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Abstract Background: Minimally invasive surfactant therapy (MIST) is a new strategy to avoid mechanical ventilation (MV) in respiratory distress syndrome. The primary aim of this study was to test MIST as a means of avoiding MV exposure and pneumothorax occurrence in moderate and late preterm infants (32 to 36 weeks’ gestational age). Methods: This was a randomized controlled trial including three Canadian centres. Patients were randomized to standard management or to the intervention if they required nasal continuous positive airway pressure of 6 cm H2O and 35% FiO2 in the first 24 hours of life. Patients from the intervention group received MIST immediately after inclusion. The primary outcome was either need for MV or development of a pneumothorax requiring a chest tube. To ensure that clinicians were not biased toward delaying intubation in the intervention group, clinical failure criteria were also used as a primary outcome. The primary outcome was analyzed using bivariate and multivariate logistic regressions. Results: Among 45 randomized patients, 24 were assigned to MIST and 21 to standard management. Eight infants (33%) from the intervention group met the primary outcome criteria versus 19 (90%) in the control group (absolute risk reduction 0.57, 95% confidence interval 0.54 to 0.60). One patient in each group reached the primary outcome because of pneumothorax occurrence. The other patients were exposed to MV. None of the patients reached the clinical failure criteria. Conclusion: MIST for respiratory distress syndrome management in moderate and late preterm infants was associated with a significant reduction of MV exposure and pneumothorax occurrence.

ObjectiveTo compare neurodevelopmental outcomes of large and appropriate for gestational age (LGA, AGA) infants <29 weeks’ gestation at 18–24 months of corrected age.Study designRetrospective cohort study using the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network databases. Primary outcome was a composite of death or significant neurodevelopmental impairment (NDI), defined as severe cerebral palsy, Bayley III cognitive, language and motor scores of <70, need for hearing aids or cochlear implant and bilateral visual impairment. Univariate and multivariable logistic analyses were applied for outcomes.ResultsThe study cohort comprised 170 LGA and 1738 AGA infants. There was no difference in significant NDI or individual components of the Bayley III between LGA and AGA groups. LGA was associated with the increased risk of death by follow-up, 44/170 (25.9%) vs. 320/1738 (18.4%) (aOR: 1.60 95% CI: 1.00–2.54).ConclusionsRisk of NDI was similar between LGA and AGA infants.

ObjectiveTo compare neurodevelopmental outcomes of preterm infants at 18–21 months corrected age (CA) whose mothers smoked during pregnancy to those whose mothers did not smoke.Study designPreterm infants born at <29 weeks of gestation and evaluated at 18–21 months CA were included. Primary outcome was a composite outcome of death or neurodevelopmental impairment (NDI).ResultsOf a total of 2760 infants, 699 met exclusion criteria. Of the remaining 2061 infants, 280 (13.6%) were exposed to maternal smoking and 1781 (86.4%) were not. The odds of the composite outcome of death or NDI (aOR 1.40; 95% CI: 1.03–1.91), NDI alone (aOR 1.43; 95% CI: 1.01–2.03), and Bayley-III motor score <85 (aOR 1.91; 95% CI: 1.31–2.81) were higher in exposed infants.ConclusionsExposure to maternal smoking was associated with adverse composite outcome of death or NDI, NDI alone and lower motor scores at 18–21 months CA.

ObjectivesIdentify determinants of neurodevelopmental outcome in preterm children.MethodsProspective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death.ResultsOf the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38%–51%) had a NDI, 17% (11%–23%) had a sNDI, 6.4% (3.1%–8.6%) had CP, 2.6% (2.5%–13.3%) had hearing aids or cochlear implants and 1.6% (0%–3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3–4.3, 0.04–3.5 and 0.12–1.96, respectively.ConclusionMost preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes.

