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Background The relationship between ABO non-identical transfusion and the outcomes of necrotizing enterocolitis (NEC), and all-cause mortality in very-low birth weight (VLBW) neonates receiving red blood cell transfusion is unknown. Study design and methods A retrospective multicenter cohort study was conducted in VLBW neonates in neonatal intensive care units between 2004 and 2016. VLBW (≤1500 grams) neonates were followed until discharge or in-hospital death. The primary exposure was ABO group. Secondary exposures included platelet count, plasma transfusions, and maternal ABO group. Outcome measures were NEC (defined as Bell stage ≥ 2) and all-cause mortality. Time-dependent Cox regression models with competing risks were used to investigate factors associated with NEC and mortality. Results Thousand and sixteen neonates were included with 10.8% developing NEC (n = 110) and 14.1% mortality (n = 143). Platelet count (hazard ratio [HR] = 0.995; 95% confidence interval [CI]: 0.922-0.998) and number of plasma transfusions (HR = 2.908; 95% CI:1.265-6.682) were associated with NEC, while ABO group (non-O vs. O) was not (HR = 0.761; 95% CI: 0.393-1.471). Higher all-cause mortality occurred in neonates without NEC who were non-O compared with O (HR = 17.5; 95% CI: 1.784-171.692), but not in neonates with NEC (HR = 1.112; 95% CI: 0.142-8.841). Plasma transfusion was associated with increased mortality in both groups. Discussion ABO non-identical transfusion was not associated with NEC or mortality in neonates with NEC. It was associated with increased mortality in neonates without NEC. As many neonatal intensive care units transfuse only O group blood as routine practice, future trials are needed to investigate the association between this practice and neonatal mortality. more...

To assess the association between time of birth and mortality among preterm infants. Population-based study of infants born 22–36 weeks gestation (GA) in Canada from 2010 to 2015 (n = 173 789). Multivariable logistic regression models assessed associations between timing of birth and mortality. Among infants 22–27 weeks GA, evening birth was associated with higher mortality than daytime birth (adjusted odds ratio [AOR] 1.14, 95% CI 1.01–1.29). Among infants 28–32 weeks GA and 33–36 weeks GA, night birth was associated with lower mortality than daytime birth (AOR 0.75, 95% CI 0.59–0.95; AOR 0.78, 95% CI 0.62–0.99, respectively). Sensitivity analysis excluding infants with major congenital anomaly revealed that associations between hour of birth and mortality among infants born 28–32 and 33–36 weeks GA decreased or were not statistically significant. Higher mortality among extremely preterm infants during off-peak hours may suggest variations in available resources based on time of day. more...

Objective This study aimed to evaluate whether the initial pressure level on high continuous positive airway pressure (CPAP; ≥9 cm H2O), in relation to preextubation mean airway pressure (Paw), influences short-term clinical outcomes in preterm neonates. Study Design In this retrospective cohort study, preterm neonates preextubation Paw + 3 cm H2O. Secondary outcomes included individual components of the primary outcome, along with other clinical and safety outcomes. Results Over a 10-year period (Jan 2011–Dec 2020), 175 infants were extubated from mean Paw >9 cm H2O to high CPAP pressures. Twenty-seven patients (median GA = 24.7, [interquartile range (IQR)]: (24.0–26.4) weeks and chronological age = 31, IQR: [21–40] days) were classified into the “higher level CPAP” group while 148 infants (median GA = 25.4, IQR: [24.6–26.6] weeks and chronological age = 26, IQR: [10–39] days) comprised the “equivalent CPAP” group. There was no difference in the primary outcome (44 vs. 51%; p = 0.51), including postadjustment for confounders (adjusted OR [aOR] = 0.47 [95% confidence interval (CI): 0.17–1.29; p = 0.14]). However, reintubation risk within 7 days was lower with higher level CPAP (7 vs. 37%; p Conclusion In this cohort, use of initial distending CPAP pressures 2 to 3 cm H2O higher than preextubation Paw did not alter the primary outcome of failure but did lower the risk of reintubation. The latter is an interesting hypothesis-generating finding that requires further confirmation. Key Points more...

ObjectiveTo evaluate annual trends in the administration and duration of respiratory support among preterm infants.DesignRetrospective cohort study.SettingTertiary neonatal intensive care units in the Canadian Neonatal Network.Patients8881 extremely preterm infants born from 2010 to 2017 treated with endotracheal and/or non-invasive positive pressure support (PPS).Main outcome measuresCompeting risks methods were used to investigate the outcomes of mortality and time to first successful extubation, definitive extubation, weaning off PPS, and weaning PPS and/or low-flow oxygen, according to gestational age (GA). Cox proportional hazards and regression models were fitted to evaluate the trend in duration of respiratory support, survival and surfactant treatment over the study period.ResultsThe percentages of infants who died or were weaned from respiratory support were presented graphically over time by GA. Advancing GA was associated with ordinally earlier weaning from respiratory support. Year over year, infants born at 23 weeks were initially and definitively weaned from endotracheal and all PPS earlier (HR 1.06, 95% CI 1.01 to 1.11, for all outcomes), while survival simultaneously increased (OR 1.11, 95% CI 1.03 to 1.18). Infants born at 26 and 27 weeks remained on non-invasive PPS longer (HR 0.97, 95% CI 0.95 to 0.98 and HR 0.97, 95% CI 0.95 to 0.99, respectively). Early surfactant treatment declined among infants born at 24–27 weeks GA.ConclusionsInfants at the borderline of viability have experienced improved survival and earlier weaning from all forms of PPS, while those born at 26 and 27 weeks are spending more time on PPS in recent years. GA-based estimates of the duration of respiratory support and survival may assist in counselling, benchmarking, quality improvement and resource planning. more...

