhance antenatal and pre-operative counseling and also suggest that some infants who receive staged closure may benefit from primary repair.

Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age.

BACKGROUND: Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. The authors hypothesised: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for intraventricular hemorrhage (IVH) (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age. DESIGN/METHODS: The authors retrospectively identified ELBW infants with SIP in the Neonatal Research Network's generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted OR for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18-22 months corrected age. RESULTS: Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25 to 2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or neurodevelopmental impairment (NDI) (adjusted OR 1.85; 95% CI 1.32 to 2.60) and NDI among survivors (adjusted OR 1.75, 95% CI 1.20 to 2.55). CONCLUSION: Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes.

Neurodevelopmental outcomes of triplets or higher-order extremely low birth weight infants.

BACKGROUND: Extremely low birth weight twins have a higher rate of death or neurodevelopmental impairment than singletons. Higher-order extremely low birth weight multiple births may have an even higher rate of death or neurodevelopmental impairment. METHODS: Extremely low birth weight (birth weight 401-1000 g) multiple births born in participating centers of the Neonatal Research Network between 1996 and 2005 were assessed for death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined by the presence of 1 or more of the following: moderate to severe cerebral palsy; mental developmental index score or psychomotor developmental index score less than 70; severe bilateral deafness; or blindness. Infants who died within 12 hours of birth were excluded. Maternal and infant demographic and clinical variables were compared among singleton, twin, and triplet or higher-order infants. Logistic regression analysis was performed to establish the association between singletons, twins, and triplet or higher-order multiples and death or neurodevelopmental impairment, controlling for confounding variables that may affect death or neurodevelopmental impairment. RESULTS: Our cohort consisted of 8296 singleton, 2164 twin, and 521 triplet or higher-order infants. The risk of death or neurodevelopmental impairment was increased in triplets or higher-order multiples when compared with singletons (adjusted odds ratio: 1.7 [95% confidence interval: 1.29-2.24]), and there was a trend toward an increased risk when compared with twins (adjusted odds ratio: 1.27 [95% confidence: 0.95-1.71]). CONCLUSIONS: Triplet or higher-order births are associated with an increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age when compared with extremely low birth weight singleton infants, and there was a trend toward an increased risk when compared with twins.

Twin gestation and neurodevelopmental outcome in extremely low birth weight infants.

OBJECTIVE: The purpose of this work was to compare the risk-adjusted incidence of death or neurodevelopmental impairment at 18 to 22 months' corrected age between twin and singleton extremely low birth weight infants. We hypothesized that twin gestation is independently associated with increased risk of death or adverse neurodevelopmental outcomes at 18 to 22 months' corrected age in these infants. METHODS: We conducted a retrospective study of inborn extremely low birth weight infants admitted to Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18 to 22 months' corrected age. Neurodevelopmental impairment, the primary outcome variable, was defined as the presence of any 1 of the following: moderate or severe cerebral palsy, severe bilateral hearing loss, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of <70. Death was included with neurodevelopmental impairment as a composite outcome. Results were compared for both twins, twin A, twin B, same-gender twins, unlike-gender twins, and singleton infants. Logistic regression analysis was performed to control for demographic and clinical factors that were different among the groups. RESULTS: The cohort of infants who either died or were assessed for neurodevelopmental impairment consisted of 7630 singleton infants and 1376 twins. Logistic regression adjusting for clinical and sociodemographic risk factors showed an increased risk of death or neurodevelopmental impairment for twins as a group when compared with the singletons. On analyzing twin A and B separately as well, risk of death or neurodevelopmental impairment was increased in both twin A and twin B. CONCLUSIONS: Twin gestation in extremely low birth weight infants is associated with an independent increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age compared with singleton-gestation infants. Both first- and second-born twins are at increased risk.