Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants.

OBJECTIVE: Assess if unit-level PDA management correlates with neurodevelopmental impairment (NDI) at 18-24 months corrected postnatal age (CPA) in extremely preterm infants. STUDY DESIGN: Retrospective analysis of infants born at <29 weeks (2014-2017) across two units having distinct PDA strategies. Site 1 utilized an echocardiography-based treatment strategy aiming for accelerated closure (control). Site 2 followed a conservative approach. PRIMARY ENDPOINT: NDI, characterized by cerebral palsy, any Bayley-III composite score <85, sensorineural/mixed hearing loss, or at least unilateral visual impairment. RESULTS: 377 infants were evaluated. PDA treatment rates remained unchanged in Site 1 but eventually reached 0% in Site 2. Comparable rates of any/significant NDI were seen across both sites (any NDI: 38% vs 36%; significant NDI: 13% vs 10% for Site 1 and 2, respectively). After adjustments, NDI rates remained similar. CONCLUSION: PDA management strategies in extremely preterm newborns showed no significant impact on neurodevelopment outcomes at 18-24 months CPA.

Incidence and risk factors for autism spectrum disorder among infants born <29 weeks' gestation.

Objective: This study was aimed to assess the incidence of and risk factors for autism spectrum disorder (ASD) among preterm infants born <29 weeks' gestational age (GA). Methods: A retrospective cohort study of infants born <29 weeks' GA admitted to two tertiary neonatal intensive care units (2009 to 2017) and followed ≥18 months corrected age (CA) at a neonatal follow-up clinic. The primary outcome was ASD, diagnosed using standardized testing or provisional diagnosis at ≥18 months CA. Patient data and 18-month CA developmental outcomes were obtained from the local Canadian Neonatal Follow Up Network database and chart review. Stepwise logistic regression assessed factors associated with ASD. Results: Among 300 eligible infants, 26 (8.7%) were diagnosed with confirmed and 21 (7.0%) with provisional ASD for a combined incidence of 15.7% (95% confidence interval [CI] 11.7 to 20.3). The mean follow-up duration was 3.9 ± 1.4 years and the mean age of diagnosis was 3.7 ± 1.5 years. Male sex (adjusted odds ratio [aOR] 4.63, 95% CI 2.12 to 10.10), small for gestational age status (aOR 3.03, 95% CI 1.02 to 9.01), maternal age ≥35 years at delivery (aOR 2.22, 95% CI 1.08 to 4.57) and smoking during pregnancy (aOR 5.67, 95% CI 1.86 to 17.29) were significantly associated with ASD. Among ASD infants with a complete 18-month CA developmental assessment, 46% (19/41) had no neurodevelopmental impairment (Bayley-III<70, deafness, blindness, or cerebral palsy). Conclusions: ASD is common among infants born <29 weeks' GA and possibly associated with identified risk factors. Such findings emphasize the importance of ASD evaluation among infants <29 weeks' GA and for continued reporting of developmental outcomes beyond 18-months of corrected age.

Optimizing timing and frequency of head ultrasound screening for severe brain injury among preterm infants born <32 weeks' gestation.

OBJECTIVE: To develop a head ultrasound (HUS) screening protocol for infants born <32 weeks gestational age (GA) that accurately identifies severe brain injury (SBI) while minimizing resource use. STUDY DESIGN: Retrospective cohort study of infants born <32 weeks GA, admitted to a level 3 neonatal intensive care unit between 2011 and 2017. Timing and results of each HUS were reviewed. SBI was defined as intraventricular hemorrhage grade ≥3 and/or periventricular leukomalacia. Logistic regression models were used to identify risk factors and evaluate the predictive value of HUS at different time points during hospitalization. RESULTS: Of 651 included infants, 71 (11%) developed SBI. Risk factors for SBI were GA at birth <29 weeks (adjusted odds ratio (aOR) 2.87, 95% confidence interval (CI) 1.50-5.48), vasopressors on admission (aOR 3.08, 95%CI 1.38-6.88) and mechanical ventilation on admission (aOR 2.50, 95%CI 1.33-4.68). Infants were classified into three risk groups based on these risk factors, and combinations of 1-5 HUS time points were evaluated to determine the optimal number and timing of HUS for each group. The optimal number of screening HUS ranged from 1 for low-risk to 2 for high-risk infants. Adopting a screening protocol using the number and timing of HUS optimized by risk group could reduce the total number of HUS performed by 40% and the median number of HUS per infant from 3 (IQR 2-4) to 2 (IQR 1-3) (p < .01). CONCLUSIONS: Implementation of a risk factor-based HUS screening protocol can help reduce resource use while maintaining high sensitivity for detecting SBI.

