Adaptive designs in clinical trials: a systematic review-part I.

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 .

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

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.

Availability of Safe and Effective Therapeutic Options to Pregnant and Lactating Individuals Following the United States Food and Drug Administration Pregnancy and Lactation Labeling Rule.

OBJECTIVE: To explore the extent and type of pregnancy and lactation data of newly approved prescription drugs and assess whether the presented recommendations are data-driven, as required by the US Food and Drug Administration Pregnancy and Lactation Labeling Rule implemented in 2015. STUDY DESIGN: In this descriptive analysis, we reviewed pregnancy and lactation data of all new molecular entities approved between 2001 and 2020 in their most updated labeling. Information was collected regarding the pregnancy and lactation risk statements, the source of pregnancy and lactation data, and the design and methods of pregnancy and lactation studies in the labeling. RESULTS: Of the 422 new molecular entities, the key advisory statement for use of 133 (32%) drugs in pregnancy and 194 (46%) drugs in lactation were classified as "against use." Less than 2% of all drugs had a key advisory statement that supported their use during pregnancy or lactation. The sources of data regarding use in pregnancy were studies in human and animals in 46 (11%) and 348 (82%) drugs, respectively. For use during lactation, data included studies in human and animals in 23 (5%) and 251 (59%) drugs, respectively. The key advisory recommendation was consistent with the available human information in 4 (8%) drugs in pregnancy and 3 (13%) drugs in lactation. Prescription drug labeling contains limited data to support informed decision-making for the use of prescription drugs during pregnancy/lactation. Close collaboration among stakeholders is required to enhance the availability of data in this population.

Technical Update No. 439: Antenatal Corticosteroids at Late Preterm Gestation.

OBJECTIVE: To update recommendations for administration of antenatal corticosteroids in the late preterm period. TARGET POPULATION: Pregnant individuals at risk of preterm birth from 340 to 366 weeks gestation. OPTIONS: Administration or non-administration of a single course of antenatal corticosteroids at 340 to 366 weeks gestation. OUTCOMES: Neonatal morbidity (respiratory distress, hypoglycemia), long-term neurodevelopment, and other long-term outcomes (growth, cardiac/metabolic, respiratory). BENEFITS, HARMS, AND COSTS: Administration of antenatal corticosteroids from 340 to 366 weeks gestation decreases the risk of neonatal respiratory distress but increases the risk of neonatal hypoglycemia. The long-term impacts of antenatal corticosteroid administration from 340 to 366 weeks gestation are uncertain. EVIDENCE: For evidence on the neonatal effects of antenatal corticosteroid administration at late preterm gestation, we summarized evidence from the 2020 Cochrane review of antenatal corticosteroids and combined this with evidence from published randomized trials identified by searching Ovid MEDLINE from January 1, 2020, to May 11, 2022. Given the absence of direct evidence on the impact of late preterm antenatal corticosteroid administration on neurodevelopmental outcomes, we summarized evidence on the impact of antenatal corticosteroids across gestational ages on neurodevelopmental outcomes using the following sources: (1) the 2020 Cochrane review; and (2) evidence obtained by searching Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to January 5, 2022. We did not apply date or language restrictions. Given the absence of direct evidence on the impact of late preterm antenatal corticosteroid administration on other long-term outcomes, we summarized evidence on the impact of antenatal corticosteroids across gestational ages on other long-term outcomes by combining findings from the 2020 Cochrane review with evidence obtained by searching Ovid MEDLINE for observational studies related to long-term cardiometabolic, respiratory, and growth effects of antenatal corticosteroids from inception to October 22, 2021. We reviewed reference lists of included studies and relevant systematic reviews for additional references. See Appendix A for search terms and summaries. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix B (Tables B1 for definitions and B2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Maternity care providers, including midwives, family physicians, and obstetricians. SUMMARY STATEMENTS: RECOMMENDATIONS.

Ensuring access to innovative therapies for children, adolescents, and young adults across Canada: The single patient study experience.

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.

Two-Thirds of Preterm Parents Would Participate in a Randomized Controlled Trial Comparing Double Doses of Steroids to a Single Dose and Placebo.

Animal research strongly suggests that a single dose of antenatal corticosteroids (ACS) is as effective as a double dose to mature preterm lungs; however, a human randomized controlled trial (RCT) is urgently needed. From August to November 2020, we conducted an online survey of Canadian parents of preterm infants. Survey respondents watched a parent-to-parent video introducing an RCT to study whether the standard double dose of ACS is non-inferior to a single dose (and matching placebo). Approximately two-thirds of respondents reported they were either likely or very likely to participate in the RCT, indicating high parental interest in and support for such a trial.

