Normative values of renin and aldosterone in clinically stable preterm neonates.

BACKGROUND: There is a paucity of literature on the normative levels of plasma renin concentration (PRC) and serum aldosterone (SA) in premature neonates. This study aims to provide normative data on PRC and SA levels in preterm neonates in the first 2 weeks after birth and explore associations with maternal, perinatal, or postnatal factors. METHODS: Neonates born at 26- to 34-week gestation were recruited from two neonatal intensive care units in Canada and Australia. The direct renin assay PRC and SA were analyzed on day 1 and days 14-21 after birth to compare across categorical variables and to produce normative values. RESULTS: A total of 262 subjects were enrolled from the Canadian (29%) and Australian (71%) sites. The mean gestational age was 30 weeks, with a mean birth weight of 1457 g. The normative values of PRC and SA for neonates born between 26 + 0 and 29 + 6 weeks and 30 + 0 and 34 + 0 weeks of gestation were produced for day 1 and day 14-21 after birth. Both PRC and SA increased from day 1 to day 14-21. The more premature neonates reached a higher PRC on days 14-21 after birth but exhibited lower SA levels on day 1 after birth. When comparing gender, birth weight, and maternal risk factor categories, no statistical differences in PRC or SA were found. A small but significant decrease in PRC, but not SA, was noted for neonates with placental pathology. CONCLUSIONS: This study produced normative values of PRA and SA in clinically stable preterm neonates that can be referenced for use in clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.

Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a strategy to maintain positive airway pressure throughout the respiratory cycle through the application of a bias flow of respiratory gas to an apparatus attached to the nose. Early treatment with NCPAP is associated with decreased risk of mechanical ventilation exposure and might reduce chronic lung disease. Nasal intermittent positive pressure ventilation (NIPPV) is a form of noninvasive ventilation delivered through the same nasal interface during which patients are exposed to short inflations, along with background end-expiratory pressure. OBJECTIVES: To examine the risks and benefits of early (within the first six hours after birth) NIPPV versus early NCPAP for preterm infants at risk of or with respiratory distress syndrome (RDS). Primary endpoints are respiratory failure and the need for intubated ventilatory support during the first week of life. Secondary endpoints include the incidence of mortality, chronic lung disease (CLD) (oxygen therapy at 36 weeks' postmenstrual age), pneumothorax, duration of respiratory support, duration of oxygen therapy, and intraventricular hemorrhage (IVH). SEARCH METHODS: Searches were conducted in January 2023 in CENTRAL, MEDLINE, Embase, Web of Science, and Dissertation Abstracts. The reference lists of related systematic reviews and of studies selected for inclusion were also searched. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials. Eligible studies compared NIPPV versus NCPAP treatment, starting within six hours after birth in preterm infants (< 37 weeks' gestational age (GA)). DATA COLLECTION AND ANALYSIS: We collected and analyzed data using the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: We included 17 trials, enrolling 1958 infants in this review. NIPPV likely reduces the rate of respiratory failure (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.54 to 0.78; risk difference (RD) -0.08, 95% CI -0.12 to -0.05; 17 RCTs, 1958 infants; moderate-certainty evidence) and needing endotracheal tube ventilation (RR 0.67, 95% CI 0.56 to 0.81; RD -0.07, 95% CI -0.11 to -0.04; 16 RCTs; 1848 infants; moderate-certainty evidence) amongst infants treated with early NIPPV compared with early NCPAP. The meta-analysis demonstrated that NIPPV may reduce the risk of developing CLD compared to CPAP (RR 0.70, 95% CI 0.52 to 0.92; 12 RCTs, 1284 infants; low-certainty evidence) slightly. NIPPV may result in little to no difference in mortality (RR 0.82, 95% CI 0.62 to 1.10; 17 RCTs; 1958 infants; I2 of 0%; low-certainty evidence), the incidence of pneumothorax (RR 0.92, 95% CI 0.60 to 1.41; 16 RCTs; 1674 infants; I2 of 0%; low-certainty evidence), and rates of severe IVH (RR 0.98, 95% CI 0.53 to 1.79; 8 RCTs; 977 infants; I2 of 0%; low-certainty evidence). AUTHORS' CONCLUSIONS: When applied within six hours after birth, NIPPV likely reduces the risk of respiratory failure and the need for intubation and endotracheal tube ventilation in very preterm infants (GA 28 weeks and above) with respiratory distress syndrome or at risk for RDS. It may also decrease the rate of CLD slightly. However, most trials enrolled infants with a gestational age of approximately 28 to 32 weeks with an overall mean gestational age of around 30 weeks. As such, the results of this review may not apply to extremely preterm infants that are most at risk of needing mechanical ventilation or developing CLD. Additional studies are needed to confirm these results and to assess the safety of NIPPV compared with NCPAP alone in a larger patient population.