ObjectiveTo examine whether the family integrated care (FICare) programme, a multifaceted approach which enables parents to be engaged as primary caregivers in the neonatal intensive care unit, impacts infant neurodevelopment and growth at 18 months’ corrected age.Design/MethodsProspective cohort study of infants born <29 weeks’ gestational age (GA) who participated in the FICare cluster randomised control trial (cRCT) and were assessed in the Canadian Neonatal Follow-Up Network (CNFUN). The primary outcome measure, Cognitive or Language composite score <85 on the Bayley-III, was compared between FICare exposed and routine care children using logistic regression, adjusted for potential confounders and employing generalised estimation equations to account for clustering of infants within sites.ResultsOf 756 infants <29 weeks’ GA in the FICare cRCT, 505 were enrolled in CNFUN and 455 were assessed (238 FICare, 217 control). Compared with controls, FICare infants had significantly higher incidence of intraventricular haemorrhage (IVH) (19.5% vs 11.7%, p=0.024) and higher proportion of employed mothers (76.6% vs 73.6%, p=0.043). There was no significant difference in the odds of the primary outcome (adjusted OR: 0.92 (0.59 to 1.42) FiCare vs Control) on multivariable analyses adjusted for GA, IVH and maternal employment. However, Bayley-III Motor scores (adjusted difference in mean (95% CI) 3.87 (1.22 to 6.53) and body mass index 0.67 (0.36 to 0.99) were higher in the FICare group.ConclusionsVery preterm infants exposed to FICare had no significant difference in incidence of cognitive or language delay but had better motor development.Trial registration numberParticipants in this cohort study were previously enrolled in a registered trial: NCT01852695

ObjectiveTo assess the neurodevelopmental outcomes of preterm neonates who received inhaled nitric oxide (iNO) in the first week of age for hypoxaemic respiratory failure (HRF).MethodsIn this retrospective cohort study, we included neonates born at <29 weeks gestational age (GA) between January 2010 and December 2018 who had a neurodevelopmental assessment at 18–24 months corrected age (CA) at one of the Canadian Neonatal Follow-Up Network clinics. The primary outcome was neurodevelopmental impairment (NDI). We performed propensity score-matched analysis to compare the outcomes of those who received and did not receive iNO.ResultsOf the 5612 eligible neonates, 460 (8.2%) received iNO in the first week of age. Maternal age, receipt of antenatal corticosteroids, GA and birth weight were lower in the iNO group compared with the no-iNO group. Neonates in the iNO group had higher illness severity scores and higher rates of preterm prolonged rupture of membranes and were small for GA. Severe brain injury, bronchopulmonary dysplasia and mortality were higher in the iNO group. Of the 4889 survivors, 3754 (77%) neonates had follow-up data at 18–24 months CA. After propensity score matching, surviving infants who received rescue iNO were not associated with higher odds of NDI (adjusted OR 1.34; 95% CI 0.85 to 2.12).ConclusionsIn preterm neonates <29 weeks GA with HRF, rescue iNO use was not associated with worse neurodevelopmental outcomes among survivors who were assessed at 18–24 months CA.

ObjectivesHealth status (HS)/ health-related quality of life measures, completed by self or proxy, are important outcome indicators. Most HS literature on children born preterm includes adolescents and adults with limited data at preschool age. This study aimed to describe parent-reported HS in a large national cohort of extreme preterm children at preschool age and to identify clinical and sociodemographic variables associated with HS.MethodsInfants born before 29 weeks’ gestation between 2009 and 2011 were enrolled in a prospective longitudinal national cohort study through the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN). HS, at 36 months’ corrected age (CA), was measured with the Health Status Classification System for Pre-School Children tool completed by parents. Information about HS predictors was extracted from the CNN and CNFUN databases.ResultsOf 811 children included, there were 79, 309 and 423 participants in 23–24, 25–26 and 27–28 weeks’ gestational age groups, respectively. At 36 months’ CA, 78% had a parent-reported health concern, mild in >50% and severe in 7%. Most affected HS attributes were speech (52.1%) and self-care (41.4%). Independent predictors of HS included substance use during pregnancy, infant male sex, Score for Neonatal Acute Physiology-II, bronchopulmonary dysplasia, severe retinopathy of prematurity, caregiver employment and single caregiver.ConclusionMost parents expressed no or mild health concerns for their children at 36 months’ CA. Factors associated with health concerns included initial severity of illness, complications of prematurity and social factors.