Objective To evaluate the changes in the associations of antenatal corticosteroids (ACS) with neonatal mortality and severe neurological injury over time (2003-17). Design National, population-representative, retrospective cohort study. Setting Level III neonatal intensive care units participating in the Canadian Neonatal Network. Population All infants born at 230/7 -336/7 weeks of gestation (n = 43 456). Methods We estimated the associations between exposure to ACS and neonatal outcomes by year of birth. Year of birth was considered both continuously and categorically as three consecutive epochs. Main outcome measure Neonatal mortality and severe neurological injury. Results The absolute rates of neonatal mortality and severe neurological injury decreased during the study period in both the ACS and No ACS groups. For infants born at 230/7 -306/7 weeks of gestation, ACS was associated with similar reductions in neonatal mortality across the three epochs (9.0% versus 18.1%, adjusted relative risk [aRR] 0.54, 95% CI 0.47-0.61 in 2003-09; 7.6% versus 19.6%, aRR 0.51, 95% CI 0.44-0.59 in 2010-13; and 7.3% versus 14.5%, aRR 0.56, 95% CI 0.46-0.68 in 2014-17) and in severe neurological injury (13.2% versus 25.8%, aRR 0.57, 95% CI 0.50-0.64 in 2003-09; 7.4% versus 17.4%, aRR 0.53, 95% CI 0.43-0.66 in 2010-14; and 7.2% versus 14.8%, aRR 0.59, 95% CI 0.48-0.74 in 2014-17). Conclusion Despite the ongoing improvements in neonatal care of preterm infants, as reflected by the gradual decrease in the absolute rates of neonatal mortality and severe neurological injury, the association of ACS treatment with neonatal mortality and severe neurological injury among extremely preterm infants born at 23-30 weeks of gestation has remained stable throughout the study period of 15 years. Tweetable abstract Despite the gradual decrease in the rates of neonatal mortality and severe neurological injury, antenatal corticosteroids remain an important intervention in the current era of neonatal care. more...

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).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.• 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.• 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. more...

BACKGROUND: Preterm infants are at risk of lung atelectasis due to various anatomical and physiological immaturities, placing them at high risk of respiratory failure and associated harms. Nasal continuous positive airway pressure (CPAP) is a positive pressure applied to the airways via the nares. It helps prevent atelectasis and supports adequate gas exchange in spontaneously breathing infants. Nasal CPAP is used in the care of preterm infants around the world. Despite its common use, the appropriate pressure levels to apply during nasal CPAP use remain uncertain. OBJECTIVES: To assess the effects of 'low' (≤ 5 cm H(2)O) versus 'moderate‐high' (> 5 cm H(2)O) initial nasal CPAP pressure levels in preterm infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation. SEARCH METHODS: We ran a comprehensive search on 6 November 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi‐randomized trials. SELECTION CRITERIA: We included RCTs, quasi‐RCTs, cluster‐RCTs and cross‐over RCTs randomizing preterm infants of gestational age < 37 weeks or birth weight < 2500 grams within the first 28 days of life to different nasal CPAP levels. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal to collect and analyze data. We used the GRADE approach to assess the certainty of the evidence for the prespecified primary outcomes. MAIN RESULTS: Eleven trials met inclusion criteria of the review. Four trials were parallel‐group RCTs reporting our prespecified primary or secondary outcomes. Two trials randomized 316 infants to low versus moderate‐high nasal CPAP for initial respiratory support, and two trials randomized 117 infants to low versus moderate‐high nasal CPAP following endotracheal extubation. The remaining seven studies were cross‐over trials reporting short‐term physiological outcomes. The most common potential sources of bias were absent or unclear blinding of personnel and assessors and uncertain selective reporting. Nasal CPAP for initial respiratory support after birth and neonatal resuscitation None of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta‐analysis. No trials reported on moderate‐severe neurodevelopmental impairment at 18 to 26 months. The remaining five outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate‐high nasal CPAP levels improve the outcomes of: death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.56 to 1.85; 1 trial, 271 participants); mortality by hospital discharge (RR 1.04, 95% CI 0.51 to 2.12; 1 trial, 271 participants); BPD at 28 days of age (RR 1.10, 95% CI 0.56 to 2.17; 1 trial, 271 participants); BPD at 36 weeks' PMA (RR 0.80, 95% CI 0.25 to 2.57; 1 trial, 271 participants), and treatment failure or need for mechanical ventilation (RR 1.00, 95% CI 0.63 to 1.57; 1 trial, 271 participants). We assessed the certainty of the evidence as very low for all five outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. Nasal CPAP following mechanical ventilation and endotracheal extubation One of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta‐analysis. On the basis of these data, we are uncertain whether low or moderate‐high nasal CPAP levels improve the outcome of treatment failure or need for mechanical ventilation (RR 1.52, 95% CI 0.92 to 2.50; 2 trials, 117 participants; I(2) = 17%; risk difference 0.15, 95% CI −0.02 to 0.32; number needed to treat for an additional beneficial outcome 7, 95% CI −50 to 3). We assessed the certainty of the evidence as very low due to risk of bias, inconsistency across the studies, and imprecise effect estimates. No trials reported on moderate‐severe neurodevelopmental impairment at 18 to 26 months or BPD at 28 days of age. The remaining three outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate‐high nasal CPAP levels improve the outcomes of: death or BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants); mortality by hospital discharge (RR 2.94, 95% CI 0.12 to 70.30; 1 trial, 93 participants), and BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants). We assessed the certainty of the evidence as very low for all three outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. AUTHORS' CONCLUSIONS: There are insufficient data from randomized trials to guide nasal CPAP level selection in preterm infants, whether provided as initial respiratory support or following extubation from invasive mechanical ventilation. We are uncertain as to whether low or moderate‐high nasal CPAP levels improve morbidity and mortality in preterm infants. Well‐designed trials evaluating this important aspect of a commonly used neonatal therapy are needed. more...

