William A. Carey

ADHD and Learning Disabilities in Former Late Preterm Infants: A Population-Based Birth Cohort

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.

MicroRNA-mRNA interactions in a murine model of hyperoxia-induced bronchopulmonary dysplasia

BackgroundBronchopulmonary dysplasia is a chronic lung disease of premature neonates characterized by arrested pulmonary alveolar development. There is increasing evidence that microRNAs (miRNAs) regulate translation of messenger RNAs (mRNAs) during lung organogenesis. The potential role of miRNAs in the pathogenesis of BPD is unclear.ResultsFollowing exposure of neonatal mice to 80% O2 or room air (RA) for either 14 or 29 days, lungs of hyperoxic mice displayed histological changes consistent with BPD. Comprehensive miRNA and mRNA profiling was performed using lung tissue from both O2 and RA treated mice, identifying a number of dynamically regulated miRNAs and associated mRNA target genes. Gene ontology enrichment and pathway analysis revealed that hyperoxia modulated genes involved in a variety of lung developmental processes, including cell cycle, cell adhesion, mobility and taxis, inflammation, and angiogenesis. MiR-29 was prominently increased in the lungs of hyperoxic mice, and several predicted mRNA targets of miR-29 were validated with real-time PCR, western blotting and immunohistochemistry. Direct miR-29 targets were further validated in vitro using bronchoalveolar stem cells.ConclusionIn newborn mice, prolonged hyperoxia induces an arrest of alveolar development similar to that seen in human neonates with BPD. This abnormal lung development is accompanied by significant increases in the levels of multiple miRNAs and corresponding decreases in the levels of predicted mRNA targets, many of which have known or suspected roles in pathways altered in BPD. These data support the hypothesis that dynamic regulation of miRNAs plays a prominent role in the pathophysiology of BPD.

Outcome of Patients Initiating Chronic Peritoneal Dialysis During the First Year of Life

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.

Off-Label Use of Inhaled Nitric Oxide After Release of NIH Consensus Statement

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.

Medical Management of Extremely Low-Birth-Weight Infants in the First Week of Life: A Survey of Practices in the United States

We sought to determine the current practices of neonatologists in their management of extremely low-birth-weight (< 1000 g) infants. We directly mailed an anonymous survey to the medical directors of 809 neonatal intensive care units in the United States. More than one-third of those surveyed responded, with a substantial majority from intensive care (level III) nurseries or extracorporeal membrane oxygenation centers. Academic centers and private practice environments were both well represented. Some traditional practices have changed, such as beginning resuscitation with 40% rather than 100% oxygen. Many practices vary based on whether neonates are cared for in private versus academic centers, including initial resuscitation method, type of ventilation used, use of intraventricular hemorrhage prophylaxis, and routine antibiotic therapy. Parenteral nutrition composition and the use of inhaled nitric oxide differ based on the responding centers participation in clinical trials. The number of years in practice as a neonatologist does not affect practice decisions. Among all our findings, the prevalence of one potentially harmful practice, the continued use of dexamethasone for corticosteroid therapy, was particularly noteworthy. In conclusion, the strength of evidence does not always predict whether practices are adopted or abandoned. Further research is necessary to clarify the optimal management for this high-risk patient population.

Survival of outborns with congenital diaphragmatic hernia: the role of protective ventilation, early presentation and transport distance: a retrospective cohort study

BackgroundCongenital diaphragmatic hernia (CDH) is a congenital malformation associated with life-threatening pulmonary dysfunction and high neonatal mortality. Outcomes are improved with protective ventilation, less severe pulmonary pathology, and the proximity of the treating center to the site of delivery. The major CDH treatment center in Croatia lacks a maternity ward, thus all CDH patients are transferred from local Zagreb hospitals or remote areas (outborns). In 2000 this center adopted protective ventilation for CDH management. In the present study we assess the roles of protective ventilation, transport distance, and severity of pulmonary pathology on survival of neonates with CDH.MethodsThe study was divided into Epoch I, (1990–1999, traditional ventilation to achieve normocapnia), and Epoch II, (2000–2014, protective ventilation with permissive hypercapnia). Patients were categorized by transfer distance (local hospital or remote locations) and by acuity of respiratory distress after delivery (early presentation-occurring at birth, or late presentation, ≥6 h after delivery). Survival between epochs, types of transfers, and acuity of presentation were assessed. An additional analysis was assessed for the potential association between survival and end-capillary blood CO2 (PcCO2), an indirect measure of pulmonary pathology.ResultsThere were 83 neonates, 26 in Epoch I, and 57 in Epoch II. In Epoch I 11 patients (42 %) survived, and in Epoch II 38 (67 %) (P = 0.039). Survival with early presentation (N = 63) was 48 % and with late presentation 95 % (P <0.001). Among early presentation, survival was higher in Epoch II vs. Epoch I (57 % vs. 26 %, P = 0.031). From multiple logistic regression analysis restricted to neonates with early presentation and adjusting for severity of disease, survival was improved in Epoch II (OR 4.8, 95%CI 1.3–18.0, P = 0.019). Survival was unrelated to distance of transfer but improved with lower partial pressure of PcCO2 on admission (OR 1.16, 95%CI 1.01–1.33 per 5 mmHg decrease, P = 0.031).ConclusionsThe introduction of protective ventilation was associated with improved survival in neonates with early presentation. Survival did not differ between local and remote transfers, but primarily depended on severity of pulmonary pathology as inferred from admission capillary PcCO2.

Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders

CNS regeneration 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 stimulate CNS repair 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 antibody HIgM12. HIgM12 reverses motor deficits in chronically demyelinated mice, a model of MS. Here, we identified polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) as the antigen for HIgM12 by using different NCAM knockout strains and through PSA removal from the NCAM protein core. Antibody binding to CNS tissue and primary cells, antibody‐mediated cell adhesion, and neurite outgrowth on HIgM12‐coated nitrocellulose was detected only in the presence of PSA as assessed by western blotting, immunoprecipitation, immunocytochemistry, and histochemistry. We conclude that HIgM12 mediates its in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases. The human antibody HIgM12 stimulates neurite outgrowth in vitro and 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.

Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle

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.

Perceptions and practices of therapeutic hypothermia in American neonatal intensive care units.

OBJECTIVE In 2005, therapeutic hypothermia (TH) was used in few American neonatal intensive care units (NICUs) with great variability in practices. We hypothesized that TH would be used with greater frequency and uniformity today. STUDY DESIGN We surveyed directors of 797 NICUs queried in our prior study to determine attitudes toward and practices of TH. RESULTS Of the 781 participants with valid addresses, we received completed surveys from 330 (42.3%). There was an increase in the number of respondents who believed that TH is effective (85% versus 31%, p < 0.0001). More NICUs used TH (50% versus 6%, p < 0.0001) and nearly all not offering TH transferred eligible neonates to centers that did (97% versus 29%, p < 0.0001). There has been increased standardization of TH practices with regard to enrollment criteria, duration, and methods of monitoring. CONCLUSION TH has become standard of care for the treatment of HIE in the United States. Most NICUs that use TH adhere to protocols, but variation still exists in TH practices.

Emergency Video Telemedicine Consultation for Newborn Resuscitations: The Mayo Clinic Experience

OBJECTIVE To describe the Mayo Clinic experience with emergency video telemedicine consultations for high-risk newborn deliveries. PATIENTS AND METHODS From March 26, 2013, through December 31, 2015, the Division of Neonatal Medicine offered newborn telemedicine consultations to 6 health system sites. A wireless tablet running secure video conferencing software was used by the local care teams. Descriptive data were collected on all consultations. After each telemedicine consult, a survey was sent to the neonatologist and referring provider to assess the technology, teamwork, and user satisfaction. RESULTS During the study, neonatologists conducted 84 telemedicine consultations, and 64 surveys were completed. Prematurity was the most frequent indication for consultation (n=32), followed by respiratory distress (n=15) and need for advanced resuscitation (n=14). After the consult, nearly one-third of the infants were able to remain in the local hospital. User assessment of the technology revealed that audio and video quality were poor or unusable in 16 (25%) and 12 (18.8%) of cases, respectively. Providers failed to establish a video connection in 8 consults (9.5%). Despite technical issues, providers responded positively to multiple questions assessing teamwork (86.0% [n=37 of 43] to 100.0% [n=17 of 17] positive responses per question). In 93.3% (n=14 of 15) of surveyed cases, the local provider agreed that the telemedicine consult improved patient safety, quality of care, or both. CONCLUSION Telemedicine consultation for neonatal resuscitation improves patient access to neonatology expertise and prevents unnecessary transfers to a higher level of care. A highly reliable technology infrastructure that provides high-quality audio and video should be considered for any emergency telemedicine service.