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a useful method for providing respiratory support after extubation. Nasal intermittent positive pressure ventilation (NIPPV) can augment NCPAP by delivering ventilator breaths via nasal prongs. OBJECTIVES: Primary objective To determine the effects of management with NIPPV versus NCPAP on the need for additional ventilatory support in preterm infants whose endotracheal tube was removed after a period of intermittent positive pressure ventilation. Secondary objectives To compare rates of abdominal distension, gastrointestinal perforation, necrotising enterocolitis, chronic lung disease, pulmonary air leak, mortality, duration of hospitalisation, rates of apnoea and neurodevelopmental status at 18 to 24 months for NIPPV and NCPAP. To compare the effect of NIPPV versus NCPAP delivered via ventilators versus bilevel devices, and assess the effects of the synchronisation of ventilation, and the strength of interventions in different economic settings. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was January 2023. SELECTION CRITERIA: We included randomised and quasi-randomised trials of ventilated preterm infants (less than 37 weeks' gestational age (GA)) ready for extubation to non-invasive respiratory support. Interventions were NIPPV and NCPAP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. respiratory failure. Our secondary outcomes were 2. endotracheal reintubation, 3. abdominal distension, 4. gastrointestinal perforation, 5. necrotising enterocolitis (NEC), 6. chronic lung disease, 7. pulmonary air leak, 8. mortality, 9. hospitalisation, 10. apnoea and bradycardia, and 11. neurodevelopmental status. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 19 trials (2738 infants). Compared to NCPAP, NIPPV likely reduces the risk of respiratory failure postextubation (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.67 to 0.84; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 8 to 17; 19 trials, 2738 infants; moderate-certainty evidence) and endotracheal reintubation (RR 0.78, 95% CI 0.70 to 0.87; NNTB 12, 95% CI 9 to 25; 17 trials, 2608 infants, moderate-certainty evidence), and may reduce pulmonary air leaks (RR 0.57, 95% CI 0.37 to 0.87; NNTB 50, 95% CI 33 to infinite; 13 trials, 2404 infants; low-certainty evidence). NIPPV likely results in little to no difference in gastrointestinal perforation (RR 0.89, 95% CI 0.58 to 1.38; 8 trials, 1478 infants, low-certainty evidence), NEC (RR 0.86, 95% CI 0.65 to 1.15; 10 trials, 2069 infants; moderate-certainty evidence), chronic lung disease defined as oxygen requirement at 36 weeks (RR 0.93, 95% CI 0.84 to 1.05; 9 trials, 2001 infants; moderate-certainty evidence) and mortality prior to discharge (RR 0.81, 95% CI 0.61 to 1.07; 11 trials, 2258 infants; low-certainty evidence). When considering subgroup analysis, ventilator-generated NIPPV likely reduces respiratory failure postextubation (RR 0.49, 95% CI 0.40 to 0.62; 1057 infants; I2 = 47%; moderate-certainty evidence), while bilevel devices (RR 0.95, 95% CI 0.77 to 1.17; 716 infants) or a mix of both ventilator-generated and bilevel devices likely results in little to no difference (RR 0.87, 95% CI 0.73 to 1.02; 965 infants). AUTHORS' CONCLUSIONS: NIPPV likely reduces the incidence of extubation failure and the need for reintubation within 48 hours to one-week postextubation more effectively than NCPAP in very preterm infants (GA 28 weeks and above). There is a paucity of data for infants less than 28 weeks' gestation. Pulmonary air leaks were also potentially reduced in the NIPPV group. However, it has no effect on other clinically relevant outcomes such as gastrointestinal perforation, NEC, chronic lung disease or mortality. Ventilator-generated NIPPV appears superior to bilevel devices in reducing the incidence of respiratory failure postextubation failure and need for reintubation. Synchronisation used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. Future trials should enrol a sufficient number of infants, particularly those less than 28 weeks' GA, to detect differences in death or chronic lung disease and should compare different categories of devices, establish the impact of synchronisation of NIPPV on safety and efficacy of the technique as well as the best combination of settings for NIPPV (rate, peak pressure and positive end-expiratory). Trials should strive to match the mean airway pressure between the intervention groups to allow a better comparison. Neurally adjusted ventilatory assist needs further assessment with properly powered randomised trials.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Factors associated with hypothermia within the first 6 hours of life in infants born at ≥340 weeks' gestation: a multivariable analysis.

