CPAP Versus NIPPV Postextubation in Preterm Neonates: A Comparative-Effectiveness Study.

BACKGROUND AND OBJECTIVES: Nasal intermittent positive pressure ventilation (NIPPV) has been shown to be superior to nasal continuous positive airway pressure (CPAP) postextubation in preterm neonates. However, studies have not permitted high CPAP pressures or rescue with other modes. We hypothesized that if CPAP pressures >8 cmH2O and rescue with other modes were permitted, CPAP would be noninferior to NIPPV. METHODS: We conducted a pragmatic, comparative-effectiveness, noninferiority study utilizing network-based real-world data from 22 Canadian NICUs. Centers self-selected CPAP or NIPPV as their standard postextubation mode for preterm neonates <29 weeks' gestation. The primary outcome was failure of the initial mode ≤72 hours. Secondary outcomes included failure ≤7 days, and reintubation ≤72 hours and ≤7 days. Groups were compared using a noninferiority adjusted risk-difference (aRD) margin of 0.05, and margin of no difference. RESULTS: A total of 843 infants extubated to CPAP and 974 extubated to NIPPV were included. CPAP was not noninferior (and inferior) to NIPPV for failure of the initial mode ≤72 hours (33.0% vs 26.3%; aRD 0.07 [0.03 to 0.12], Pnoninferiority(NI) = .86), and ≤7 days (40.7% vs 35.8%; aRD 0.09 [0.05 to 0.13], PNI = 0.97). However, CPAP was noninferior (and equivalent) to NIPPV for reintubation ≤72 hours (13.2% vs 16.1%; aRD 0.01 [-0.05 to 0.02], PNI < .01), and noninferior (and superior) for reintubation ≤7 days (16.4% vs 22.8%; aRD -0.04 [-0.07 to -0.001], PNI < .01). CONCLUSIONS: CPAP was not noninferior to NIPPV for failure ≤72 hours postextubation; however, it was noninferior to NIPPV for reintubation ≤72 hours and ≤7 days. This suggests CPAP may be a reasonable initial postextubation mode if alternate rescue strategies are available.

Maternal and neonatal complications during delivery according to passive versus active second stage in woman with medical conditions (ComPActSS).

Background: The incidence of serious complications during vaginal delivery with a passive second stage in women with medical conditions is unknown. Methods: Our retrospective cohort study with matched groups (pairing 1 passive with 2 active second stage) included women who had a medical delivery plan from the high risk obstetric team at our center. The primary outcome was a composite of major maternal and neonatal complications. Results: The primary outcome occurred in 50% (12/24) of women in the passive group versus 35.4% (17/48) (p = 0.24) in the active group. In the passive group, we observed a longer passive second stage of labor (28 vs. 8 min, p < 0.001), a tendency towards more assisted vaginal births (29.2% vs. 12.5%, p = 0.08), and more traumatic deliveries (16.7% vs. 0%, p = 0.012). Conclusion: The higher proportion of complications in women who had a passive second stage should encourage physicians to make this recommendation only in selected cases.

Just-In-Time Neonatal Endotracheal Intubation Simulation Training: A Randomized Controlled Trial.

OBJECTIVE: To assess if simulation-based just-in-time training (JITT, short video and simulation) is superior to video training (5-minute video) in acquiring skill in neonatal endotracheal intubation (ETI). STUDY DESIGN: A Canadian multicenter randomized trial recruited junior residents who performed neonatal ETI from July 2017 to June 2021. The primary outcomes were overall and first attempt ETI success rate. Secondary outcomes included number of attempts, duration of attempts, ETI-related complications, and residents' confidence level. Statistical analysis included generalized estimating equations, mixed model analysis, Mann-Whitney test, and χ² tests. RESULTS: Sixty-five residents performed 139 ETI. The overall success rate was similar for both groups (67% vs 70%, P = .71). However, the first attempt success rate was higher for the simulation-based JITT group (54% vs 41%, P = .035). The mean duration of attempts was shorter (35 [SD, 9] vs 62 [SD, 9] seconds, P = .048) and the median number of attempts had a tendency to be lower for the simulation-based JITT group (1 [IQR, 1; 1] vs 1 [IQR, 1; 2], P = .02). There were more mucosal trauma events in the simulation-based JITT group (P = .02). Residents in both groups reported similar confidence level in performing ETI. CONCLUSIONS: Compared with video training, simulation-based JITT for neonatal ETI did not improve overall success rate. However, simulation-based JITT improved first attempt success rate and decreased the number and the duration of ETI attempts. With its positive clinical impact, simulation-based JITT can become an educational adjunct to neonatal ETI training for residents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02809924.

