Carey, William A.

CONTEXT:The effectiveness of many interventions aimed at reducing the risk of retinopathy has not been well established.OBJECTIVE:To estimate the effectiveness of nutritional interventions, oxygen saturation targeting, blood transfusion management, and infection prevention on the incidence of retinopathy of prematurity (ROP).DATA SOURCES:A comprehensive search of several databases was conducted, including Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through March 2014.STUDY SELECTION:We included studies that evaluated nutritional interventions, management of supplemental oxygen, blood transfusions, or infection reduction and reported the incidence of ROP and mortality in neonates born at <32 weeks.DATA EXTRACTION:We extracted patient characteristics, interventions, and risk of bias indicators. Outcomes of interest were any stage ROP, severe ROP or ROP requiring treatment, and mortality.RESULTS:We identified 67 studies enrolling 21 819 infants. Lower oxygen saturation targets reduced the risk of developing any stage ROP (relative risk [RR] 0.86, 95% confidence interval [CI], 0.77–0.97) and severe ROP or ROP requiring intervention (RR 0.58, 95% CI, 0.45–0.74) but increased mortality (RR 1.15, 95% CI, 1.04–1.29). Aggressive parenteral nutrition reduced the risk of any stage ROP but not severe ROP. Supplementation of vitamin A, E, or inositol and breast milk feeding were beneficial but only in observational studies. Use of transfusion guidelines, erythropoietin, and antifungal agents were not beneficial.LIMITATIONS:Results of observational studies were not replicated in randomized trials. Interventions were heterogeneous across studies.CONCLUSIONS:At the present time, there are no safe interventions supported with high quality evidence to prevent severe ROP.

BACKGROUND AND OBJECTIVE: Among children with end-stage renal disease (ESRD), those who initiated chronic dialysis during the first year of life historically were less likely to survive or receive a kidney transplant compared with those who initiated dialysis later in childhood. We hypothesized that recently treated infants have experienced improved outcomes. METHODS: We queried the North American Pediatric Renal Trials and Collaborative Studies database, obtaining information on 628 children who initiated maintenance peritoneal dialysis for treatment of ESRD at <1 year of age. We further subcategorized these children by age (neonates, ≤31 days and infants, 32–365 days) and date of dialysis initiation (past, 1992–1999, and recent, 2000–2012). RESULTS: Survival while on dialysis and overall survival were significantly better among neonates and infants in the recent cohort. Overall survival at 3 years after dialysis initiation was 78.6% and 84.6% among the recently treated neonates and infants, respectively. Neonates and infants in the recent cohort also were more likely to terminate dialysis for transplantation, and graft survival was improved among recently transplanted infants (3-year graft survival 92.1%). CONCLUSIONS: Among children who initiate chronic peritoneal dialysis for treatment of ESRD in the first year of life, survival has improved in recent years. Graft survival also has improved for the subset of these patients who received a kidney transplant.

AbstractCNSregeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long‐term prognosis in patients. Approachable molecular targets that stimulateCNSrepair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibodyHIgM12.HIgM12 reverses motor deficits in chronically demyelinated mice, a model ofMS. Here, we identified polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) as the antigen forHIgM12 by using differentNCAMknockout strains and throughPSAremoval from theNCAMprotein core. Antibody binding toCNStissue and primary cells, antibody‐mediated cell adhesion, and neurite outgrowth onHIgM12‐coated nitrocellulose was detected only in the presence ofPSAas assessed by western blotting, immunoprecipitation, immunocytochemistry, and histochemistry. We conclude thatHIgM12 mediates it'sin vivoandin vitroeffects through binding toPSAand has the potential to be an effective therapy forMSand neurodegenerative diseases.imageThe human antibody HIgM12 stimulates neurite outgrowthin vitroand promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)‐positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro‐motor disorders including multiple sclerosis.

BACKGROUND:Inhaled nitric oxide (iNO) therapy is an off-label medication in infants <34 weeks’ gestational age. In 2011, the National Institutes of Health released a statement discouraging routine iNO use in premature infants. The objective of this study was to describe utilization patterns of iNO in American NICUs in the years surrounding the release of the National Institutes of Health statement. We hypothesized that iNO prescription rates in premature infants have remained unchanged since 2011.METHODS:The Pediatrix Medical Group Clinical Data Warehouse was queried for the years 2009–2013 to describe first exposure iNO use among all admitted neonates stratified by gestational age.RESULTS:Between 2009 and 2013, the rate of iNO utilization in 23- to 29-week neonates increased from 5.03% to 6.19%, a relative increase of 23% (confidence interval: 8%–40%; P = .003). Of all neonates who received iNO therapy in 2013, nearly half were <34 weeks’ gestation, with these infants accounting for more than half of all first exposure iNO days each year of the study period.CONCLUSIONS:The rates of off-label iNO use in preterm infants continue to rise despite evidence revealing no clear benefit in this population. This pattern of iNO prescription is not benign and comes with economic consequences.