BACKGROUND: Lack of appropriate temperature management has been associated with significant adverse outcomes in preterm and low birthweight neonates. There is a lack of similar investigations in the late preterm (340-366) and term (≥370) neonate population. Our aim was to identify key risk factors as well as clinical outcomes associated with hypothermia in this population. METHODS: A retrospective chart review was conducted at the Ottawa Hospital including all eligible infants ≥340 weeks' gestation over a one-month period in November 2020. Infant, maternal, and delivery room variables were collected, including prematurity, maternal temperature, delivery mode, birthweight, and premature rupture of membranes, as well as clinical outcomes such as NICU/SCN admission and length of stay. Regression models were generated, adjusted for covariates, and stepwise regression was performed. RESULTS: Four hundred forty infants were included in the analysis; 26.8% (118/440) were hypothermic within 6 hours of delivery. In the multivariable analysis, prematurity, low 5 minute Apgar score (< 7) or need for resuscitation, maternal hypertension, and absence of premature rupture of membranes > 18 hours or suspected maternal infection were significantly associated with hypothermia within 6 hours of delivery (p < 0.05). Multivariable analysis of clinical outcomes demonstrated a significant association between hypothermia within 6 hours of delivery and NICU/SCN admission (OR = 2.87; 95% CI 1.36, 6.04), need for respiratory support or diagnosis of respiratory distress syndrome (OR = 3.94; 95% CI 1.55, 10.50), and length of stay (exp(ß) = 1.20; 95% bootstrap CI 1.04, 1.37). CONCLUSIONS: Our results suggest there are similar factors associated with hypothermia in our study population of infants born at ≥340 weeks' gestation compared to prior studies in preterm and low-birthweight infants. Furthermore, hypothermia is associated with higher risk of adverse outcomes, which highlights the need to prevent hypothermia in all newborns.

Comparative performance of head ultrasound and MRI in detecting preterm brain injury and predicting outcomes: A systematic review.

AIM: To systematically review the literature to compare the performance of head ultrasound (HUS) and magnetic resonance imaging (MRI) in their ability to detect brain injury and their predictive value for neurodevelopmental outcomes. METHODS: This was a systematic review based on literature search in three electronic databases (MEDLINE, EMBASE, Cochrane Library) and additional sources for studies on routine brain injury screening in preterm neonates published during 2000-May 2020. Studies were included if they reported on the comparative performance of HUS and MRI in detecting preterm brain injury and/or their predictive value for neurodevelopmental outcomes. Findings from the included studies underwent narrative synthesis. RESULTS: Forty-six studies were included. In comparison with HUS, MRI detected more anomalies and provided more details on the severity and the extent of preterm brain injury, particularly for white matter injury and cerebellar haemorrhage. Neonatal neuroimaging predicted outcomes with high negative predictive value but relatively low positive predictive value. The prognostic value of neonatal neuroimaging varied according to several factors including modality and timing of imaging, and tools used for grading brain injury. CONCLUSION: Compared with HUS, MRI offers a better characterisation of preterm brain injury and may enhance the ability to predict neurodevelopmental outcomes.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Extremely low gestational age infants: Developing a multidisciplinary care bundle.