Neonatal outcomes of twins <29 weeks gestation of mothers with hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are associated with dysfunctional placentation and are a major cause of maternal and neonatal morbidity and mortality. Twin pregnancies have a larger placental mass and are a risk factor for HDP. The effect of HDP on neonatal outcomes in twin pregnancies is unknown. METHODS: Retrospective cohort study using the Canadian Neonatal Network database from 2010-2018 of twin infants <29 weeks gestation born to mothers with HDP and normotensive pregnancies. Using multivariable models, we determined adjusted odds ratios (AORs) and 95% confidence intervals (CI) for mortality, bronchopulmonary dysplasia, severe neurologic injury, severe retinopathy of prematurity (ROP), necrotizing enterocolitis, and nosocomial infection in twin infants of mothers with HDP compared to twin infants of normotensive mothers. RESULTS: Of the 2414 eligible twin infants <29 weeks gestational age, 164 (6.8%) were born to mothers with HDP and had higher odds of severe ROP (AOR 2.48, 95% CI 1.34-4.59). Preterm twin infants born to mothers with HDP also had higher odds of mortality (AOR 2.02, 95% CI 1.23-3.32). There was no difference in other outcomes. CONCLUSION: Preterm twin infants <29 weeks gestation of HDP mothers have higher odds of severe ROP and mortality. IMPACT: Hypertensive disorders of pregnancy, associated with placental dysfunction, are a major cause of maternal and neonatal morbidity and mortality. Twin pregnancy, associated with a larger placental mass, is a risk factor for hypertensive disorders of pregnancy. The effect of hypertensive disorders of pregnancy on outcomes of preterm twins is unknown. Preterm twins of mothers with hypertensive disorders of pregnancy are at higher risk of severe retinopathy of prematurity and mortality. Our data can be used to counsel parents and identify infants at higher risk of severe retinopathy of prematurity and mortality.

Association of umbilical cord blood gas values with mortality and severe neurologic injury in preterm neonates <29 weeks' gestation: a national cohort study.

BACKGROUND: 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 of <29 weeks' gestation is unclear. OBJECTIVE: 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. STUDY DESIGN: 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. EXPOSURE: Various cut-offs of umbilical cord blood gas values and lactate values were studied. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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 with >2.5-fold higher posttest probability of mortality, and an umbilical cord arterial or venous lactate value of <3 was associated with a 2.5-fold lower posttest probability of mortality. An umbilical cord arterial lactate value of <3 was associated with a lower posttest probability of severe neurological injury. CONCLUSION: In preterm neonates of <29 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.

Association of Delivery Room and Neonatal Intensive Care Unit Intubation, and Number of Tracheal Intubation Attempts with Death or Severe Neurological Injury among Preterm Infants.

