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Objective: To compare the safety and efficacy of the novel surfactant Surfaxin®, which contains KL4-peptide, against the predominately used animal derived (porcine) surfactant, Curosurf®, in the prevention of RDS. Methods: [...]

Background: Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community., Methods: Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein., Results: Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials., Conclusion: This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. STUDY PROTOCOL REGISTRATION: https://doi.org/10.1186/s13063-018-2934-7 ., (© 2024. The Author(s).)

Background: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age., Methods: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle., Discussion: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants., Trial Registration: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS., Competing Interests: Several authors of this paper (TS, TL-M, IH, MT, KA, TLe), and the INC were involved in the development of INC NAESS. There are however no commercial or financial relationships that could be construed as a potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salaets, Lacaze-Masmonteil, Hokuto, Gauldin, Taha, Smits, Thewissen, Van Horebeek, Shoraisham, Mohammad, Suzuki, Komachi, Michels, Turner, Allegaert and Lewis.)

Innovative therapeutic approaches are needed to alleviate the burden of life-limiting, rare, and chronic conditions affecting children, adolescents, and young adults (CAYA). This includes a need for improved access to both clinical research and to non-approved or off-label therapies, together with, ultimately, more therapies achieving regulatory approval in Canada. The single patient study (SPS), also known as an open label individual patient (OLIP) study, was introduced by Health Canada to open access to non-marketed drugs where a clinical trial is not readily available, but the drug is considered too investigational to be managed on a standard Special Access Program. SPS is designed for patients who have a serious or life-threatening condition and have exhausted available treatment options. Our report summarizes this relatively new development in the Canadian regulatory environment and highlights the opportunities and challenges as identified by regulators, pharmaceutical representatives, academic researchers, and patient/parent advocates., Competing Interests: RJD reports payment from Bayer Canada for chairing a virtual symposium. DAM received consulting fees from ymAbs Therapeutics, Clarity Pharmaceuticals and EUSA Pharma, payment/honoraria from HMP Global, Ology Medical Education, WebMD Global and Platform Q Health Education, and is on an advisory board for Clarity Pharmaceuticals and ymAbs Therapeutics. DAM also reports that his institution received a research grant from BMS. JAW reports that his institution received research funding from Novartis, Daiichi Sankyo and Syndax for a clinical trial, received payment from Amgen for an educational event, and participation on advisory boards for Jazz Pharmaceuticals. There are no other disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Competing interests: Catherine Litalien is a co-founder and the medical and scientific director of the Rosalind & Morris Goodman Family Pediatric Formulations Centre (GPFC) of the CHU Ste-Justine (unpaid). Andrea Gilpin was (at the time of article submission) and Sophie Bérubé is an employee of the GPFC. Charlotte Moore-Hepburn reports participation with the Canadian Paediatric Society and Children’s Mental Health Ontario. Michael Rieder holds the Chair in Pediatric Clinical Pharmacology from the Canadian Institutes of Health Research and GlaxoSmithKline at the University of Western Ontario. Stuart MacLeod has received consulting fees as a member of the scientific advisory committee for Reformulary Group and payment from the Ontario Genomics Institute for participation on the research oversight committee. No other competing interests were declared.