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To conduct a network meta‐analysis to evaluate the benefits and adverse effects of various NRS modes when used as primary support modes for preterm infants. more...

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and adverse effects of various NRS modes when used as post‐extubation support for preterm infants. more...

To compare short term respiratory outcomes in preterm infants treated with bovine lipid extract surfactant or poractant alfa.Prospective comparative effectiveness cohort study of infants32 weeks' gestational age requiring surfactant in thirteen centers. Each center provided bovine lipid extract surfactant for a set period of time in the year 2019 and then changed to poractant alfa for the remainder of the year. The primary outcome was total duration of respiratory support.968 infants were included. 494 received bovine lipid extract surfactant and 474 received poractant alfa. No difference was observed in the total duration of respiratory support (mechanical ventilation or non-invasive) (median 38 vs 40.5 days), need to re-dose surfactant, bronchopulmonary dysplasia, survival to discharge, or length of admission.In this pragmatic study, we did not identify any difference in short term outcomes between the groups based on the type of surfactant received. more...

To evaluate clinical outcomes associated with extubation timing among extremely preterm neonates.Neonates26 weeks' GA admitted to four tertiary neonatal centers were included if they met predetermined extubation criteria within first postnatal week and classified into early extubation (≤24 h; exposure group) and delayed extubation (24 h; control group) after meeting extubation criteria. Patients with known severe IVH and/or significant PDA prior to meeting extubation criteria were excluded.Of 197 included infants, 75 were in exposure group. Survival without BPD (aOR 1.26; 95% CI 0.62-2.56; P = 0.52) and survival without severe IVH (aOR 1.98; 95% CI 0.93-4.23; P = 0.08) were not different, adjusted for GA, SNAP, number of surfactant doses and center.Extubation within 24 h of meeting extubation criteria in neonates26 weeks' GA was not associated with survival without BPD or survival without severe IVH. However, confounding by indication cannot be ruled out without a prospective trial. more...

Umbilical cord arterial and venous blood gas values reflect the acid-base balance status of a newborn at birth. Derangement in these values has been linked to poor neonatal outcomes in term and late preterm neonates; however, the utility of these values in preterm neonates of29 weeks' gestation is unclear.This study aimed to determine the associations of umbilical cord arterial and venous blood gas values with neonatal mortality and severe neurologic injury in extremely preterm neonates and to identify the cutoff values associated with 2.5-fold increases or decreases in the posttest probabilities of outcomes.This was a retrospective cohort study of neonates who were born at 23+0 to 28+6 weeks' gestation between January 1, 2018 and December 31, 2019, and who were admitted to neonatal units in Canada.Various cut-offs of umbilical cord blood gas values and lactate values were studied.The main outcomes were mortality before discharge from the neonatal unit and severe neurologic injury defined as grade 3 or 4 periventricular or intraventricular hemorrhage or periventricular leukomalacia. The outcome rates were calculated for various cutoff values of umbilical cord blood gas parameters and were adjusted for birthweight, gestational age, sex, and multiple births. Likelihood ratios were calculated to derive posttest probabilities.A total of 1040 and 1217 neonates had analyzable umbilical cord arterial and venous blood gas values, respectively. In the cohort, the mean (standard deviation) gestational age was 26.5 (1.5) weeks, the mean birthweight was 936 (215) g, the prevalence of mortality was 10% (105/1040), and the prevalence of severe neurologic injury was 9% (92/1016). An umbilical cord arterial pH of ≤7.1 and base excess of ≤-12 mmol/L were associated with2.5-fold higher posttest probability of mortality, and an umbilical cord arterial or venous lactate value of3 was associated with a 2.5-fold lower posttest probability of mortality. An umbilical cord arterial lactate value of3 was associated with a lower posttest probability of severe neurological injury.In preterm neonates of29 weeks' gestation, low umbilical cord arterial pH and high umbilical cord arterial base excess values were associated with a clinically important increase in the posttest probability of mortality, whereas low umbilical cord arterial or venous lactate values were associated with a decrease in the posttest probability of mortality. more...