BACKGROUND: Clinical experience in managing extremely low gestational age infants, particularly those born <24 weeks' gestation, is limited in Canada. Our goal was to develop a bedside care bundle for infants born <26 weeks' gestation, with special considerations for infants of <24 weeks, to harmonize and improve quality of care. METHODS: We created a multidisciplinary working group with experience in caring for preterm infants, searched the literature from 2000 to 2019 to identify best practices for the care of extremely preterm infants and consulted colleagues across Canada and internationally. Iterative improvements were made following the Plan-Do-Study-Act methodology. RESULTS: A care bundle, created in October 2015, was divided into three time periods: initial resuscitation/stabilization, the first 72 hours and days 4 to 7, with each period subdivided in 8 to 12 care themes. Revisions and practice changes were implemented to improve skin integrity, admission temperature, timing of initiation of feeds, reliability of transcutaneous CO2 monitoring and ventilation. Of 127 infants <26 weeks admitted between implementation and end of 2019, 78 survived to discharge (61%). CONCLUSION: It will be important to determine, with ongoing auditing and further evaluation, whether our care bundle led to improvements of short- and long-term outcomes in this population. Our experience may be useful to others caring for extremely low gestational age infants.

Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants.

Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.

Cumulative effect of evidence-based practices on outcomes of preterm infants born at <29 weeks' gestational age.

BACKGROUND: Extremely preterm infants born at <29 weeks' gestational age are at high risk of death or severe neurological injury. Several individual evidence-based practices have been associated with neuroprotection. OBJECTIVE: The objective of the study was to investigate the cumulative effect of 4 evidence-based practices and their association with death and/or severe neurological injury among infants born at <29 weeks' gestational age. STUDY DESIGN: Observational study of infants born at 230-286 weeks gestational age admitted to neonatal intensive care units participating in the Canadian Neonatal Network from 2015 through 2017. We evaluated 4 practices: antenatal corticosteroids, antenatal MgSO4 for neuroprotection, deferred cord clamping ≥30 seconds, and normothermia on admission. The effect of exposure to 1, 2, 3, and all 4 evidence-based practices compared with none on death and/or severe neurological injury was assessed using multivariable logistic regression models adjusted for patient characteristics. RESULTS: Rate of death and/or severe neurological injury was 20% (873 of 4297) and varied based on exposure to evidence-based practices: none, 34% (54 of 157); 1, 27% (171 of 626); 2, 20% (295 of 1448); 3, 18% (263 of 1448); and all 4, 14% (90 of 618). Significantly lower odds of death and/or severe neurological injury were observed with exposure to antenatal corticosteroids (adjusted odds ratio, 0.52, 95% confidence interval, 0.40-0.69) and deferred cord clamping (adjusted odds ratio, 0.81, 95% confidence interval, 0.68-0.96) but not MgSO4 (adjusted odds ratio, 0.88, 95% confidence interval, 0.72-1.08) or normothermia (adjusted odds ratio, 0.96, 95% confidence interval, 0.79-1.16). Infants exposed to ≥2 evidence-based practices had significantly lower odds of death and/or severe neurological injury than those exposed to no evidence-based practices (adjusted odds ratio, 0.61, 95% confidence interval, 0.43-0.88). CONCLUSION: Among infants born at <29 weeks' gestational age, exposure to at least 2 of the evidence-based practices assessed was associated with decreased odds of death and/or severe neurological injury.

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.

Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants.

Historically, postnatal corticosteroids have been used to prevent and treat bronchopulmonary dysplasia (BPD), a significant cause of morbidity and mortality in preterm infants. Administering dexamethasone to prevent BPD in the first 7 days post-birth has been associated with increasing risk for cerebral palsy, while early inhaled corticosteroids appear to be associated with an increased risk of mortality. Neither medication is presently recommended to prevent BPD. New evidence suggests that prophylactic hydrocortisone, when initiated in the first 48 hours post-birth, at a physiological dose, and in the absence of indomethacin, improves survival without BPD, with no adverse neurodevelopmental effects at 2 years. This therapy may be considered by clinicians for infants at highest risk for BPD. Routine dexamethasone therapy for all ventilator-dependent infants is not recommended, but after the first week post-birth, clinicians may consider a short course of low-dose dexamethasone (0.15 mg/kg/day to 0.2 mg/kg/day) for individual infants at high risk for, or with evolving, BPD. There is no evidence that hydrocortisone is an effective or safe alternative to dexamethasone for treating evolving or established BPD. Current evidence does not support inhaled corticosteroids for the treatment of BPD.