Objectives: International data on listeriosis during infancy from large populations are essential to guide evidence-based empiric antibiotic guidelines for sepsis in infancy. We aimed to determine the incidence, clinical manifestations, and outcome of listeriosis in infants <6 months of age in Canada and Switzerland., Methods: Prospective, active surveillance of listeriosis in infants <6 months of age was conducted through the Canadian Paediatric Surveillance Program (May 2015 to April 2017) and the Swiss Paediatric Surveillance Unit (April 2017 to March 2018). Confirmed and probable cases were included., Results: In Canada, eight sporadic listeriosis cases were reported (incidence, 1.1/100,000 live births/year). In Switzerland, four cases were reported (incidence, 4.5/100,000 live births/year) of which three were part of a confirmed outbreak with an unclear source. In the two countries, eight of the 12 cases (66.6%) presented as early-onset disease (within the first 7 days of life) and none presented after 28 days life., Conclusions: Neonatal listeriosis is rare. Infants presenting with sepsis, especially after 4 weeks of life, may not routinely require empiric antibiotic coverage for listeriosis. Outbreak-related cases still occur. Continued surveillance is important., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Topical nitroglycerin (TNG) ointment has been used for almost 3 decades to treat neonatal peripheral tissue ischemia, but this product is now no longer being produced by its Canadian manufacturer. Our aim was to investigate the efficacy and safety of TNG products in newborns in neonatal intensive care units., Methods: In this systematic review we searched Embase, CINAHL, MEDLINE, PubMed and Web of Science from inception to April 2020 for studies on the use of TNG products (TNG ointment, TNG spray, glyceryl trinitrate [GTN] patch) for the treatment of neonatal tissue ischemia. We did not apply language or study design limitations. Animal studies and duplicate records were excluded. Two reviewers screened and extracted data. The Tool for Evaluating the Methodological Quality of Case Reports and Case Series was used to assess the risk of bias of individual studies., Results: We included 23 articles (20 case reports, 2 case series and 1 retrospective audit) describing the use of TNG ointment, TNG spray or GTN patch in the treatment of 39 tissue ischemia events in 37 newborns. Twenty-three (62.2%), 12 (32.4%), 1 (2.7%) and 1 (2.7%) infants received TNG ointment, GTN patch, both TNG ointment and GTN patch, and TNG spray, respectively. Nineteen (76.0%) and 7 (53.8%) injuries treated with TNG ointment and GTN patch showed complete recovery, respectively. Two (16.7%) infants treated with GTN patch experienced adverse events (i.e., methemoglobinemia) requiring treatment discontinuation., Interpretation: TNG ointment presents a safe therapeutic modality for salvage therapy of neonatal tissue ischemia. Engagement of stakeholders is essential to address its recent commercial inaccessibility in Canada., Competing Interests: Competing interests: None declared., (© 2021 Joule Inc. or its licensors.)

Background: Optimal drug therapy in children relies on the availability of pediatric-specific information. We aimed to describe the current status of pediatric pharmacotherapy data in monographs of new drugs approved by Health Canada., Methods: In this descriptive analysis, we reviewed the quality and quantity of monographs of new drugs approved by Health Canada between Jan. 1, 2007, and Dec. 31, 2016. We excluded drugs withdrawn from the Canadian market and drugs with primary indications irrelevant to pediatrics. We determined the percentage of included drug monographs that listed pediatric-specific information., Results: During this study period, Health Canada approved 281 drugs, 270 of which met our inclusion criteria. Pediatric-specific information and indication were present in 127 (47.1%) and 75 (27.8%) of the drug monographs, respectively. Of all pediatric age groups, neonates had the lowest number of indications listed in the product monographs (7, 2.6%). Only 9 (60%) oral drugs indicated for children 6 years of age or younger were available in child-friendly, age-appropriate dosage forms., Interpretation: Most of the new drugs approved by Health Canada do not contain pediatric or neonatal indications in their product monographs, and therefore, are used "off-label." Regulatory mechanisms are required to promote both neonatal and pediatric drug development and submission of available pediatric data by manufacturers to Health Canada., Competing Interests: Competing interests: Anthony Chan has a patent issued for antithrombin-heparin covalent complex. No other competing interests were declared., (Copyright 2020, Joule Inc. or its licensors.)

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD., Competing Interests: Declarations of Interest The authors declare no competing interests., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