OBJECTIVE: The study aimed to assess the association of tracheal intubation (TI) and where it is performed, and the number of TI attempts with death and/or severe neurological injury (SNI) among preterm infants. STUDY DESIGN: Retrospective cohort study of infants born 23 to 32 weeks, admitted to a single level-3 neonatal intensive care unit (NICU) between 2015 and 2018. Exposures were location of TI (delivery room [DR] vs. NICU) and number of TI attempts (1 vs. >1). Primary outcome was death and/or SNI (intraventricular hemorrhage grade 3-4 and/or periventricular leukomalacia). Multivariable logistic regression analysis was used to assess association between exposures and outcomes and to adjust for confounders. RESULTS: Rate of death and/or SNI was 2.5% (6/240) among infants never intubated, 12% (13/105) among NICU TI, 32% (31/97) among DR TI, 20% (17/85) among infants with one TI attempt and 23% (27/117) among infants with >1 TI attempt. Overall, median number of TI attempts was 1 (interquartile range [IQR]: 1-2). Compared with no TI, DR TI (adjusted odds ratio [AOR]: 9.04, 95% confidence interval [CI]: 3.21-28.84) and NICU TI (AOR: 3.42, 95% CI: 1.21-10.61) were associated with higher odds of death and/or SNI. The DR TI was associated with higher odds of death and/or SNI compared with NICU TI (AOR: 2.64, 95% CI: 1.17-6.22). The number of intubation attempts (1 vs. >1) was not associated with death and/or SNI (AOR: 0.95, 95% CI: 0.47-2.03). CONCLUSION: The DR TI is associated with higher odds of death and/or SNI compared with NICU TI, and may help identify higher risk infants. There was no association between the number of TI attempts and death and/or SNI. KEY POINTS: · Delivery room intubation correlates with morbidity.. · Less than 2 intubation attempts are not associated with IVH.. · Provider training reduces intubation attempts..

Outcomes of Extremely Premature Infants Comparing Patent Ductus Arteriosus Management Approaches.

OBJECTIVE: To evaluate the change in the proportion of deaths/bronchopulmonary dysplasia (BPD) among premature infants (born <26 and 26-29 weeks of gestational age) following a policy change to a strict nonintervention approach, compared with standard treatment. STUDY DESIGN: We examined 1249 infants (341 born <26 weeks of gestational age) at 2 comparable sites. Site 1 (control) continued medical treatment/ligation, and site 2 (exposed) changed to a nonintervention policy in late 2013. Using the difference-in-differences approach, which accounts for time-invariant differences between sites and secular trends, we assessed changes in death or BPD separately among infants born 26-29 weeks and <26 weeks of gestational age in 2 epochs (epoch 1: 2011-2013; epoch 2: 2014-2017). RESULTS: Baseline characteristics were similar across sites and epochs. Medical treatment/ligation use remained stable at site 1 but declined progressively to 0% at site 2, indicating adherence to policy. We saw no difference in death/BPD among infants born at 26-29 weeks of gestational age (12%, 95% CI -1% to 24%). However, incidence of death/BPD increased by 31% among infants born <26 weeks of gestational age (95% CI 10%-51%) in site 2, whereas there was no change in outcomes in site 1. The Score for Neonatal Acute Physiology-Version II, used as a control outcome, did not change in either site, suggesting that our findings were not due to changes in patients' severity. CONCLUSIONS: Adherence to a strict conservative policy did not impact death or BPD among 26 weeks but was associated with a significant rise in infants born <26 weeks.

Fluid status in the first 10 days of life and death/bronchopulmonary dysplasia among preterm infants.

OBJECTIVE: To investigate the association between fluid and sodium status in the first 10 postnatal days and death/bronchopulmonary dysplasia (BPD) among infants born <29 weeks' gestation. STUDY DESIGN: Single center retrospective cohort study (2015-2018) of infants born 23-28 weeks'. Three exposure variables were evaluated over the first 10 postnatal days: cumulative fluid balance (CFB), median serum sodium concentration, and maximum percentage weight loss. Primary outcome was death and/or BPD. Multivariable logistic regression adjusting for patient covariates was used to assess the association between exposure variables and outcomes. RESULTS: Of 191 infants included, 98 (51%) had death/BPD. Only CFB differed significantly between BPD-free survivors and infants with death/BPD: 4.71 dL/kg (IQR 4.10-5.12) vs 5.11 dL/kg (IQR 4.47-6.07; p < 0.001). In adjusted analyses, we found an association between higher CFB and higher odds of death/BPD (AOR 1.56, 95% CI 1.11-2.25). This was mainly due to the association of CFB with BPD (AOR 1.60, 95% CI 1.12-2.35), rather than with death (AOR 1.08, 95% CI 0.54-2.30). CONCLUSION: Among preterm infants, a higher CFB in the first 10 days after delivery is associated with higher odds of death/BPD. IMPACT: Previous studies suggest that postnatal fluid status influences survival and respiratory function in neonates. Fluid balance, serum sodium concentration, and daily weight changes are commonly used as fluid status indicators in neonates. We found that higher cumulative fluid balance in the first 10 days of life was associated with higher odds of death/bronchopulmonary dysplasia in neonates born <29 weeks. Monitoring of postnatal fluid balance may be an appropriate non-invasive strategy to favor survival without bronchopulmonary dysplasia. We developed a cumulative fluid balance chart with corresponding thresholds on each day to help design future trials and guide clinicians in fluid management.