Clinical burden associated with therapies for cardio-pulmonary critical decompensation in preterm neonates across Canadian neonatal intensive care units.

The aim of this retrospective cohort study was to study the clinical burden associated with cardio-pulmonary critical decompensations (CPCDs) in preterm neonates and factors associated with mortality. Through the Canadian Neonatal Network (30 tertiary NICUs, 2010-2017), we identified infants < 32-week gestational age with CPCDs, defined by "significant exposure" to cardiotropes and/or inhaled nitric oxide (iNO): (1) either therapy for ≥ 3 consecutive days, (2) both for ≥ 2 consecutive days, or (3) any exposure within 2 days of death. Early CPCDs (≤ 3 days of age) and late CPCDs (> 3 days) were examined separately. Outcomes included CPCD-incidence, mortality, and inter-site variability using standardized ratios (observed/adjusted expected rate) and network funnel plots. Mixed-effects analysis was used to quantify unit-level variability in mortality. Overall, 10% of admissions experienced CPCDs (n = 2915). Late CPCDs decreased by ~ 5%/year, while early CPCDs were unchanged during the study period. Incidence and CPCD-associated mortality varied between sites, for both early (0.6-7.5% and 0-100%, respectively) and late CPCDs (2.5-15% and 14-83%, respectively), all p < 0.01. Units' late-CPCD incidence and mortality demonstrated an inverse relationship (slope = -2.5, p < 0.01). Mixed-effects analysis demonstrated clustering effect, with 6.4% and 8.6% of variability in mortality after early and late CPCDs respectively being site-related, unexplained by available patient-level characteristics or unit volume. Mortality was higher with combined exposure than with only-cardiotropes or only-iNO (41.3%, 24.8%, 21.5%, respectively; p < 0.01). CONCLUSIONS: Clustering effects exist in CPCD-associated mortality among Canadian NICUs, with higher incidence units showing lower mortality. These data may aid network-level benchmarking, patient-level risk stratification, parental counseling, and further research and quality improvement work. WHAT IS KNOWN: • Preterm neonates remain at high risk of acute and chronic complications; the most critically unwell require therapies such as cardiotropic drugs and inhaled nitric oxide. • Infants requiring these therapies are known to be at high risk for adverse neonatal outcomes and for mortality. WHAT IS NEW: • This study helps illuminate the national burden of acute cardio-pulmonary critical decompensation (CPCD), defined as the need for cardiotropic drugs or inhaled nitric oxide, and highlights the high risk of morbidity and mortality associated with this disease state. • Significant nationwide variability exists in both CPCD incidence and associated mortality; a clustering effect was observed with higher incidence sites showing lower CPCD-associated mortality.

Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children.

OBJECTIVES: To determine whether maternal supplementation with high-dose docosahexaenoic acid (DHA) in breastfed, very preterm neonates improves neurodevelopmental outcomes at 18 to 22 months' corrected age (CA). METHODS: Planned follow-up of a randomized, double-blind, placebo-controlled, multicenter trial to compare neurodevelopmental outcomes in breastfed, preterm neonates born before 29 weeks' gestational age (GA). Lactating mothers were randomized to receive either DHA-rich algae oil or a placebo within 72 hours of delivery until 36 weeks' postmenstrual age. Neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) at 18 to 22 months' CA. Planned subgroup analyses were conducted for GA (<27 vs ≥27 weeks' gestation) and sex. RESULTS: Among the 528 children enrolled, 457 (86.6%) had outcomes available at 18 to 22 months' CA (DHA, N = 234, placebo, N = 223). The mean differences in Bayley-III between children in the DHA and placebo groups were -0.07 (95% confidence interval [CI] -3.23 to 3.10, P = .97) for cognitive score, 2.36 (95% CI -1.14 to 5.87, P = .19) for language score, and 1.10 (95% CI -2.01 to 4.20, P = .49) for motor score. The association between treatment and the Bayley-III language score was modified by GA at birth (interaction P = .07). Neonates born <27 weeks' gestation exposed to DHA performed better on the Bayley-III language score, compared with the placebo group (mean difference 5.06, 95% CI 0.08-10.03, P = .05). There was no interaction between treatment group and sex. CONCLUSIONS: Maternal DHA supplementation did not improve neurodevelopmental outcomes at 18 to 22 months' CA in breastfed, preterm neonates, but subgroup analyses suggested a potential benefit for language in preterm neonates born before 27 weeks' GA.