Listeriosis in infants: Prospective surveillance studies in Canada and Switzerland.

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.

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.

A call for a streamlined ethics review process for multijurisdictional, child health research studies.

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.

Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis.

OBJECTIVE: To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis. STUDY DESIGN: All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age. RESULTS: Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis. CONCLUSIONS: This individual patient data meta-analysis showed that early low-dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants.

Cell-based therapy for bronchopulmonary dysplasia in preterm infants 1.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Currently, there is no specific treatment available. Preclinical studies support cell therapy as a promising therapy for BPD in preterm infants. A successful translation to a safe and effective clinical intervention depends on multiple factors including the perspective of neonatal health care providers. A 2-hour workshop with 40 Canadian neonatologists was held to enhance the design of a phase II trial of stem cells for babies at risk for BPD, with a focus on the population to target and the outcomes to measure in such a trial. The consensus was that infants recruited in an early trial of stem cells should be the ones with the highest risk of developing severe BPD. This risk should be established based on known antenatal, perinatal, and postnatal risk factors. The primary outcome in a phase II trial will be focussed on a non-clinical outcome (e.g., a dose-finding study or a safety study). With other aspects of a translational study discussed, this workshop contributed to accelerate the design of a first Canadian clinical cell-therapy study for BPD in preterm infants.

Neuroprotection from acute brain injury in preterm infants.

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.

A Common Language: What Exactly Does 34 Weeks Gestation Mean?

There are multiple conventions for gestational age notation, which lead to different interpretations of completed weeks. This variability is exemplified by the different gestational age ranges recommended for administration of antenatal corticosteroid prophylaxis. Antenatal corticosteroid prophylaxis is widely recommended for women at risk of preterm delivery up to 34 completed weeks gestation. According to the World Health Organization, 34 completed weeks refers to the time period from the first day of the last menstrual period (day zero) to 34 weeks and 6 days of gestation (i.e., to 34+6 34 weeks, or 244 days gestation). However, an alternative convention interprets 34 completed weeks as the period from the first day of the last menstrual period to 33+6 36 weeks' gestation (i.e., 237 days' gestation). These inconsistencies in gestational age notation may have led to different practice recommendations for antenatal corticosteroid prophylaxis worldwide. Agreeing on the World Health Organization notation and interpretation of completed weeks may help promote clear communication within our discipline and more precise and effective knowledge dissemination.

No. 364-Antenatal Corticosteroid Therapy for Improving Neonatal Outcomes.

OBJECTIVE: To assess the benefits and risks of antenatal corticosteroid therapy for women at risk of preterm birth or undergoing pre-labour Caesarean section at term and to make recommendations for improving neonatal and long-term outcomes. OPTIONS: To administer or withhold antenatal corticosteroid therapy for women at high risk of preterm birth or women undergoing pre-labour Caesarean section at term. OUTCOMES: Perinatal morbidity, including respiratory distress syndrome, intraventricular hemorrhage, bronchopulmonary dysplasia, infection, hypoglycemia, somatic and brain growth, and neurodevelopment; perinatal mortality; and maternal morbidity, including infection and adrenal suppression. INTENDED USERS: Maternity care providers including midwives, family physicians, and obstetricians. TARGET POPULATION: Pregnant women. EVIDENCE: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to September 2017. Medical Subject Heading (MeSH) terms and key words related to pregnancy, prematurity, corticosteroids, and perinatal and neonatal mortality and morbidity were used. Statements from professional organizations including that of the National Institutes of Health, the American College of Obstetricians and Gynecologists, the Society for Maternal Fetal Medicine, the Royal College of Obstetricians and Gynaecologists, and the Canadian Pediatric Society were reviewed for additional references. Randomized controlled trials conducted in pregnant women evaluating antenatal corticosteroid therapy and previous systematic reviews on the topic were eligible. Evidence from systematic reviews of non-experimental (cohort) studies was also eligible. VALIDATION METHODS: This Committee Opinion has been reviewed and approved by the Maternal-Fetal Medicine Committee of the SOGC and approved by SOGC Council. BENEFITS, HARMS, AND/OR COSTS: A course of antenatal corticosteroid therapy administered within 7 days of delivery significantly reduces perinatal morbidity/mortality associated with preterm birth between 24 + 0 and 34 + 6 weeks gestation. When antenatal corticosteroid therapy is given more than 7 days prior to delivery or after 34 + 6 weeks gestation, the adverse effects may outweigh the benefits. Evidence on long-term effects is scarce, and potential neurodevelopment harms are unquantified in cases of late preterm, term, and repeated exposure to antenatal corticosteroid therapy. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to evaluate the need for a complete or partial update of the guideline. If important evidence is published prior to the 5-year time point, an update will be issued to reflect new knowledge and recommendations. SPONSORS: The guideline was developed with resources provided by the Society of Obstetricians and Gynaecologists of Canada with support from the Canadian Institutes of Health Research (APR-126338). SUMMARY STATEMENTS: RECOMMENDATIONS: Gestational Age Considerations Agents, Dosage, Regimen, and Target Timing Subpopulations and Special Consideration.