To be time and resource efficient in neonatal research and to answer clinically relevant questions with validity and generalizability, large numbers of infants from multiple hospitals need to be included. Multijurisdictional research in Canada is currently fraught with research ethics review process hurdles that lead to delays, administrative costs, and possibly termination of projects. We describe our experience applying for ethics review to 13 sites in 7 provinces for a project comparing two standard of care therapies for preterm born infants with respiratory distress syndrome. We welcome the current opportunity created by the Institute of Human Development Child and Youth Health and the Institute for Genetics, to collaboratively identify practical solutions that would benefit Canadian researchers, Research Ethics Boards, and children and families., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypoxic ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. Our study sought to examine whether patterns of newborn screening analytes differed between infants with and without neonatal HIE in order to identify opportunities for potential use of these analytes for diagnosis in routine clinical practice. We linked a population-based newborn screening registry with health databases to identify cases of HIE among term infants (≥37 weeks' gestation) in Ontario from 2010-2015. Correlations between HIE and screening analytes were examined using multivariable logistic regression models containing clinical factors and individual screening analytes (acyl-carnitines, amino acids, fetal-to-adult hemoglobin ratio, endocrine markers, and enzymes). Among 731,841 term infants, 3,010 were diagnosed with HIE during the neonatal period. Multivariable models indicated that clinical variables alone or in combination with hemoglobin values were not associated with HIE diagnosis. Although the model was improved after adding acyl-carnitines and amino acids, the ability of the model to identify infants with HIE was moderate. Our findings indicate that analytes associated with catabolic stress were altered in infants with HIE; however, future research is required to determine whether amino acid and acyl-carnitine profiles could hold clinical utility in the early diagnosis or clinical management of HIE. In particular, further research should examine whether cord blood analyses can be used to identify HIE within a clinically useful timeframe or to guide treatment and predict long-term health outcomes.

Infants born at ≤32 +6 weeks gestation are at higher risk for intracranial ischemic and hemorrhagic injuries, which often occur in the first 72 hours postbirth. Antenatal strategies to reduce the incidence of acute brain injuries include administering maternal corticosteroids and prompt antibiotic treatment for chorioamnionitis. Perinatal strategies include delivery within a tertiary centre, delayed cord clamping, and preventing hypothermia. Postnatal strategies include empiric treatment with antibiotics when chorioamnionitis is suspected, the cautious use of inotropes, the avoidance of blood PCO2 fluctuation, and neutral head positioning. Clinicians should be aware of the policies and procedures that, especially when combined, can provide neuroprotection for preterm infants.

Background: The management and outcomes of preterm births can vary greatly even among developed nations with the same access to medicine, technology and expertise. We aimed to compare aspects of obstetrical management and mortality for preterm infants in France and Ontario, Canada., Methods: The Better Outcomes Registry & Network (BORN) Information System in Ontario and Épidémiologique sur les petits âges gestationnels (EPIPAGE-2) in France collected information on maternal demographics, obstetrical characteristics, obstetrical interventions and neonatal outcomes for infants born between 22 and 34 weeks gestation. We used standardized covariate definitions and extracted data from 2011 (for EPIPAGE-2) and from 2012 and 2013 (for BORN) to conduct a cohort study comparing the 2 data sets (stratified into gestational age groups of 22-26, 27-31 and 32-34 wk) using multivariable logistic regression models., Results: Mothers in the BORN cohort were older (30.7 yr v. 29.6 yr) but less likely to have gestational hypertension (13.4% v. 17.9%) than those in the EPIPAGE-2 cohort. Infants from EPIPAGE-2 had lower birth weights (1.3 kg v. 1.5 kg) and were more likely to be born in an institution with level 3 care (71.9% v. 55.8%). After adjustment for these differences, there was significantly higher neonatal mortality among infants from EPIPAGE-2 in the 22-26 week gestation age group (adjusted odds ratio 2.81; 95% confidence interval 1.17 to 6.74)., Interpretation: Even after we adjusted for both intrinsic population differences and differences in management between Ontario and France, we found a higher rate of neonatal mortality at earlier gestational ages in France. This may be related to differences in ethical approaches and/or postnatal management and should be explored further., Competing Interests: Competing interests: None declared., (Copyright 2019, Joule Inc. or its licensors.)