Effects of maternal docosahexaenoic acid supplementation on brain development and neurodevelopmental outcomes of breastfed preterm neonates: protocol for a follow-up at preschool age of a randomised clinical trial (MOBYDIckPS).

INTRODUCTION: Docosahexaenoic acid (DHA), an omega-3 fatty acid, is important for brain development with possible implications in neurodevelopmental outcomes. In the two-arm, randomised, double-blind, placebo-controlled Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants trial, very preterm infants (<29 weeks' gestation) were supplemented in high doses of DHA or placebo until they reached 36 weeks' postmenstrual age. We propose a long-term neurodevelopmental follow-up of these children. This protocol details the follow-up at 5 years of age, which aims to (1) confirm our long-term recruitment capacity and (2) determine the spectrum of neurodevelopmental outcomes at preschool age following neonatal DHA supplementation. METHODS AND ANALYSIS: This long-term follow-up involves children (n=194) born to mothers (n=170) randomised to DHA (n=85) or placebo (n=85) from the five sites in Quebec when they will be 5 years' corrected age. The primary outcome measure is related to the long-term recruitment capacity, which we determined as successful if 75% (±10%, 95% CI) of the eligible children consent to the 5-year follow-up study. Interviews with mothers will be conducted to assess various aspects of neurodevelopment at preschool age (executive functions, behavioural problems, global development and health-related quality of life), evaluated with standardised neurodevelopmental questionnaires. In addition, a semistructured interview conducted in a subset of the mothers will be used to determine their acceptability and identify barriers and enablers to their eventual participation to the next phase of the trial. This follow-up study will require approximately 22 months to be completed. ETHICS AND DISSEMINATION: This study was approved by the CHU de Québec-Université Laval Research Ethics Board (MP-20-2022-5926). Mothers will provide informed consent before participating in this study. Findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02371460.

Neurodevelopmental outcomes of singleton large for gestational age infants <29 weeks' gestation: a retrospective cohort study.

OBJECTIVE: To compare neurodevelopmental outcomes of large and appropriate for gestational age (LGA, AGA) infants <29 weeks' gestation at 18-24 months of corrected age. STUDY DESIGN: Retrospective 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. RESULTS: The 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). CONCLUSIONS: Risk of NDI was similar between LGA and AGA infants.

Impact of the Withdrawal of Palivizumab Immunoprophylaxis on the Incidence of Respiratory Syncytial Virus (RSV) Hospitalizations Among Infants Born at 33 to 35 Weeks' Gestational Age in the Province of Quebec, Canada: The RSV-Quebec Study.

BACKGROUND: Infants born at 33-35 completed weeks' gestational age (wGA) aged <6 months at the start of or born during respiratory syncytial virus (RSV) season and classified as moderate/high risk of severe RSV disease were included in a palivizumab RSV prophylaxis program in the province of Quebec, Canada, until 2014-2015. We assessed the impact of withdrawal of this indication on lower respiratory tract infection (LRTI)/RSV hospitalizations (H) in this population. METHODS: We conducted a 4-year, retrospective, cohort study in 25 Quebec hospitals (2 seasons with and 2 without palivizumab prophylaxis for moderate- to high-risk infants). Our primary outcome was LRTI/RSV-H incidence. We compared LRTI/RSV-H incidence before (2013-2015; seasons 1 + 2 [S1/2]) and after (2015-2017; S3/4) the change in indication. RESULTS: We identified 6457 33-35 wGA births. LRTI/RSV-H occurred in 105/3353 infants (3.13%) in S1/2 and 130/3104 (4.19%) in S3/4. Among LRTI/RSV-H, 86.4% were laboratory-confirmed RSV-H. Adjusting for sex, wGA, and birth month, S3/4 was significantly associated with increased LRTI/RSV-H incidence (adjusted odds ratio [aOR], 1.36; 95% confidence interval [CI], 1.04-1.76) but not with laboratory-confirmed RSV-H (aOR, 1.19; 95% CI, 0.90-1.58). Mean duration of LRTI/RSV-H was 5.6 days; 22.6% required intensive care unit admission. Comparing S3/4 with S1/2, infant percentage with LRTI/RSV-H classified as moderate/high risk increased from 27.8% to 41.9% (P = .11). CONCLUSIONS: In a province-wide study, we observed a significant increase in LRTI/RSV-H incidence among infants born at 33-35 wGA in the 2 years after withdrawal of RSV prophylaxis.