"Optimal surfactant delivery protocol using the bovine lipid extract surfactant: a quality improvement study".

IMPORTANCE: Episodes of severe airway obstruction (SAO) are reported during surfactant administration. OBJECTIVE: To evaluate adherence to and impact of a surfactant protocol on adverse events. METHODS: An evidence-based protocol for surfactant administration was developed (2011), implemented (2012) and re-implemented (2014), including three major steps: lung recruitment, manual bagging, and bolus instillation. Three epochs were evaluated: E0 (2010), E1 (2015) and E2 (2018). Adherence was defined as compliance with all steps. Adverse events such as hypoxia (<80%) and severe airway obstruction (SAO) were investigated. RESULTS: 197 infants (246 administrations) were included: E0 81 (110), E1 52 (63), and E2 64 (73). Adherence improved from 49% (E1) to 67% (E2). Full adherence to protocol significantly decreased SAO from 26% to 1.25% (E2; p < 0.005) and hypoxia/bradycardia events (5 to 0% E2; p < 0.005), without any side effects. CONCLUSIONS: Adherence to a surfactant administration protocol improved over time and significantly decreased important adverse events.

Actuarial Survival Based on Gestational Age in Days at Birth for Infants Born at <26 Weeks of Gestation.

OBJECTIVE: To provide comprehensive, contemporary information on the actuarial survival of infants born at 22-25 weeks of gestation in Canada. STUDY DESIGN: In a retrospective cohort study, we included data from preterm infants of 22-25 weeks of gestation admitted to neonatal intensive care units participating in the Canadian Neonatal Network between 2010 and 2017. Infants with major congenital anomalies were excluded. We calculated gestational age using in vitro fertilization date, antenatal ultrasound dating, last menstrual period, obstetrical estimate, or neonatal estimate (in that order). Infants were followed until either discharge or death. Each day of gestational age was considered a category except for births at 22 weeks, where the first 4 days were grouped into one category and the last 3 days were grouped into another category. For each day of life, an actuarial survival rate was obtained by calculating how many infants survived to discharge out of those who had survived up to that day. RESULTS: Of 4335 included infants, 85, 679, 1504, and 2067 were born at 22, 23, 24, and 25 weeks of gestation, respectively. Survival increased from 32% at 22 weeks to 83% at 254-6/7 weeks. Graphs of actuarial survival developed for the first 6 weeks after birth in male and female children indicated a steep increase in survival during the first 7-10 days postnatally. CONCLUSIONS: Survival increased steadily with postnatal survival and was dependent on gestational age in days and sex of the child.

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

OBJECTIVE: To examine the differences and trends of outcomes of preterm boys and girls born at <29 weeks' gestation. DESIGN: A retrospective cohort study. SETTING: Data collected by the Canadian Neonatal Network. PATIENTS: Neonates born at <29 weeks' gestation between January 2007 and December 2016. MAIN OUTCOME MEASURES: We examined rate differences in mortality, major morbidities (bronchopulmonary dysplasia, severe brain injury, retinopathy of prematurity, necrotising enterocolitis and late-onset sepsis) and care practices (antenatal steroids, magnesium sulfate, maternal antibiotics, ventilation and surfactant administration) between boys and girls and evaluated trends in these rate differences over the study period. Our primary outcome was a composite of mortality and any one of the five morbidities. RESULTS: Our study included 8219 boys and 6934 girls with median gestational age of 26 (IQR 25-28) weeks. The composite of death or major morbidity was more common in boys (adjusted risk ratio 1.07, 95% CI 1.05 to 1.10) and remained higher in boys over the study period. The gap between boys and girls for mortality, however, decreased over time: the slope for boys was -0.043 (95% CI -0.071 to -0.015) and for girls was -0.012 (95% CI -0.045 to 0.020) (p=0.04). All other morbidities remained higher in boys. Care practices changed at similar rates between the sexes. CONCLUSION: The difference between the mortality rates for boys and girls decreased over the study period but the difference between rates of the major morbidities was unchanged. More research is needed to understand biological differences and outcome disparities.