Background: Parents take neonates to the emergency department for many reasons, often nonurgent, pressuring an already burdened system. We aimed to characterize these visits and families to identify potential strategies to decrease neonatal emergency department visits., Methods: We developed and implemented a survey that explored characteristics of neonates and parents/guardians evaluated in the emergency department, perspectives of parents and use of health care services. Parents presenting with a neonate to the emergency department in 5 large academic hospitals in Ontario were surveyed between December 2013 and June 2015. We used descriptive statistics to report survey data and explored correlations between factors., Results: A total of 1533 surveys were completed. The most common reasons for presenting were jaundice (441 [28.8%]) and feeding issues (251 [16.4%]). The majority of respondents (73.9% [1104/1494]) had received advice before going to the emergency department. In most cases (86.4% [954/1104]), this was from a health care provider, who frequently advised going to the emergency department. Although most parents (86.8% [1280/1475]) reported high confidence in caring for a sick or injured child, 42.3% (643/1519) were unsure of the severity, and most (90.4% [578/639]) of these parents felt that the infant required assessment immediately or the same day. Of parents who felt the condition was not serious, 83.2% (198/238) thought that same-day evaluation was required. Nearly half of respondents (44.4% [621/1400]) said they would have gone to their health care provider with a same-day appointment, and 28.1% (344/1225) would have gone to their care provider with a next-day appointment., Interpretation: Parents' reported confidence in caring for sick or injured infants does not match the perceived urgency of neonatal conditions, which likely contributes to emergency department overuse. Any system to decrease nonurgent emergency department use by neonates would need to be immediately responsive, providing same-day help., Competing Interests: Competing interests: None declared., (Copyright 2018, Joule Inc. or its licensors.)

The incidence of infant opioid withdrawal has grown rapidly in many countries, including Canada, in the last decade, presenting significant health and early brain development concerns. Increased prenatal exposure to opioids reflects rising prescription opioid use as well as the presence of both illegal opiates and opioid-substitution therapies. Infants are at high risk for experiencing symptoms of abstinence or withdrawal that may require assessment and treatment. This practice point focuses specifically on the effect(s) of opioid withdrawal and current management strategies in the care of infants born to mothers with opioid dependency.

Background: Preterm birth (birth before 37 wk of gestation) occurs in about 8% of pregnancies in Canada and is associated with high mortality and morbidity rates that substantially affect infants, their families and the health care system. Our overall goal is to create a transdisciplinary platform, the Canadian Preterm Birth Network (CPTBN), where investigators, stakeholders and families will work together to improve childhood outcomes of preterm neonates., Methods: Our national cohort will include 24 maternal-fetal/obstetrical units, 31 neonatal intensive care units and 26 neonatal follow-up programs across Canada with planned linkages to provincial health information systems. Three broad clusters of projects will be undertaken. Cluster 1 will focus on quality-improvement efforts that use the Evidence-based Practice for Improving Quality method to evaluate information from the CPTBN database and review the current literature, then identify potentially better health care practices and implement identified strategies. Cluster 2 will assess the impact of current practices and practice changes in maternal, perinatal and neonatal care on maternal, neonatal and neurodevelopmental outcomes. Cluster 3 will evaluate the effect of preterm birth on babies, their families and the health care system by integrating CPTBN data, parent feedback, and national and provincial database information in order to identify areas where more parental support is needed, and also generate robust estimates of resource use, cost and cost-effectiveness around preterm neonatal care., Interpretation: These collaborative efforts will create a flexible, transdisciplinary, evaluable and informative research and quality-improvement platform that supports programs, projects and partnerships focused on improving outcomes of preterm neonates., Competing Interests: Competing interests: None declared., (Copyright 2018, Joule Inc. or its licensors.)

Neonatal sepsis is associated with high mortality and morbidity, yet challenges with available diagnostic approaches can lead to delays in therapy. Our study assessed whether newborn screening analytes could be utilized to identify associations with neonatal sepsis. We linked a newborn screening registry with health databases to identify cases of sepsis among infants born in Ontario from 2010-2015. Correlations between sepsis and screening analytes were examined within three gestational age groups (early preterm: <34 weeks; late preterm: 34-36 weeks; term: ≥37 weeks), using multivariable logistic regression models. We started with a model containing only clinical factors, then added groups of screening analytes. Among 793,128 infants, 4,794 were diagnosed with sepsis during the neonatal period. Clinical variables alone or in combination with hemoglobin values were not strongly predictive of neonatal sepsis among infants born at term or late preterm. However, model fit improved considerably after adding markers of thyroid and adrenal function, acyl-carnitines, and amino acids. Among infants born at early preterm gestation, neither clinical variables alone nor models incorporating screening analytes adequately predicted neonatal sepsis. The combination of clinical variables and newborn screening analytes may have utility in identifying term or late preterm infants at risk for neonatal sepsis.