Objective: To evaluate the association of a combined exposure to antenatal steroids and prophylactic indomethacin with the outcome of spontaneous intestinal perforation (SIP) among neonates born at 7 days before birth) exposures. The co-exposure was prophylactic indomethacin. The primary outcome was SIP. Multivariable logistic regression analysis was used to calculate aORs. Results: Among 4720 eligible infants, 4121 (87%) received antenatal steroids and 1045 (22.1%) received prophylactic indomethacin. Among infants exposed to antenatal steroids, those who received prophylactic indomethacin had higher odds of SIP (aOR 1.61, 95% CI 1.14-2.28) compared with no prophylactic indomethacin. Subgroup analyses revealed recent antenatal steroids exposure with prophylactic indomethacin had higher odds of SIP (aOR 1.67, 95% CI 1.15-2.43), but latent antenatal steroids exposure with prophylactic indomethacin did not (aOR 1.24, 95% CI 0.48-3.21), compared with the respective groups with no prophylactic indomethacin. Among those not exposed to antenatal steroids, mortality was lower among those who received prophylactic indomethacin (aOR 0.45, 95% CI 0.28-0.73) compared with no prophylactic indomethacin. Conclusions: In preterm neonates of more...

Objective The aim of this study was to compare outcomes following receipt of high continuous positive airway pressure (CPAP) versus nasal intermittent positive pressure ventilation (NIPPV) in extremely preterm neonates. Study design We retrospectively compared outcomes of preterm neonates (22-28 weeks' gestation) following their first episode of either high CPAP (≥ 9 cmH2O) or NIPPV. Primary outcome was failure of high CPAP or NIPPV within 7 days, as determined by either need for intubation or use of an alternate noninvasive mode. Results During the 3-year study period, 53 infants received high CPAP, while 119 patients received NIPPV. There were no differences in the primary outcome (adjusted odds ratio 1.21; 95% confidence interval 0.49-3.01). The use of alternate mode of noninvasive support was higher with the use of high CPAP but no other outcome differences were noted. Conclusion Based on this cohort, there was no difference in incidence of failure between high CPAP and NIPPV, although infants receiving high CPAP were more likely to require an alternate mode of noninvasive support. Key points · Use of high CPAP pressures (defined as ≥9 cmH2O) is gradually increasing during care of preterm neonates.. · Limited data exists regarding its efficacy and safety.. · This study compares high CPAP with NIPPV, and demonstrates comparable short-term clinical outcomes.. more...

Objective To evaluate the physiological impact of high CPAP (≥9 cmH2O) vs. NIPPV at equivalent mean airway pressures. Study design In this cross-over study, preterm neonates on high CPAP or NIPPV were placed on the alternate mode. After 30 min, left and right ventricular cardiac output and work of breathing indices were assessed, following which patients were placed back on the original mode and a similar procedure ensued. Results Fifteen infants with mean (SD) postmenstrual age 32.7 (3.0) weeks, and weight 1569 (564) grams were included. No differences in LVO [320 (63) vs. 331 (86) mL/kg/min, P = 0.46] or RVO [420 (135) vs. 437 (141) mL/kg/min, P = 0.19] were noted during high CPAP vs. NIPPV, along with no differences in work of breathing indices. Conclusion High CPAP pressures did not adversely impact cardiac output or work of breathing compared to NIPPV at equivalent mean airway pressure. more...

Objective The study aimed to systematically review and analyze the impact of nasal intermittent positive pressure ventilation (NIPPV) versus continuous positive airway pressure (CPAP) on apnea of prematurity (AOP) in preterm neonates. Study Design In this systematic review and meta-analysis, experimental studies enrolling preterm infants comparing NIPPV (synchronized, nonsynchronized, and bi-level) and CPAP (all types) were searched in multiple databases and screened for the assessment of AOP. Primary outcome was AOP frequency per hour (as defined by authors of included studies). Results Out of 4,980 articles identified, 18 studies were included with eight studies contributing to the primary outcome. All studies had a high risk of bias, with significant heterogeneity in definition and measurement of AOP. There was no difference in AOPs per hour between NIPPV versus CPAP (weighted mean difference = −0.19; 95% confidence interval [CI]: −0.76 to 0.37; eight studies, 456 patients). However, in a post hoc analysis evaluating the presence of any AOP (over varying time periods), the pooled odds ratio (OR) was lower with NIPPV (OR: 0.46; 95% CI: 0.32–0.67; 10 studies, 872 patients). Conclusion NIPPV was not associated with decrease in AOP frequency, although demonstrated lower odds of developing any AOP. However, definite recommendations cannot be made based on the quality of the published evidence. Key Points more...