N° 364 - La Corticothérapie Prénatale Pour Améliorer Les Issues Néonatales.

OBJECTIF: Évaluer les avantages et les risques de la corticothérapie prénatale chez les femmes qui présentent un risque d'accouchement prématuré ou qui subissent une césarienne à terme avant début de travail, et formuler des recommandations visant l'amélioration des issues néonatales et des issues à long terme. OPTIONS: Administrer ou ne pas administrer une corticothérapie prénatale aux femmes qui présentent un risque élevé d'accouchement prématuré ou qui subissent une césarienne avant travail à terme. RéSULTATS: Morbidité périnatale, notamment le syndrome de détresse respiratoire, l'hémorragie intraventriculaire, la dysplasie bronchopulmonaire, l'infection, l'hypoglycémie, ainsi que les troubles de la croissance somatique et cérébrale et du neurodéveloppement; mortalité périnatale; et morbidité maternelle, notamment l'infection et la suppression surrénalienne. UTILISATEURS CIBLES: Fournisseurs de soins de maternité, notamment les sages-femmes, les médecins de famille et les obstétriciens. POPULATION CIBLE: Femmes enceintes. ÉVIDENCE: Nous avons interrogé les bases de données Medline, PubMed et Embase ainsi que la Bibliothèque Cochrane, de leur création au mois de septembre 2017. Nous nous sommes servis de Medical Subjet Headings (MeSH) et de mots clés en lien avec la grossesse, la prématurité, les corticostéroïdes ainsi que la mortalité et la morbidité périnatales et néonatales. Nous avons également consulté les déclarations d'organismes professionnels tels que les National Institutes of Health, l'American College of Obstetricians and Gynecologists, la Society for Maternal-Fetal Medicine, le Royal College of Obstetricians and Gynaecologists et la Société canadienne de pédiatrie pour obtenir des références additionnelles. Les essais cliniques randomisés évaluant la corticothérapie prénatale menés sur des femmes enceintes et les revues systématiques antérieures sur le sujet étaient admissibles, tout comme les données venant de revues systématiques d'études non expérimentales (études de cohorte). VALEURS: La présente opinion de comité a été révisée et approuvée par le Comité de médecine fœto-maternelle de la SOGC, et approuvée par le Conseil de la SOGC. AVANTAGES, INCONVéNIENTS ET COûTS: L'administration d'une corticothérapie prénatale dans les sept jours précédant l'accouchement réduit significativement la morbidité et la mortalité périnatales associées à la naissance prématurée survenant entre 24+0 et 34+6 semaines de grossesse. Si la corticothérapie prénatale est administrée plus de sept jours avant l'accouchement ou après 34+6 semaines de grossesse, les effets indésirables peuvent surpasser les avantages. Les données probantes sur l'impact à long terme de la corticothérapie prénatale sont rares. Par ailleurs, les effets neurodéveloppementaux néfastes potentiels de l'exposition répétée à la corticothérapie prénatale ou de l'administration de corticostéroïdes en période préterme tardive ou à terme n'ont pas été quantifiés. MIS-à-JOUR à LA DIRECTIVE: Une revue des données probantes sera menée cinq ans après la publication de la présente directive clinique afin d'évaluer si une mise à jour complète ou partielle s'impose. Si de nouvelles données probantes importantes sont publiées avant la fin de ces cinq ans, une mise à jour tenant compte des nouvelles connaissances et recommandations sera publiée. COMMANDITAIRES: La présente directive clinique a été élaborée à l'aide de ressources fournies par la Société des obstétriciens et gynécologues du Canada et avec l'appui des Instituts de recherche en santé du Canada (APR-126338). MOTS CLéS: Corticothérapie prénatale, maturation fœtale, prématurité, période préterme tardive, césarienne avant travail DÉCLARATION SOMMAIRES: RECOMMANDATIONS: Considérations relatives à l'âge gestationnel.

Managing infants born to mothers who have used opioids during pregnancy.

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.

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit.

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.