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10 -6 ). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10 -4 ) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10 -5 ), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

Objectives: To compare the efficacy and safety of poractant alfa and bovine lipid extract surfactant in preterm infants., Study Design: Randomized, partially-blinded, multicenter trial. Infants <32 weeks needing surfactant before 48 hours were randomly assigned to receive poractant alfa or bovine lipid extract surfactant. The primary outcome was being alive and extubated at 48 hours post-randomization. Secondary outcomes included need for re-dosing, duration of respiratory support and oxygen, bronchopulmonary dysplasia, mortality and complications during administration., Results: Three centers recruited 87 infants (mean 26.7 weeks and 906 grams) at a mean age of 5.9 hours, between March 2013 and December 2015. 21/42 (50%) were alive and extubated at 48 hours in the poractant alfa group vs 26/45 (57.8%) in the bovine lipid extract surfactant group; adjusted OR 0.76 (95% CI 0.30-1.93) (p = 0.56). No differences were observed in the need to re-dose. Duration of oxygen support (41.5 vs 62 days; adjusted OR 1.69 95% CI 1.02-2.80; p = 0.04) was reduced in infants who received poractant alfa. We observed a trend in bronchopulmonary dysplasia among survivors (51.5% vs 72.1%; adjusted OR 0.35 95%CI 0.12-1.04; p = 0.06) favoring poractant alfa. Twelve infants died before discharge, 9 in the poractant alfa group and 3 in the bovine lung extract group. Severe airway obstruction following administration was observed in 0 (poractant alfa) and 5 (bovine lipid extract surfactant) infants (adjusted OR 0.09 95%CI <0.01-1.27; p = 0.07)., Conclusion: No statistically significant difference was observed in the proportion of infants alive and extubated within 48h between the two study groups. Poractant alfa may be more beneficial and associated with fewer complications than bovine lipid extract surfactant. However, we observed a trend towards higher mortality in the poractant alfa group. Larger studies are needed to determine whether observed possible benefits translate in shorter hospital admissions, or other long term benefits and determine whether there is a difference in mortality.

Background: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU., Methods: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations., Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome., Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU., (© 2016 Canadian Medical Association or its licensors.)

Objective: To evaluate the efficacy, safety, and maternal satisfaction of a newly established integrative postpartum community-based clinic providing comprehensive support for mothers during the first month after discharge from the hospital. Our primary interests were breastfeeding rates, readmission and patient satisfaction., Methods: A randomized controlled trial was conducted in Ottawa, Canada, where 472 mothers were randomized via a 1:2 ratio to either receive standard of care (n = 157) or to attend the postpartum breastfeeding clinic (n = 315). Outcome data were captured through questionnaires completed by the participants at 2, 4, 12 and 24 weeks postpartum. Unadjusted and adjusted logistic regression models were conducted to determine the effect of the intervention on exclusive breastfeeding at 12 weeks (primary outcome). Secondary outcomes included breastfeeding rate at 2, 4 and 24 weeks, breastfeeding self-efficacy scale, readmission rate, and satisfaction score., Results: More mothers in the intervention group (n = 195, 66.1%) were exclusively breastfeeding at 12 weeks compared to mothers in the control group (n = 81, 60.5%), however no statistically significant difference was observed (OR = 1.28; 95% CI:0.84-1.95)). The rate of emergency room visits at 2 weeks for the intervention group was 11.4% compared to the standard of care group (15.2%) (OR = 0.69; 95% CI: 0.39-1.23). The intervention group was significantly more satisfied with the overall care they received for breastfeeding compared to the control group (OR = 1.96; 95% CI: 3.50-6.88))., Conclusion: This new model of care did not significantly increase exclusive breastfeeding at 12 weeks. However, there were clinically meaningful improvements in the rate of postnatal problems and satisfaction that support this new service delivery model for postpartum care. A community-based multidisciplinary postpartum clinic is feasible to implement and can provide appropriate and highly satisfactory care to mother-baby dyads. This model of care may be more beneficial in a population that is not already predisposed to breastfeed., Trial Registration: ClinicalTrials.gov NCT02043119.

