Dexamethasone, Prednisolone, and Methylprednisolone Use and 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants.

Importance: Practice variability exists in the use of corticosteroids to treat or prevent bronchopulmonary dysplasia in extremely preterm infants, but there is limited information on longer-term impacts. Objective: To describe the use of corticosteroids in extremely preterm infants and evaluate the association with neurodevelopmental outcomes. Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) randomized clinical trial, conducted at 19 participating sites and 30 neonatal intensive care units (NICUs) in the US. Inborn infants born between 24 0/7 and 27 6/7 weeks gestational age between December 2013 and September 2016 were included in analysis. Data analysis was conducted between February 2021 and January 2022. Exposures: Cumulative dose of dexamethasone and duration of therapy for dexamethasone and prednisolone or methyl prednisolone were evaluated. Main Outcomes and Measures: Demographic and clinical characteristics were described in infants who did or did not receive corticosteroids of interest and survived to discharge. Neurodevelopmental outcomes at 2 years of age were evaluated using the Bayley Scales of Infant Development-Third Edition (BSID-III) at corrected age 2 years. Results: A total of 828 extremely preterm infants (403 [49%] girls; median [IQR] gestational age, 26 [25-27] weeks) born at 19 sites who survived to discharge were included in this analysis, and 312 infants (38%) were exposed to at least 1 corticosteroid of interest during their NICU stay, including 279 exposed to dexamethasone, 137 exposed to prednisolone or methylprednisolone, and 79 exposed to both. Exposed infants, compared with nonexposed infants, had a lower birth weight (mean [SD], 718 [168] g vs 868 [180] g) and were born earlier (mean [SD] gestational age, 25 [1] weeks vs 26 [1] weeks). The median (IQR) start day was 29 (20-44) days for dexamethasone and 53 (30-90) days for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. The median (IQR) cumulative dose of dexamethasone was 1.3 (0.9-2.8) mg/kg. After adjusting for potential confounders, treatment with dexamethasone for longer than 14 days was associated with worse neurodevelopmental outcomes, with mean scores in BSID-III 7.4 (95% CI, -12.3 to -2.5) points lower in the motor domain (P = .003) and 5.8 (95% CI, -10.9 to -0.6) points lower in the language domain (P = .03), compared with unexposed infants. Conclusions and Relevance: These findings suggest that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at corrected age 2 years. Potential unmeasured differences in the clinical conditions of exposed vs unexposed infants may contribute to these findings. Improved standardization of treatment and documentation of indications would facilitate replication studies.

Postnatal maximal weight loss, fluid administration, and outcomes in extremely preterm newborns.

OBJECTIVE: Evaluate maximal weight loss (MWL) and total fluid administration (TFA) association in first week after birth with outcomes among extremely preterm (EP) newborns. STUDY DESIGN: We performed a retrospective analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating first-week MWL, TFA, and association with in-hospital outcomes. RESULTS: Among n = 883 included EP neonates, n = 842 survived ≥ 7 days and were included in outcome analyses. MWL between 5% to 15% was associated with decreased odds of necrotizing enterocolitis compared to MWL > 15% (OR 0.49, 95% CI 0.25-0.98). Average TFA > 150 mL/kg birthweight/day was associated with increased odds of necrotizing enterocolitis (OR 3.22, 95% CI 1.40-7.42) and patent ductus arteriosus requiring surgery (OR 2.14, 95% CI 1.10-4.15). CONCLUSION: MWL between 5% to 15% is a potentially optimal window of MWL. Increasing average TFA in the first week is associated with adverse neonatal outcomes. Prospective studies evaluating MWL and TFA and relationship to outcomes in EP neonates are needed. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273, https://clinicaltrials.gov/ct2/show/NCT01378273 .

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

OBJECTIVES: To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial.

BACKGROUND: In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants. METHODS: Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). FINDINGS: Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years. INTERPRETATION: Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice. FUNDING: PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

OBJECTIVES: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. STUDY DESIGN: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. RESULTS: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. CONCLUSIONS: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial.

OBJECTIVES: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). STUDY DESIGN: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. RESULTS: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. CONCLUSIONS: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01378273.

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age. Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Main Outcomes and Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. Conclusions and Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.

Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN).