Mode of delivery and neonatal outcomes in extremely preterm Vertex/nonVertex twins.

BACKGROUND: One of the controversies in the management of twin gestations relates to mode of delivery, especially when the second twin is in a nonvertex presentation (Vertex/nonVertex pairs) and birth is imminent at extremely low gestation. OBJECTIVE: We hypothesized that, for Vertex/nonVertex twins born before 28 weeks' gestation, cesarean delivery would be associated with a lower risk of adverse neonatal outcomes than trial of vaginal delivery. Our aim was to test this hypothesis by comparing the neonatal outcomes of Vertex/nonVertex twins born before 28 weeks' gestation by mode of delivery using a large national cohort. STUDY DESIGN: This work is a retrospective cohort study of all twin infants born at 240/7 to 276/7 weeks' gestation and admitted to level III neonatal intensive care units participating in the Canadian Neonatal Network (2010-2017). Exposure is defined a trial of vaginal delivery for Vertex/nonVertex twins. Nonexposed (control) groups are defined as cases where both twins were delivered by cesarean delivery, either in vertex or nonvertex presentation (control group 1) or owing to the nonvertex presentation of the first twin (control group 2). Outcome measures are defined as a composite of neonatal death, severe neurologic injury, or birth trauma. RESULTS: A total of 1082 twin infants (541 twin pairs) met the inclusion criteria: 220 Vertex/nonVertex pairs, of which 112 had a trial of vaginal delivery (study group) and 108 had cesarean delivery for both twins (control group 1); 170 pairs with the first twin in nonvertex presentation, all of which were born by cesarean delivery (control group 2); and 151 pairs with both twins in vertex presentation (vertex or nonvertex). In the study group, the rate of urgent cesarean delivery for the second twin was 30%. The rate of the primary outcome in the study group was 42%, which was not significantly different compared with control group 1 (37%; adjusted relative risk, 0.93; 95% confidence interval, 0.71-1.22) or control group 2 (34%; adjusted relative risk, 1.20; 95% confidence interval, 0.92-1.58). The findings remained similar when outcomes were analyzed separately for the first and second twins. CONCLUSION: For preterm Vertex/nonVertex twins born at <28 weeks' gestation, we found no difference in the risk of adverse neonatal outcome between a trial of vaginal delivery and primary cesarean delivery. However, a trial of vaginal delivery was associated with a high rate of urgent cesarean delivery for the second twin.

Procedural Interventions and Stabilization Times During Interfacility Neonatal Transport.

OBJECTIVE: Transport teams perform multiple procedural interventions during the stabilization of critically ill neonates. The setting of this study was a national cohort of interfacility neonatal transports from nontertiary centers. METHODS: A retrospective cohort study of neonatal transports having interventional procedures using the Canadian Neonatal Transport Network database during 2014 to 2016. Demographics and procedures associated with stabilization times ≤ 120 versus > 120 minutes were analyzed. Predictors of stabilization time were evaluated using multivariable logistic regression analysis. RESULTS: Among 3,350 neonatal transports analyzed, the 3 most frequently performed procedures were peripheral intravenous insertion, arterial blood gas sampling, and endotracheal tube insertion, with success rates of 85.2%, 89.1%, and 95.3%, respectively. The frequency of procedures varied across gestational age subgroups, and success rates were lower for umbilical arterial catheter insertions. After adjustment for confounders, more invasive procedures and a higher number of interventions were associated with longer stabilization times. CONCLUSION: The type and frequency of procedures performed had a significant impact on stabilization time. Any procedures that are nonessential for stabilization at the nontertiary center, such as umbilical arterial catheter insertion, could be minimized to promote timely admission to tertiary centers. The demonstrated variations in procedural success among teams provide useful information for benchmarking and promote the sharing of training practices.

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.

Cost-analysis of Withdrawing Immunoprophylaxis for Respiratory Syncytial Virus in Infants Born at 33-35 Weeks Gestational Age in Quebec: A Multicenter Retrospective Study.

BACKGROUND: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA. METHODS: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator). RESULTS: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient). CONCLUSIONS: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

Efficacy of minimally invasive surfactant therapy in moderate and late preterm infants: A multicentre randomized control trial.

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.