Objective To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). Study design Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. Results Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (−4.8 days less than reference, 95% CI –7.3 to −2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI –12.3 to −11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. Conclusions We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries. more...

BACKGROUND: To evaluate the utility of echocardiogram (ECHO) in detection and treatment of patent ductus arteriosus (PDA) and hemodynamically significant PDA (hsPDA) in preterm neonates. METHODS: This was a retrospective case-control study of all preterm infants born or admitted to the level III Neonatal Intensive Care Unit in McMaster Children’s Hospital from January 2009 to January 2013. These cases were further classified into the following sub-groups: group A) hsPDA confirmed on ECHO; and the control, group B) PDA (but not hemodynamically significant) confirmed on ECHO. Patients without an ECHO were excluded from all analyses. The primary outcome was incidence of treatment for PDA. RESULTS: PDA treatment was administered in 83.3% and 11.2% of patients in groups A and B respectively (P more...

OBJECTIVE To compare neurodevelopmental outcomes of large and appropriate for gestational age (LGA, AGA) infants

To describe Canadian parents' experiences with mode of birth for preterm singleton pregnancies; knowledge about maternal and infant risks of the different modes of preterm birth, particularly breech birth; and communication preferences with respect to mode of birth.We conducted an online survey of Canadian parents who had experienced the preterm birth of a live-born infant between 2010 and 2019. Data were collected from August to September 2019. The sample size was calculated as requiring 96 participants.Of the 153 respondents, 152 were mothers. Respondents were approximately evenly split between those who had experienced an extremely preterm birth (28 wk), a very preterm birth (28-31 wk), or a moderate-to-late preterm birth (32-36 wk). Most parents reported that mode of birth was discussed before the birth (61.7%, 73.3% and 77.3% for extremely, very, and moderate-to-late preterm births, respectively). The minority of parents reported being given a choice about mode of birth (20.8%, 23.0%, and 36.4% for extremely, very, and moderate-to-late preterm births, respectively). The use of written material during discussion on mode of birth was rare (2.1%, 3.3% and 6.8% for extremely, very, and moderate-to-late preterm births, respectively). Of women who had a cesarean delivery, 39.6% (36/91) were unaware of the maternal risks. Many parents expressed preference for both oral and written communication during counselling on mode of birth (62.6%).Few Canadian parents reported receiving a choice about mode of preterm birth, being aware of associated risks, or receiving written information. There is an urgent need to develop tools that provide information for parents facing preterm birth. more...

Objectives To determine the incidence and risk factors for pulmonary hypertension (PH) in preterm infants with moderate to severe bronchopulmonary dysplasia (BPD) and to compare short-term outcomes. Methods Preterm infants Results Of 92 infants with BPD, 87 had echocardiographic assessment, of whom 24 (28%) had PH. On multiple logistic regression after adjustment for gestational age and sex, no significant risk factors for PH were identified based on data from this cohort. There were no differences in resource utilization or clinical outcomes including survival to discharge. Conclusion Approximately one out of four patients with moderate to severe BPD were identified as having PH. No significant risk factors for PH were identified. No differences in outcomes were identified for those with and without PH. more...

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 220–286weeks (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 220–236weeks 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 260–286weeks, 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. more...

Objectives To identify characteristics and outcomes of infants who received multiple doses of surfactant vs those who received one dose or none. Study design In this retrospective study, we included neonates of 22–28 weeks’ gestation admitted to NICUs in the Canadian Neonatal Network. Patients were divided into three groups: no surfactant, single dose, and multiple doses. The primary outcome was a composite of mortality or any of the major morbidities, including severe neurological injury, bronchopulmonary dysplasia, or ≥stage 3 retinopathy of prematurity. Results Of 8024 eligible neonates, 2461 (31%) did not receive surfactant, 3545 (44%) received one dose, and 2018 (25%) received >1 dose. Receiving one or more doses of surfactant was associated with significantly higher adjusted odds of mortality or major morbidities in a dose-dependent manner. Conclusions Receiving one or more doses of surfactant was associated with adverse neonatal outcomes. Receipt of more than one dose may reflect underlying severe lung immaturity. more...