BACKGROUND: To determine the prevalence and severity of acute kidney injury (AKI) at different time frames in relation to gestational age (GA) and birthweight (BW) in extremely low gestational age neonates (ELGAN). Our hypothesis is that ELGAN with lower GA and lower BW have higher AKI rates. METHODS: A total of 923 ELGAN enrolled in the Preterm Erythropoietin Neuroprotection Trial were evaluated from birth until death or hospital discharge. AKI was defined according to kidney disease: improving global outcomes (KDIGO) definition from clinically-derived serum creatinine (SCr) measurements. Severe AKI was defined as stage 2 or higher. RESULTS: For the entire cohort, 351/923 (38.0%, CI = 34.8-41.3%) had at least one episode of stage 1 or higher AKI and 168/923 (18.2%, CI = 15.7-20.7%) had at least one episode of severe (stage 2 or higher) AKI. The prevalence of AKI stage 1 or higher for the entire cohort during the early (days 3-7), middle (days 8-14), and late follow-up period (after day 14) was 112/923 (12.1%, CI = 10.0-14.3%), 142/891 (15.9%, CI = 13.5-18.4%), and 249/875 (28.5%, CI = 25.4-31.5%), respectively. The rates of severe AKI during the hospital course were 27.8%, 21.9%, 13.6%, and 9.4% for the 24-, 25-, 26-, and 27-week GA groups, respectively. AKI rates were significantly higher with decreasing GA and decreasing BW for stated time trends (all p < 0.01 using tests for trend). CONCLUSIONS: AKI is relatively common in ELGAN during their initial hospital course and is associated with lower GA and BW.

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.).

Acute Kidney Injury and Bronchopulmonary Dysplasia in Premature Neonates Born Less than 32 Weeks' Gestation.

OBJECTIVE: This study aimed to evaluate the association between acute kidney injury (AKI) and bronchopulmonary dysplasia (BPD) in infants born <32 weeks of gestational age (GA). STUDY DESIGN: Present study is a secondary analysis of premature infants born at <32 weeks of GA in the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) retrospective cohort (n = 546). We stratified by gestational age and used logistic regression to determine association between AKI and moderate or severe BPD/mortality. RESULTS: Moderate or severe BPD occurred in 214 of 546 (39%) infants, while death occurred in 32 of 546 (6%); the composite of moderate or severe BPD/death occurred in 246 of 546 (45%). For infants born ≤29 weeks of gestation, the adjusted odds ratio (OR) of AKI and the primary outcome was 1.15 (95% confidence interval [CI] = 0.47-2.86; p = 0.76). Infants born between 29 and 32 weeks of gestation with AKI had four-fold higher odds of moderate or severe BPD/death that remained after controlling for multiple factors (adjusted OR = 4.21, 95% CI: 2.07-8.61; p < 0.001). CONCLUSION: Neonates born between 29 and 32 weeks who develop AKI had a higher likelihood of moderate or severe BPD/death than those without AKI. Further studies are needed to validate our findings and evaluate mechanisms of multiorgan injury.

Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates.

Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14+CD16+ (double-positive) and CD14+CD16- (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life (DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.

Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes. STUDY DESIGN: A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (<24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed. RESULTS: In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1ß, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort. CONCLUSIONS: Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study. TRIAL REGISTRATION: ClinicalTrials.gov: 01913340.

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.

Vitamin A status after prophylactic intramuscular vitamin A supplementation in extremely low birth weight infants.

BACKGROUND: Vitamin A supplementation (VAS) is recommended to prevent bronchopulmonary dysplasia (BPD). Our objective was to evaluate the effect of VAS on vitamin A (VA) status. We hypothesized that VAS would improve VA status in extremely low birth weight (ELBW) infants. MATERIALS AND METHODS: Retrospective chart review of infants 1 year before and after initiation of VAS (5000 IU 3 times a week intramuscularly [IM]; total 12 doses). Linear regression was used to model impact of VAS on VA status (retinol level and retinol/retinol binding protein [RBP] ratio). Models were adjusted for time and generalized estimating equations were used to account for intraindividual correlation. RESULTS: Sixty-seven infants (mean gestational age 26 ± 2 weeks; mean body weight 803 ± 142 g) were included; 35 received VAS and 32 did not (no-VAS). Both groups had similar baseline characteristics. Infants who received VAS had mean retinol levels that were 9.0 mcg/dL (95% confidence interval [CI], 4.9-13.2; P < .001) higher and mean retinol/RBP ratios that were 0.21 (95% CI, 0.07-0.36; P = .005) higher than the no-VAS group. Retinol and retinol/RBP ratio increased with time (P < .001). Fewer infants in the VAS group had VA deficiency (retinol/RBP ratios <0.7) compared with the no-VAS group. Culture-positive sepsis was more common in the VAS group (48% vs 12%; P = .002). CONCLUSIONS: VA status in ELBW infants was improved and maintained over the first month of life with IM VAS. Because of concerns for potential risks of repeated injections, further studies are indicated to evaluate the optimal mode of VA delivery in preterm infants.

Effects of transfusions in extremely low birth weight infants: a retrospective study.