Routine imaging of the preterm neonatal brain.

Routine brain imaging to detect injuries affecting preterm infants is used to predict long-term outcomes and identify complications that might necessitate an intervention. Although magnetic resonance imaging may be indicated in some specific cases, head ultrasound is the most widely used technique and, because of portability and ease of access, is the best modality for routine imaging. Routine head ultrasound examination is recommended for all infants born at or before 31+6 weeks gestation. For preterm neonates born between 32+0 to 36+6 weeks gestation, routine head ultrasound is recommended only in presence of risk factors for intracranial hemorrhage or ischemia. Brain imaging in the first 7 to 14 days postbirth is advised to detect most germinal matrix and intraventricular hemorrhages. Repeat imaging at 4 to 6 weeks of age is recommended to detect white matter injury.

Effect of oxygen saturation targets on the incidence of bronchopulmonary dysplasia and duration of respiratory supports in extremely preterm infants.

BACKGROUND: Recent clinical practice changes in neonatal care resulted in higher, narrower oxygen saturation target ranges for preterm infants. The effect of targeting higher or lower oxygen saturations on respiratory outcomes of preterm infants and duration of hospitalization has not been extensively reviewed in the context of current care, but could have significant implications. METHODS: A multicentre retrospective cohort of 145 preterm infants was conducted; 105 had lower oxygen saturation targets (88 to 92%), 40 had higher targets (90 to 95%). The primary outcome was bronchopulmonary dysplasia (BPD). Secondary outcomes included duration of invasive/noninvasive respiratory support, oxygen therapy, and hospitalization. The primary outcome was compared using Fisher's exact test. Secondary outcomes were evaluated with survival analysis and Wilcoxon rank sum test. RESULTS: The difference in incidence of BPD in the lower (N=56, 53.3%) and higher saturation groups (N=14, 35.0%) was not statistically significant (relative risk [RR]=0.66 [0.41, 1.04], P=0.06). The difference in duration of mechanical ventilation in the lower (median 7.8 days, interquartile range [IQR] 3.7 to 15.9) and higher saturation groups (median 4.5, IQR 1.9 to 12.3) approached statistical significance (P=0.05). There were no statistically significant differences in the durations of other respiratory supports or hospital stay between the two groups. CONCLUSIONS: The results of this study approached statistical significance and suggest that higher, narrower oxygen saturation targets may result in a clinically important reduction in BPD incidence and duration of mechanical ventilation. These results require validation in a larger sample to refine optimal targets.

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.

So You Want to Give Stem Cells to Babies? Neonatologists and Parents' Views to Optimize Clinical Trials.

OBJECTIVE: To identify barriers and enablers that may influence parents' and neonatologists' participation in clinical trials of mesenchymal stromal cells for bronchopulmonary dysplasia. STUDY DESIGN: This qualitative study involved one-on-one semistructured interviews with parents of extremely preterm infants (n = 18) and neonatologists (n = 16). Interview guides and directed content analysis were framed using the theoretical domains framework, a tool specifically developed for implementation research to identify influences on behavior. RESULTS: Key barriers for parents included their lack of knowledge about clinical trial processes in general, stem cells, and concerns about their risks and side effects. Importantly, parents preferred to be approached for recruitment directly by a neonatologist, either before delivery or 1 or 2 weeks after birth. However, the majority of neonatologists felt that approaching parents was not part of their role. Neonatologists reported competing priorities, time commitment, costs, and lack of institutional support as significant barriers to their ability to recruit patients. CONCLUSIONS: By integrating stakeholders early into the development of a clinical trial of mesenchymal stromal cell therapy, we identified and can address important barriers to enrollment. Some identified barriers were unanticipated and could have compromised recruitment had they not been identified by this study. We suggest that this approach can be used more broadly for other early phase clinical trials in pediatrics.