Impact of antenatal corticosteroid (ACS) in context of maternal body mass index (BMI) as it relates to neonatal outcomes remains unclear. We sought to evaluate effects of ACS on clinical outcomes of preterm infants based on maternal BMI.We performed a retrospective cohort study among neonates 23-33 weeks' GA at a tertiary neonatal intensive care unit from 2011 to 2015. Outcomes of neonates exposed to any ACS and pre-pregnancy maternal BMI ≥ 25 (N = 491) were compared with maternal BMI 25 (N = 484). A priori planned subgroup analyses based on ACS exposure (partial ACS; complete ACS ≤ 7 days prior to delivery (PTD); and complete ACS 7 days PTD) were conducted. Primary outcome was composite of mortality or any of moderate/severe bronchopulmonary dysplasia, severe neurologic injury, severe retinopathy of prematurity, necrotizing enterocolitis stage, or primary bloodstream infection.Preterm neonates with maternal BMI ≥ 25 (exposed to any ACS) were not at increased risk of composite outcome vs. BMI 25 (adjusted odd ratio (aOR) 1.03, 95% confidence interval (CI) 0.84-1.48), nor any individual neonatal morbidities. Similar findings were noted in subgroup analyses by type of ACS exposure.Impact of ACS on neonatal outcomes do not appear to be influenced by maternal BMI based on data from this cohort. However, further research is required to definitively elucidate the impact of BMI on ACS with regards to pharmacokinetics and neonatal outcomes. more...

Infants with restricted growth for age are frequently exposed to insufficient placental circulation and are more likely to develop postnatal complications. Delayed cord clamping at birth for these infants requires further exploration.This study aimed to compare the short-term neonatal outcomes of delayed cord clamping with that of early cord clamping in small for gestational age preterm infants and to explore whether the effects of delayed cord clamping in small for gestational age preterm infants are different from that in non-small for gestational age preterm infants.We conducted a national retrospective cohort study, including infants born at33 weeks' gestation and admitted to the Canadian Neonatal Network units between January 2015 and December 2017. Small for gestational age infants (birthweight of10th percentile for gestational age and sex) who received delayed cord clamping ≥30 seconds were compared with those who received early cord clamping. In addition, non-small for gestational age infants who received delayed cord clamping were compared with those who received early cord clamping. The main study outcomes included composite outcome of mortality or major morbidity, neonatal morbidity rate, mortality rate, peak serum bilirubin, and number of blood transfusions. Multivariable logistic and linear regression models with a generalized estimation equation approach were used to account for the clustering of infants within centers.Overall, 9722 infants met the inclusion criteria. Of those infants, 1027 (10.6%) were small for gestational age. The median (interquartile range) gestational age was 31 weeks (range, 28-32 weeks). After adjusting for potential confounders, delayed cord clamping in small for gestational age infants was associated with a reduction in the composite outcome of mortality or major morbidity (adjusted odds ratio, 0.60; 95% confidence interval, 0.42-0.86) compared with early cord clamping. There was no difference between the 2 groups in peak serum bilirubin. Many associated benefits of delayed cord clamping in small for gestational age infants were similar to those in non-small for gestational age infants.Delayed cord clamping in small for gestational age preterm infants was associated with decreased odds of mortality or major morbidity. Many of the benefits of delayed cord clamping in the small for gestational age preterm infants were similar to those identified in the non-small for gestational age preterm infants. more...

Pregnancy-induced hypertension (PIH) is associated with preterm delivery but its independent impact on neonatal outcomes remains unclear. We sought to systematically review and meta-analyze clinical outcomes of preterm infants37 weeks' gestation born to mothers with and without PIH.Medline, Embase, PsychINFO and CINAHL were searched from January 2000 to October 2016. Studies with low-moderate risk of bias reporting neonatal outcomes based on PIH as primary exposure variable were included. Data were extracted independently by two co-authors.PIH was associated with lower mortality (3 studies; adjusted odds ratio (aOR) 0.65; 95% confidence interval (CI) 0.54 to 0.79), lower severe retinopathy of prematurity (ROP) (2 studies; aOR 0.83; 0.72 to 0.96) and lower severe brain injury (2 studies; unadjusted OR (uOR) 0.57; 0.49 to 0.66). No association between PIH and short-term respiratory outcomes, bronchopulmonary dysplasia (BPD) or necrotizing enterocolitis (NEC) was identified. In subgroup analysis among infants29 weeks' gestation, BPD odds were higher (3 studies; aOR 1.15; 1.06 to 1.26), whereas mortality lower (2 studies; aOR 0.73; 0.69 to 0.77). In subgroup analysis limited to severe PIH, odds of mortality (3 studies; uOR 2.36; 1.07 to 5.22) and invasive ventilation (3 studies; uOR 3.26; 1.11 to 9.61) were higher. In subgroup analysis limited to preeclampsia, odds of BPD (3 studies; uOR 1.21; 95% CI:1.03 to 1.43) and NEC were higher (3 studies; uOR 2.79; 95% CI:1.57 to 4.96).PIH was associated with reduced odds of mortality and ROP (all infants), but higher odds for BPD (29 weeks' gestation). The paradoxical reduction in mortality may be due to survival bias and deserves further exploration in future studies. more...