Association of Caloric Intake, Protein Intake, and Enteral Feeding Initiation with Weight Gain in Infants Born 32 to 34 Weeks' Gestation.

OBJECTIVE: This study aimed to determine the association of caloric intake, protein intake, and enteral feed initiation time in the first 3 days of life with weight loss percentage (%WL) at 7 days among infants born 32 to 34 weeks' gestational age (GA). STUDY DESIGN: This is a retrospective cohort study of 252 infants admitted to a neonatal intensive care unit. Patient data included patient characteristics, daily weight, intake, and method of nutrition in the first 3 days. Multivariate linear regression was used to explore associations between outcome (%WL at day 7 of life) and exposures (caloric intake, protein intake, and enteral feed initiation time) and adjusted for covariates (GA, birth weight, and sex). RESULTS: Median 7 days %WL was 2.3% (interquartile range: -5.2, 1.2). Average caloric intake and average protein intake in the first 3 days were 57 kcal/kg/d and 2.3 g/kg/d. In the adjusted linear regression, caloric intake and protein intake (coefficient = 0.03, 95% confidence interval [CI]: -0.06, 0.09 and coefficient = 0.11, 95% CI: -0.36, 2.30) were not associated with %WL at 7 days. Enteral feeds ≤12 hours were associated with less %WL at 7 days of life (Coef = -0.15, 95% CI: -2.67, -0.17). CONCLUSION: Enteral feeds ≤12 hours after delivery is associated with lower %WL at 7 days among preterm infants 32 to 34 weeks' GA.

Neonates with a 10-min Apgar score of zero: Outcomes by gestational age.

BACKGROUND: The current resuscitation guidelines for neonates recommend considering stopping resuscitation efforts if the heart rate remains undetectable after 10 min of adequate resuscitation. However, this recommendation does not take into account the gestational age (GA) of the neonates. We determined the outcomes of neonates with a 10-min Apgar score of zero (Apgar10 = 0) with respect to their GA. METHODS: In a retrospective matched cohort study, we studied neonates admitted to the Canadian Neonatal Network NICUs between 2010 and 2016 with an Apgar10 = 0. The neonates were divided into 3 subgroups according to their GA: (1) ≥36 weeks', (2) 320/7-356/7 weeks', and (3) <32 weeks'. Each neonate with Apgar10 = 0 was matched 1:1 with neonates of same GA and sex but Apgar10 = 1-2 and Apgar10 = 3-5. Survival and brain injury were compared between matched groups. RESULTS: 177 neonates had Apgar10 = 0. Survival to discharge was significantly different between GA groups [≥36 weeks' 61% vs. 320/7-356/7 weeks' 58% vs. <32 weeks' 35%, p = 0.04]. Survival to discharge was similar to their matched cohort with Apgar10 = 1-2 for neonates born at ≥36 weeks' (61% vs. 66%) and between 320/7 to 356/7 weeks' (58% vs. 54%), but significantly different for neonates <32 weeks (35% vs. 61%, p = 0.04). CONCLUSION: Neonates with Apgar10 = 0 had different outcomes depending on their GA. Less than half of neonates born at <32 weeks GA survived; however, a majority of neonates born at 320/7-356/7 weeks' and ≥36 weeks' GA survived at similar rates than their matched neonates with Apgar10 = 1-2.

Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns.

Bronchopulmonary dysplasia (BPD) is a common long-term complication in premature newborns requiring ventilatory support and is the most common cause of chronic diffuse lung disease in this population. We present the clinical course of a premature newborn with a complicated neonatal respiratory course that was initially thought to be related to BPD, but it did not respond to the typical therapies for this condition. Due to the findings of periventricular nodular heterotopia, the diagnosis of a filamin A gene mutation was eventually made, which explained the respiratory pathology of this patient. When time of onset and clinical course do not correlate with typical BPD, one should consider alternative diagnoses in premature infants, including neonatal diffuse lung disease.