OBJECTIVES: To determine the risks and benefits associated with the transfusion of packed red blood cells (PRBCs) in extremely low birth weight (ELBW) infants. We hypothesized that when ELBW infants underwent transfusion with the University of Washington Neonatal Intensive Care Unit (NICU) 2006 guidelines, no clinical benefit would be discernible. STUDY DESIGN: We conducted a retrospective chart review of all ELBW infants admitted to the NICU in 2006. Information on weight gain, apnea, heart rate, and respiratory support was collected for 2 days preceding, the day of, and 3 days after PRBC transfusion. The incidence, timing, and severity of complications of prematurity were documented. RESULTS: Of the 60 ELBW infants admitted to the NICU in 2006, 78% received PRBC transfusions. Transfusions were not associated with improved weight gain, apnea, or ventilatory/oxygen needs. However, they were associated with increased risk of bronchopulmonary dysplasia, necrotizing enterocolitis, and diuretic use (P < .05). Transfusions correlated with phlebotomy losses, gestational age, and birth weight. No association was found between transfusions and sepsis, retinopathy of prematurity, or erythropoietin use. CONCLUSIONS: When our 2006 PRBC transfusion guidelines were used, no identifiable clinical benefits were identified, but increased complications of prematurity were noted. New, more restrictive guidelines were developed as a result of this study.

Effects of binge alcohol exposure in the second trimester on intracerebral arteriolar function in third trimester fetal sheep.

Fetal alcohol syndrome is a leading cause of mental retardation, but mechanisms of alcohol-associated brain damage remain elusive. Chronic alcohol exposure attenuates fetal and neonatal hypoxic cerebral vasodilation in sheep. We therefore hypothesized that alcohol could alter development of cerebrovascular responses to adenosine, a putative mediator of hypoxic cerebral vasodilation. The objective of this study was to examine the effect of earlier fetal alcohol exposure on later reactivity to adenosine in fetal sheep cerebral arterioles. Penetrating intracerebral arterioles were harvested from the brains of third trimester fetal sheep previously exposed in the second trimester to maternal alcohol "binges" (1.5 g/kg IV over 90 min, 5 days/week for 4 weeks) or same-volume saline infusions. Arterioles were cannulated with a micropipette system and luminally pressurized. Fetal alcohol exposure did not affect spontaneous myogenic tone, but enhanced the dilator response of penetrating arterioles to extraluminal acidosis (pH 6.8). Alcohol exposure also resulted in an increase in maximal vessel response to CGS-21680, an adenosine A2A receptor agonist, but did not alter the concentration-dependent response curves to adenosine. Our results suggest that earlier alcohol exposure does not impair the subsequent responsiveness of fetal cerebral arterioles to vasodilator agents. Thus, alteration in cerebral vascular response to hypoxia in fetal sheep may not be attributed to changes in vascular reactivity to adenosine.

Fetal alcohol exposure alters cerebrovascular reactivity to vasoactive intestinal peptide in adult sheep.

Chronic fetal alcohol exposure impairs neural and vascular development. We have previously shown that fetal alcohol exposure is associated with attenuated hypoxic cerebral vasodilation and reduced neuronal vasoactive intestinal peptide (VIP) expression in fetal sheep. In the present study, we tested the hypothesis that fetal alcohol exposure alters vascular development, leading to altered cerebral vascular reactivity to VIP in adulthood. Penetrating intracerebral arterioles were harvested from the brains of adult (10-13 months old) offspring of ewes that had received intravenous infusions of alcohol (1.5 g/kg) or same-volume saline (90 min/day, 5 days/week) during days 30-82 of gestation (full term = 145 days). The isolated arterioles were cannulated with a micropipette system that allowed luminal perfusion and control of luminal pressure and developed spontaneous tone at 40 degrees C and 60 mm Hg luminal pressure. There was no difference in myogenic tone between arterioles exposed prenatally to alcohol (n = 18) and saline controls (n = 17). However, fetal alcohol exposure significantly (p = 0.03) enhanced the dilator responses of adult intracerebral arterioles to VIP [0.1 nM to 1 microM, logEC(50): -8.6 +/- 0.2 (alcohol) vs. -7.4 +/- 0.8 (saline)]. In contrast, there was no difference in dilator responses to H(+) (pH 6.8 buffer), to adenosine (10 nM to 0.1 mM), or to CGS21680 (an adenosine A(2A) receptor agonist, 0.01 nM to 10 microM). Thus, fetal alcohol exposure alters vasomotor sensitivity to VIP in adult intracerebral arterioles - perhaps a compensatory response to alcohol-induced underdevelopment of neurotransmitter pathways involved in cerebral vascular regulation.

Inhaled nitric oxide in preterm infants undergoing mechanical ventilation.

BACKGROUND: Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial. METHODS: We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. RESULTS: Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns. CONCLUSIONS: Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).