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects ( CHDs ) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007–2015 at 24 to 31 weeks’ gestation with birth weights CHDs were defined by International Classification of Diseases, Ninth Revision ( ICD‐9 ) and Tenth ( ICD‐10 ) codes and categorized as those compromising systemic output, causing sustained cyanosis, or resulting in congestive heart failure. The primary outcome was in‐hospital mortality. Secondary outcomes were neonatal brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. Adjusted and propensity score–matched odds ratios ( ORs ) were calculated. Analyses were stratified by type of CHD , gestational age, and network. A total of 609 (0.77%) infants had severe CHD and 76 371 without any malformation served as controls. The mean gestational age and birth weight were 27.8 weeks and 1018 g, respectively. The mortality rate was 18.6% in infants with CHD and 8.9% in controls (propensity score–matched OR , 2.30; 95% CI , 1.61–3.27). Severe CHD was not associated with neonatal brain injury, necrotizing enterocolitis, or retinopathy of prematurity, whereas the OR for bronchopulmonary dysplasia increased. Mortality was higher in all types, with the highest propensity score–matched OR (4.96; 95% CI, 2.11–11.7) for CHD causing congestive heart failure. While mortality did not differ between groups at OR for mortality in infants with CHD increased to 10.9 (95% CI, 5.76–20.70) at 31 weeks’ gestational age. Rates of CHD and mortality differed significantly between networks. Conclusions Severe CHD is associated with significantly increased mortality in very preterm infants. more...

Objective To determine the delivery efficiency of budesonide aerosol via a mesh nebulizer in a neonatal ventilator model. Design/method In an in-vitro ventilated neonatal model, budesonide suspension was administered using a mesh nebulizer. A collection filter was placed distal to the endotracheal tube and budesonide captured by the filter was measured using UV spectroscopy. The ventilator was, in turn, either on high frequency or conventional ventilation mode and the nebulizer was placed either proximal (close to the endotracheal tube) or distal (between the wet side of humidifier and the inspiratory circuit). Each combination (nebulizer position and ventilation mode) to assess budesonide delivery was tested five times. Results Overall delivery of budesonide to the distal end of the endotracheal tube a small percentage of the total dose administered. The deposition with conventional ventilation was 2.12% (±1.06) and 1.26% (±0.27), with proximal and distal placement of the nebulizer, respectively. With high-frequency ventilation, the deposition percentages were 1.82% (±0.82) and 1.69% (±0.23), with proximal and distal nebulizer placement, respectively. Conclusion Only a small percentage of administered budesonide is delivered to the distal endotracheal tube, irrespective of ventilation mode, and nebulizer placement. more...

OBJECTIVE: Previously conducted cost-effectiveness analyses of pulse oximetry screening (POS) for critical congenital heart defects (CCHDs) have shown it to be a cost-effective endeavour, but the geographical setting of Ontario in relation to its vast yet sparsely populated regions presents unique challenges. The objective of this study was to estimate the cost-effectiveness of POS for CCHD in Ontario, Canada. METHODS: A cost-effectiveness analysis, comparing POS to no POS, was conducted from the Ontario healthcare payer perspective using a Markov model. The base case was defined as a well-appearing newborn at 24 h of age. Outcome measures, including quality-adjusted life months (QALMs), lifetime costs, and incremental cost-effectiveness ratios (ICER) [ΔCost/ΔQALMs], were calculated over a lifetime horizon. All outcomes were discounted at 1.5% per year. Cost-effectiveness was assessed using an a priori ICER threshold of CAD$4166.67 per QALM (equivalent to CAD$50,000 per quality-adjusted life year). Deterministic and probabilistic sensitivity analyses were conducted to assess parameter uncertainty. RESULTS: Implementation of POS is expected to lead to timely diagnosis of 51 CCHD cases annually. The incremental cost of performing POS was estimated to be $27.27 per screened individual, with a gain of 0.02455 QALMs. This yielded an ICER of CAD$1110.79 per QALM, well below the pre-determined threshold. The probabilistic sensitivity analysis estimated a 92.3% chance of routine implementation of POS being cost-effective. CONCLUSION: Routine implementation of POS for CCHD in Ontario is expected to be cost-effective. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.17269/s41997-019-00280-7) contains supplementary material, which is available to authorized users. more...

To develop and validate an itemized costing algorithm for in-patient neonatal intensive care unit (NICU) costs for infants born prematurely that can be used for quality improvement and health economic analyses.We sourced patient resource use data from the Canadian Neonatal Network database, with records from infants admitted to 30 tertiary NICUs in Canada. We sourced unit cost inputs from Ontario hospitals, schedules of benefits, and administrative sources. Costing estimates were generated by matching patient resource use data to the appropriate unit costs. All cost estimates were in 2017 Canadian dollars and assigned from the perspective of a provincial public payer. Results were validated using previous estimates of inpatient NICU costs and hospital case-cost estimates.We assigned costs to 27 742 infants born prematurely admitted from 2015 to 2017. Mean (SD) gestational age and birth weight of the cohort were 31.8 (3.5) weeks and 1843 (739) g, respectively. The median (IQR) cost of hospitalization before NICU discharge was estimated as $20 184 ($9739-51 314) for all infants; $11 810 ($6410-19 800) for infants born at gestational age of 33-36 weeks; $30 572 ($16 597-$51 857) at gestational age of 29-32 weeks; and $100 440 ($56 858-$159 3867) at gestational age of29 weeks. Cost estimates correlated with length of stay (r = 0.97) and gestational age (r = -0.65). The estimates were consistent with provincial resource estimates and previous estimates from Canada.NICU costs for infants with preterm birth increase as gestation decreases and length of stay increases. Our cost estimates are easily accessible, transparent, and congruent with previous cost estimates. more...