Reducing blood loss and the need for blood transfusions in extremely preterm infants is part of effective care. Delayed cord clamping is well supported by the evidence and is recommended for infants who do not immediately require resuscitation. Cord milking may be an alternative to delayed cord clamping; however, more research is needed to support its use. In view of concerns regarding the increased risk for cognitive delay, clinicians should avoid using hemoglobin transfusion thresholds lower than those tested in clinical trials. Higher transfusion volumes (15 mL/kg to 20 mL/kg) may decrease exposure to multiple donors. Erythropoietin is not recommended for routine use due to concerns about retinopathy of prematurity. Elemental iron supplementation (2 mg/kg/day to 3 mg/kg/day once full oral feeds are achieved) is recommended to prevent later iron deficiency anemia. Noninvasive monitoring (eg, for carbon dioxide, bilirubin) and point-of-care testing reduce the need for blood sampling. Clinicians should strive to order the minimal amount of blood sampling required for safe patient care, and cluster samplings to avoid unnecessary skin breaks.

Background: Recruitment is a challenge in developing population-representative pregnancy and birth cohorts., Methods: We developed a collaborative recruitment infrastructure (CRI) to recruit pregnant women for 4 pregnancy cohorts using: faxes from obstetrical offices, in-clinic recruiters, university and funder-driven free-media events, paid-media, and attendance at relevant tradeshows. Recruitment rates and demographic differences were compared between recruitment methods., Results: We received 5008 referrals over 40 months. Compared to fax, free-media referrals were 13 times more likely to be recruited (OR 13.0, 95% CI 4.2, 40.4: p < 0.001) and paid-media referrals were 4 times more likely to be recruited (OR 4.6, 95% CI 2.1, 10.3: p < 0.001). Among paid-media advertisements, free-to-read print (e.g. Metro) was the most effective (OR 3.3, 95% CI 2.3, 4.5: p < 0.05). Several demographic differences were identified between recruitment methods and against a reference population. Between recruitment methods, media recruits had a similar proportion families with incomes ≥ $40,000 (paid-media: 94.4%; free-media: 93.3%) compared to fax recruits (95.7%), while in-clinic recruits were less likely to have family incomes ≥ $40,000 (88.8%, p < 0.05). Maternal recruits from fax and in-clinic were more likely to attend university (Fax: 92.6%, in-clinic 89.8%) versus the reference population (52.0%; p < 0.05 for both) and both were less likely to smoke (Fax: 6.8%, in-clinic 4.2%) versus reference (18.6%; p < 0.05 for both). However, while fax referrals were more likely to be Caucasian (85.9% versus reference 77.5%; p < 0.05), in-clinic referrals were not significantly different (78.2%; P > 0.05)., Conclusion: Recruitment methods result in different recruitment rates and participant demographics. A variety of methods are required to recruit a generalizable sample.