Supplemental oxygen, used to treat hypoxia in preterm and term neonates, increases the risk of neonatal lung diseases, such as bronchopulmonary dysplasia (BPD) and asthma. There is a known sex predilection for BPD, but the underlying mechanisms are not clear. We tested the hypothesis that altered, local estradiol following hyperoxia contributes to pathophysiological changes observed in immature lung. In human fetal airway smooth muscle (fASM) cells exposed to normoxia or hyperoxia, we measured the expression of proteins involved in estrogen metabolism and cell proliferation responses to estradiol. In fASM cells, CYP1a1 expression was increased by hyperoxia, whereas hyperoxia-induced enhancement of cell proliferation was blunted by estradiol. Pharmacological studies indicated that these effects were attributable to upregulation of CYP1a1 and subsequent increased metabolism of estradiol to a downstream intermediate 2-methoxyestradiol. Microarray analysis of mouse lung exposed to 14 days of hyperoxia showed the most significant alteration in CYP1a1 expression, with minimal changes in expression of five other genes related to estrogen receptors, synthesis, and metabolism. Our novel results on estradiol metabolism in fetal and early postnatal lung in the context of hyperoxia indicate CYP1a1 as a potential mechanism for the protective effect of estradiol in hyperoxia-exposed immature lung, which may help explain the sex difference in neonatal lung diseases.

For more than a decade there has been considerable interest in the role of QT interval prolongation in the pathogenesis of sudden infant death syndrome. It has been proposed that the QT interval is a surrogate marker for autonomic instability and can be used to identify infants at risk for significant morbidity and mortality, including sudden infant death syndrome. We present the case of an infant that experienced a significant increase in his QTc, as detected by continuous QTc monitoring in the NICU after repositioning from a supine to prone position. This increase from a 413 ± 6 millisecond baseline average to 500 milliseconds was sustained for 2 hours and associated with clinically relevant apnea that ultimately required repositioning of the infant back to the supine position. Repositioning resulted in an immediate decrease of the QTc back to the previous baseline and termination of the apneic events. This case demonstrates an example of how the use of continuous QTc monitoring in the NICU setting may be used to detect QTc-accentuating factors in real time and identify situations that cause perturbations in an infant’s autonomic nervous system.

BACKGROUND AND OBJECTIVE: Previous studies suggest that former late preterm infants are at increased risk for learning and behavioral problems compared with term infants. These studies have primarily used referred clinical samples of children followed only until early school age. Our objective was to determine the cumulative incidence of attention deficit/hyperactivity disorder (ADHD) and learning disabilities (LD) in former late preterm versus term infants in a population-based birth cohort. METHODS: Subjects included all children born 1976 to 1982 in Rochester, MN who remained in the community after 5 years. This study focused on the comparison of subjects in 2 subgroups, late preterm (34 to <37 weeks) and term (37 to <42 weeks). School and medical records were available to identify individuals who met research criteria for ADHD and LD in reading, written language, and math. The Kaplan-Meier method was used to estimate the cumulative incidence of each condition by 19 years of age. Cox models were fit to evaluate the association between gestational age group and condition, after adjusting for maternal education and perinatal complications. RESULTS: We found no statistically significant differences in the cumulative incidence of ADHD or LD between the late preterm (N = 256) versus term (N = 4419) groups: ADHD (cumulative incidence by age 19 years, 7.7% vs 7.2%; P = .84); reading LD (14.2% vs 13.1%; P = .57); written language LD (13.5% vs 15.7%; P = .36), and math LD (16.1% vs 15.5%; P = .89). CONCLUSIONS: These data from a population-based birth cohort indicate that former late preterm infants have similar rates of LD and ADHD as term infants.

Diabetic ketoacidosis (DKA) during pregnancy carries significant risk of intrauterine fetal demise, but little is known about its postnatal sequelae in surviving neonates. We report here the case of an infant who was born to a mother with White's class C diabetes mellitus during an episode of DKA. Throughout pregnancy her glucose control was suboptimal, as evidenced by a predelivery glycosylated hemoglobin level of 8.1%. At 33 weeks' gestation, the mother presented with nausea and vomiting, a serum glucose concentration of 575 mg/dL, and other metabolic derangements consistent with DKA. Despite rehydration and insulin therapy, fetal distress necessitated cesarean delivery. At birth the infant required intubation, but her clinical status quickly improved and she was extubated within the first day of life. However, on day-of-life 4 she exhibited seizure-like activity, and subsequent brain MRI revealed bilateral basal ganglia infarctions. Previous research has revealed that the keto acid β-hydroxybutyrate (β-OHB) can cross the placenta into the fetal circulation and thereafter accumulate in the fetal brain, which leads to severe metabolic derangements. Furthermore, β-OHB accumulates rapidly in the basal ganglia of older children during episodes of DKA, wherein its presence is associated with neuronal injury. We suspect that transplacental transfer of maternal β-OHB led to an acquired ketoacidosis in the fetus and that accumulation of β-OHB contributed to neuronal injury and subsequent infarction of the basal ganglia. Further research is necessary to better characterize neonatal complications of maternal DKA, as well as the possible inclusion of β-OHB levels in the goal-directed treatment of this disease.