Predictors of Severe Neurologic Injury on Ultrasound Scan of the Head and Risk Factor-based Screening for Infants Born Preterm.

OBJECTIVE: To identify risk factors for severe neurologic injury (intraventricular hemorrhage grade 3 or greater and/or periventricular leukomalacia) diagnosed by ultrasound scan of the head among infants born at 300-326 weeks of gestation and compare different screening strategies. STUDY DESIGN: This was a retrospective cohort study of infants born at 300-326 weeks or >326 weeks of gestation with a birth weight <1500 g admitted to neonatal intensive care units in the Canadian Neonatal Network from 2011 to 2016. Stepwise logistic regression analysis was used to identify significant risk factors and calculate aORs and 95% CIs. Risk factor-based screening strategies were compared. RESULTS: The rate of severe neurologic injury was 3.1% among infants screened (285/9221). Significant risk factors included singleton birth (aOR 1.96, 95% CI 1.35-2.85), 5-minute Apgar <7 (aOR 1.81, 95% CI 1.30-2.50), mechanical ventilation on day 1 (aOR 2.65, 95% CI 1.88-3.71), and treatment with vasopressors on day 1 (aOR 3.23, 95% CI 2.19-4.75). Risk categories were low (no risk factor, 1.2%, 25/2137), moderate (singleton with no other risk factor: 1.8%, 68/3678), and high (≥1 risk factor among 5-minute Apgar <7, receipt of vasopressors or mechanical ventilation on day 1: 5.6%, 192/3408). Screening moderate- to high-risk infants identified 91% (260/285) of infants with severe neurologic injury and would require screening fewer infants (1647 infants per year) than screening all infants <33 weeks of gestation (2064 infants screened per year, 93% [265/285] of cases identified). CONCLUSIONS: Risk factor-based ultrasound scan of the head screening among infants born at 30-32 weeks of gestation could help optimize resources better than gestational age based screening.

Continuous Electroencephalography Monitoring for Critically Ill Neonates: A Canadian Perspective.

BACKGROUND: Continuous EEG monitoring, in the form of amplitude-integrated (aEEG) or conventional EEG (cEEG), is used in the neonatal intensive care unit (NICU) to detect subclinical central nervous system pathologies, inform management, and prognosticate neurodevelopmental outcomes. To learn more about provider attitudes and current practices in Canada, we evaluated neurologist and neonatologist opinions regarding NICU EEG monitoring. METHODS: A 15-item electronic questionnaire was distributed to 114 pediatric neurologists and 176 neonatologists working across 25 sites. RESULTS: The survey was completed by 87 of 290 physicians. Continuous EEG monitoring is utilized by 97% of pediatric neurologists and 92% of neonatologists. Neurologists and neonatologists differ in their EEG monitoring preferences. For seizure detection and diagnosis of encephalopathy, significantly more neonatologists favor aEEG alone or in combination with cEEG, whereas most neurologists prefer cEEG (p = 0.047, 0.001). There is a significant difference in the perceived gaps in monitoring patients with cEEG between neonatologists (13% would monitor more) and neurologists (41% would monitor more) (p = 0.007). Half of all respondents (53%) reported that they would be interested in attending an education session on neonatal EEG monitoring. CONCLUSIONS: Canadian neurologists and neonatologists do not agree on the best monitoring approach for critically ill neonates. Furthermore, neonatologists perceive a smaller cEEG monitoring gap as compared with neurologists. However, many participants from both specialties would like to increase long-term EEG monitoring in the NICU setting. Facilitating access to EEG monitoring and enhancing education may help to address these needs.