Aim: To compare the original normative data of the Alberta Infant Motor Scale (AIMS) (n=2202) collected 20 years ago with a contemporary sample of Canadian infants., Method: This was a cross-sectional cohort study of 650 Canadian infants (338 males, 312 females; mean age 30.9 wks [SD 15.5], range 2 wks-18 mo) assessed once on the AIMS. Assessments were stratified by age, and infants proportionally represented the ethnic diversity of Canada. Logistic regression was used to place AIMS items on an age scale representing the age at which 50% of the infants passed an item on the contemporary data set and the original data set. Forty-three items met the criterion for stable regression results in both data sets., Results: The correlation coefficient between the age locations of items on the original and contemporary data sets was 0.99. The mean age difference between item locations was 0.7 weeks. Age values from the original data set when converted to the contemporary scale differed by less than 1 week., Interpretation: The sequence and age at emergence of AIMS items has remained similar over 20 years and current normative values remain valid. Concern that the 'back to sleep' campaign has influenced the age at emergence of gross motor abilities is not supported., (© 2014 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: From a public health perspective, the follow-up of women during pregnancy and the perinatal period requires quality communication and health services that take into account the context in which these women live. However, challenges related to access to health services in French in a minority situation have been documented in recent research. The objective of this pilot study is to better understand the perceptions, the lived experiences and the needs of pregnant Francophone women living in Canada within a linguistic minority context., Methods: Given the exploratory nature of the inquiry, a mixed method descriptive study was conducted in Alberta and New Brunswick, whose populations are 2% and 33% Francophone, respectively. Two semi-structured interviews and a series of validated questionnaires were administered to 21 pregnant women during the third trimester of pregnancy and at six weeks postnatal. Based on the questionnaires, a descriptive analysis documented participants' characteristics, and qualitative interviews were transcribed, coded and analyzed through an inductive process by four independent readers to uncover key themes related to the participants' experiences., Results: Most of the women were bilingual and language in which health services were received did not appear to be a major issue for them, except during times of stress and at critical periods of the pregnancy. In contrast, almost one third of the women reported being unsatisfied with services they had received and attributed this dissatisfaction to gaps in French language services., Conclusion: Women prefer to receive health services in their mother tongue, however services are delivered in English most of the time. Participants report that during times of stress and emergency, communication in French is essential to a quality follow-up of patients. Linguistic and cultural congruence seems to be a key factor for quality care during pregnancy. A comparative study would assist in better ascertaining the relative impact of language on Francophone women's lived experiences during pregnancy.

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD.

Background: Systemic inflammation, typically attributed to sepsis, has been repeatedly linked to adverse long-term outcomes in infants born prematurely. However, it is unclear whether other factors can contribute to potentially harmful systemic inflammatory responses., Objective: To determine the timing and extent of systemic inflammation occurring in absence of infection in preterm infants exposed to intensive care., Methods: First, we screened for inflammation biomarkers most strongly linked to infection in a large prospective cohort of 425 newborns (gestational age 24-42 weeks). Second, we longitudinally measured levels of infection-related inflammation biomarkers up to 42 days of post-natal life in a series of 58 infants born ≤30 weeks of gestation exposed to intensive care. Ante- or post-natal infections were excluded using stringent definitions including rigorous histological placental examination. Spearman correlations were used to identify putative clinical factors potentially linked to inflammation., Results: Three biomarkers were most strongly associated with neonatal sepsis (IL-6, IL-8 and G-CSF) in the first cohort. Using these markers, we found a predominant early high intensity systemic inflammation period within the first 72 h of preterm infants' extra-uterine life. Remarkably, this systemic inflammatory response was of magnitude comparable to that observed during sepsis in absence of ante- or post-natal signs of infection, and correlated with the amount of supplemental oxygen exposure (r=0.51-0.60)., Conclusions: Non-infectious sources of systemic inflammation are significant in preterm infants exposed to intensive care and may contribute to intensive care-related organ injury., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Infants born prematurely are highly vulnerable to infections and also exhibit a high susceptibility to organ damage due to inflammation., Methods: To investigate homeostatic immune control early in life, we used advanced multiparameter flow cytometry to compare responses to multiple Toll-like receptor (TLR) ligands in single cells and mononuclear cell populations in term neonates versus preterm neonates born before 29 weeks of gestation., Results: Preterm neonates had globally attenuated TLR-stimulated interleukin (IL)-6, interferon-α, and, to a lesser extent, tumor necrosis factor-α responses but demonstrated relative preservation of anti-inflammatory IL-10 responses in monocytes and dendritic cell subtypes. Remarkably, preterm neonates were also profoundly deficient in the common IL-12 and IL-23 cytokines' p40 subunit, which is critical for immunity against a wide variety of microbial pathogens in mice. Consistent with the increased susceptibility to infections resulting from the lack of IL-12/IL-23 in human newborns, significantly lower serum p40 concentrations were observed at birth in infants who developed early-onset sepsis., Conclusion: To our knowledge, this study is the first detailed analysis of multiple TLR function in neonates born extremely premature. Although attenuation of proinflammatory pathways may protect against tissue-damaging immunity early in life, this previously unrecognized p40 immune deficiency appears to result in considerably increased susceptibility to infection in human preterm newborns.