BackgroundUse of bubble continuous positive airway pressure (CPAP) has generated considerable interest in neonatal care, but its comparative effectiveness compared with other forms of CPAP, especially in developed countries, remains unclear.ObjectiveTo systematically review and meta-analyse short-term clinical outcomes among preterm infants treated with bubble CPAP vs all other forms of CPAP.MethodsProspective experimental studies published from 1995 onward until October 2018 comparing bubble versus other CPAP forms in preterm neonates ResultsA total of 978 articles were identified, of which 19 articles were included in meta-analyses. Of these, 5 had a high risk of bias, 8 had unclear risk and 6 had low risk. The risk of the primary outcome (CPAP failure within 7 days) was lower with bubble CPAP (0.75; 95% CI 0.57 to 0.98; 12 studies, 1194 subjects, I2=21%). Among secondary outcomes, only nasal injury was higher with use of bubble CPAP (risk ratio (RR) 2.04, 95% CI 1.33 to 3.14; 9 studies, 983 subjects; I2=42%) whereas no differences in mortality (RR 0.82, 95% CI 0.47 to 1.92; 9 studies, 1212 subjects, I2=20%) or bronchopulmonary dysplasia (BPD) (RR 0.8, 95% CI 0.53 to 1.21; 8 studies, 816 subjects, I2=0%) were noted.ConclusionBubble CPAP may lead to lower incidence of CPAP failure compared with other CPAP forms. However, it does not appear to translate to improvement in mortality or BPD and potential for nasal injury warrants close monitoring during clinical application.Trial registration numberCRD42019120411. more...

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. more...

To examine rates and determinants of mother's own milk (MOM) feeding at hospital discharge in a cohort of infants born very preterm within the Canadian Neonatal Network (CNN).This was a population-based cohort study of infants born at33 weeks of gestation and admitted to neonatal intensive care units (NICUs) participating in the CNN between January 1, 2015, and December 31, 2018. We examined the rates and determinants of MOM use at discharge home among the participating NICUs. We used multivariable logistic regression analysis to identify independent determinants of MOM feeding.Among the 6404 infants born very preterm and discharged home during the study period, 4457 (70%) received MOM or MOM supplemented with formula. Rates of MOM feeding at discharge varied from 49% to 87% across NICUs. Determinants associated with MOM feeding at discharge were gestational age 29-32 weeks compared with26 weeks (aOR 1.56, 95% CI 1.25-1.93), primipara mothers (aOR 2.12, 95% CI 1.86-2.42), maternal diabetes (aOR 0.79, 95% CI 0.66-0.93), and maternal smoking (aOR 0.27, 95% CI 0.19-0.38). Receipt of MOM by day 3 of age was the major predictor of breast milk feeding at discharge (aOR 3.61, 95% CI 3.17-4.12).Approximately two-thirds of infants born very preterm received MOM at hospital discharge, and rates varied across NICUs. Supporting mothers to provide breast milk in the first 3 days after birth may be associated with improved MOM feeding rates at discharge. more...

Objective To evaluate the impact of prophylactic indomethacin on early death ( Study design This was a multicenter, retrospective cohort study of neonates (n = 12 515) born at 236/7 weeks of gestational age, admitted to neonatal intensive care units participating in the Canadian Neonatal Network who received prophylactic indomethacin started within the first 12 hours after birth. Univariate and multivariate analysis compared the composite outcomes of early death or severe neurologic injury and early death or spontaneous intestinal perforation. Results Of 12 515 eligible neonates, 1435 (11.5%) were exposed to prophylactic indomethacin; recipients were of lower gestational age and birth weight and had greater severity of illness (Score of Neonatal Acute Physiology with Perinatal Extension) on admission compared with nonrecipients. After we adjusted for confounders, prophylactic indomethacin was associated with reduced odds of early death or severe neurologic injury and early death or spontaneous intestinal perforation in neonates born at 23-24 weeks of gestational age. However, prophylactic indomethacin was associated with increased odds of early mortality or spontaneous intestinal perforation for neonates born at 26-28 weeks of gestational age. Conclusions Prophylactic indomethacin use was associated with benefit in neonates born at 23-24 weeks of gestational age, but with harm at 26-28 weeks of gestational age. Given the observation of significantly improved survival, a randomized controlled trial is needed to investigate the effect of prophylactic indomethacin in babies born at 23-25 weeks of gestational age. more...