La surveillance continue par électroencéphalographie dans le cas de nouveau-nés gravement malades : une perspective canadienne. Contexte: La surveillance continue par électroencéphalographie (EEG), que ce soit à amplitude intégrée (EEGai) ou conventionnelle (EEGc), est utilisée dans les unités de soins intensifs néonatals (USIN) afin de détecter des pathologies sous-cliniques du système nerveux central, de fournir des indications en matière de prise en charge et d'établir des pronostics quant à l'évolution neuro-développementale de ces nouveau-nés. Afin d'en savoir plus au sujet des attitudes des prestataires de soins et des pratiques actuelles dans ce domaine au Canada, nous avons cherché à évaluer les points de vue de neurologues et de néonatologistes en ce qui regarde la surveillance continue par EEG dans les USIN. Méthodes: Un questionnaire en ligne abordant 15 aspects a été envoyé à 114 neuro-pédiatres et à 176 néonatologistes travaillant dans 25 établissements différents. Résultats: Ce sondage a été complété par 87 médecins sur 290. Il en ressort que la surveillance continue par EEG est utilisée par 97 % des neuro-pédiatres et par 92 % des néonatologistes. Cela dit, les neuro-pédiatres et les néonatologistes n'ont pas les mêmes préférences quant à l'utilisation de cet examen. Quand il s'agit de détecter des crises convulsives et de diagnostiquer des cas d'encéphalopathie, on remarque qu'un nombre nettement plus élevé de néonatologistes favorisent la seule EEGai ou la combinent avec la EEGc tandis que davantage de neurologues ont dit préférer la seule EEGc (p = 0,047 ; p = 0,001). Qui plus est, on peut dénoter une différence notable entre les néonatologistes et les neurologues en ce qui a trait aux écarts perçus de surveillance des patients au moyen de la EEGc, 13 % des premiers assurant une surveillance supérieure alors qu'ils sont 41 % parmi les deuxièmes à assurer une surveillance supérieure (p = 0,007). Enfin, plus de la moitié des répondants (53 %) ont affirmé être intéressés à assister à des séances de formation portant sur la surveillance continue par EEG destinée aux nouveau-nés. Conclusions: Les neurologues et les néonatologistes canadiens divergent quant à la meilleure approche de surveillance dans le cas de nouveau-nés gravement malades. En outre, les néonatologistes ont tendance à percevoir un écart de surveillance moins important si on les compare aux neurologues. Néanmoins, nombreux sont les répondants formés dans ces deux spécialités qui souhaiteraient augmenter à long terme la surveillance par EEG dans les USIN. Le fait de faciliter l'accès à ces examens et d'améliorer l'enseignement pourrait ainsi permettre de répondre aux besoins.

Sustained quality improvement in outcomes of preterm neonates with a gestational age less than 29 weeks: results from the Evidence-based Practice for Improving Quality Phase 3 1.

Quality improvement initiatives in neonatology have yielded positive results; however, few programs have demonstrated sustainability. We evaluated an ongoing, national quality improvement initiative (Evidence-based Practice for Improving Quality Phase 3 (EPIQ-3)) on outcomes of preterm neonates with a gestational age (GA) of 220-286 weeks (i.e., from 22 weeks and 0 days of gestation to 28 weeks and 6 days of gestation). Data from 7459 neonates admitted to 25 Canadian centers between 2013 and 2017 were studied. Trends in mortality and major morbidities were evaluated. The number of neonates with a GA of 220-236 weeks increased from 90 in 2013 to 139 in 2017 without a significant change in any other GA categories. In the entire cohort, the odds of composite outcome of mortality or any major morbidity (adjusted odds ratio (AOR) 0.72, 95% confidence interval (CI) 0.61-0.84) and of necrotizing enterocolitis (AOR 0.66, 95% CI 0.49-0.89) were lower in 2017 than in 2013. When calculated per year, the odds of composite outcome (AOR 0.93, 95% CI 0.89-0.97) and odds of necrotizing enterocolitis (AOR 0.89, 95% CI 0.82-0.96) decreased significantly. Among the subgroup of neonates with a GA of 260-286 weeks, the odds of composite outcome (AOR 0.63, 95% CI 0.51-0.79), necrotizing enterocolitis (AOR 0.44, 95% CI 0.26-0.73), and nosocomial infection (AOR 0.64, 95% CI 0.49-0.84) were reduced. The collaborative, multidisciplinary, nationwide EPIQ-3 program improved outcomes of preterm neonates, and the improvement was sustainable over 5 years.