Chorioamnionitis is associated with increased lung and brain injury in premature infants. Ureaplasma is the microorganisms most frequently associated with preterm birth. Whether Ureaplasma-induced antenatal inflammation worsens lung and brain injury is unknown. We developed a mouse model combining antenatal Ureaplasma infection and postnatal oxygen exposure. Intraamniotic Ureaplasma Parvum (UP) increased proinflammatory cytokines in placenta and fetal lungs. Antenatal exposure to UP or broth caused mild postnatal inflammation and worsened oxygen-induced lung injury. Antenatal UP exposure induced central microgliosis and disrupted brain development as detected by decreased number of calbindin-positive and calretinin-positive neurons in the neocortex. Postnatal oxygen decreased calretinin-positive neurons in the neocortex but combined with antenatal UP exposure did not worsen brain injury. Antenatal inflammation exacerbates the deleterious effects of oxygen on lung development, but the broth effects prohibit concluding that UP by itself is a compounding risk factor for bronchopulmonary dysplasia. In contrast, antenatal UP-induced inflammation alone is sufficient to disturb brain development. This model may be helpful in exploring the pathophysiology of perinatal lung and brain injury to develop new protective strategies.

Transient local overexpression of genes that promote lung defense or repair may help to protect or promote alveolar development in premature neonates. We showed that the use of adenoviral vectors in neonates was limited by the induction of lung growth disorders. In the present work we compare the efficiency of gene transfer to the neonatal lung by three adeno-associated viral vectors: rAAV1, rAAV2, and rAAV5. Transduction efficiency was first measured in vitro, by infecting A549 immortalized human lung epithelial cells, and primary epithelial and mesenchymal cells isolated from human fetal lung. AAV vectors yielded similar low levels of luciferase gene expression in the different cell types. In vivo transduction efficiency was evaluated in newborn rats, with AAV-LacZ vectors being intratracheally instilled at 3 days of age. Both rAAV5 and rAAV1, but not rAAV2, induced significant lung beta-galactosidase expression, which persisted on day 35. Highest beta- galactosidase levels were measured with rAAV5, but remained far lower than those obtained with adenoviral vectors. A transient increase in alveolar macrophages was observed on day 6, but not on day 8, after rAAV5-LacZ instillation. Morphometric evaluation of lung structures was performed on day 21, and showed no altered lung growth. We conclude that rAAV1 or rAAV5 was more efficient at mediating gene transfer in the neonatal lung than was rAAV2, without adversely affecting lung development. However, in vivo transgene expression was relatively low, and needs to be improved for future therapeutic use of these adeno-associated vectors.

Classical serologic assays are not useful for the diagnosis of perinatal herpes simplex virus (HSV) infection during the acute phase of the disease. We report two cases of neonatal HSV infection that highlight the diagnostic value of HSV-specific IgG avidity and its contribution for further characterization of neonatal HSV infection.

The expression of the pulmonary surfactant protein A (SP-A) is developmentally regulated and controlled by several hormones. In an attempt to characterize cis-acting elements involved in the regulation of SP-A expression, we have cloned the 5' flanking sequence of the rat SP-A gene. The promoter region contains a TATA box but no CAAT box. The transcription start site has been identified by anchored polymerase chain reaction and S1 nuclease mapping of the mature and precursor transcripts. S1 mapping of precursor transcripts has confirmed the stimulating effect of glucocorticoids on SP-A rat gene transcription in vivo. This hormonal effect may be mediated by a putative glucocorticoid responsive element located 140 bp upstream from the initiation site and protected against DNase 1 digestion in footprinting experiments. In vitro transcription of a G-free reporter cassette linked to the 212-bp 5' flanking DNA fragment has established that this putative promoter region is functional. Efficient transcription of the G-free reporter cassette was obtained with cell-free fetal lung extracts, whereas no transcript was detectable with cell-free liver extracts. Comparative analysis of the human and rat 5' flanking sequences shows the presence of strongly conserved motifs, unrelated to previously known consensus sequences. Some of these motifs, specifically protected in DNase 1 footprinting studies, could therefore be involved in the regulation of SP-A gene expression.