Abstract Objective Survivors of extremely preterm birth are at risk of re-hospitalization but risk factors in the Canadian population are unknown. Our objective is to identify neonatal, sociodemographic, and geographic characteristics that predict re-hospitalization in Canadian extremely preterm neonates. Methods This is a retrospective analysis of a prospective observational cohort study that included preterm infants born 22 to 28 weeks’ gestational age from April 1, 2009 to September 30, 2011 and seen at 18 to 24 months corrected gestational age in a Canadian Neonatal Follow-Up Network clinic. Characteristics of infants re-hospitalized versus not re-hospitalized are compared. The potential neonatal, sociodemographic, and geographic factors with significant association in the univariate analysis are included in a multivariate model. Results From a total of 2,275 preterm infants born at 22 to 28 weeks gestation included, 838 (36.8%) were re-hospitalized at least once. There were significant disparities between Canadian provincial regions, ranging from 25.9% to 49.4%. In the multivariate logistic regression analysis, factors associated with an increased risk for re-hospitalization were region of residence, male sex, bronchopulmonary dysplasia, necrotizing enterocolitis, prolonged neonatal intensive care unit (NICU) stay, ethnicity, Indigenous ethnicity, and sibling(s) in the home. Conclusion Various neonatal, sociodemographic, and geographic factors predict re-hospitalization of extremely preterm infants born in Canada. The risk factors of re-hospitalization provide insights to help health care leaders explore potential preventative approaches to improve child health and reduce health care system costs.

ABSTRACT Objectives To determine the outcomes and resource usage of infants born at ≤ 25 weeks gestational age (GA). Methods Retrospective study of infants born between April 2009 and September 2011 at ≤ 25 weeks’ GA in all neonatal intensive care units in Canada with follow-up in the neonatal follow-up clinics. Short-term morbidities, neurodevelopmental impairment, significant neurodevelopmental impairment, and resource utilization of infants born at ≤ 24 weeks were compared with neonates born at 25 weeks. Results Of 803 neonates discharged alive, 636 (80.4%) infants born at ≤ 25 weeks’ GA were assessed at 18 to 24 months. Caesarean delivery, lower birth weight, and less antenatal steroid exposure were more common in infants born ≤ 24 weeks as compared with 25 weeks. They had significantly higher incidences of ductus arteriosus ligation, severe intracranial hemorrhage, retinopathy of prematurity as well as longer length of stay, central line days, days on respiratory support, days on total parenteral nutrition, days on antibiotics, and need for postnatal steroids. Neurodevelopmental impairment rates were 68.9, 64.5, and 55.6% (P=0.01) and significant neurodevelopmental impairment rates were 39.3, 29.6, and 20.9% (P<0.01) for infants ≤ 23, 24, and 25 weeks GA, respectively. Postdischarge service referrals were higher for those ≤ 23 weeks. Nonsurviving infants born at 25 weeks GA had higher resource utilization during admission than infants born less than 25 weeks. Conclusions Adverse outcomes and resource usage were significantly higher among infants born ≤ 24 weeks GA as compared with 25 weeks GA.

Hepatitis C virus (HCV) infection is a global health problem. A number of studies have implicated a direct role of cellular lipid metabolism in the HCV life cycle and inhibitors of the mevalonate pathway have been demonstrated to result in an antiviral state within the host cell. Transcriptome profiling was conducted on Huh-7 human hepatoma cells bearing subgenomic HCV replicons with and without treatment with 25-hydroxycholesterol (25-HC), an inhibitor of the mevalonate pathway that alters lipid metabolism, to assess metabolic determinants of pro- and antiviral states within the host cell. These data were compared with gene expression profiles from HCV-infected chimpanzees. Transcriptome profiling of Huh-7 cells treated with 25-HC gave 47 downregulated genes, 16 of which are clearly related to the mevalonate pathway. Fewer genes were observed to be upregulated (22) in the presence of 25-HC and 5 genes were uniquely upregulated in the HCV replicon bearing cells. Comparison of these gene expression profiles with data collected during the initial rise in viremia in 4 previously characterized HCV-infected chimpanzees yielded 54 overlapping genes, 4 of which showed interesting differential regulation at the mRNA level in both systems. These genes are PROX1, INSIG-1, NK4, and UBD. The expression of these genes was perturbed with siRNAs and with overexpression vectors in HCV replicon cells, and the effect on HCV replication and translation was assessed. Both PROX1 and NK4 regulated HCV replication in conjunction with an antiviral state induced by 25-hydroxycholesterol. Treatment of Huh-7 cells bearing HCV replicons with 25-HC leads to the downregulation of many key genes involved in the mevalonate pathway leading to an antiviral state within the host cell. Furthermore, dysregulation of a larger subset of genes not directly related to the mevalonate pathway occurs both in 25-HC-treated HCV replicon harbouring cells as well as during the initial rise in viremia in infected chimpanzees. Functional studies of 3 of these genes demonstrates that they do not directly act as antiviral gene products but that they indirectly contribute to the antiviral state in the host cell. These genes may also represent novel biomarkers for HCV infection, since they demonstrate an outcome-specific expression profile.