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OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

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OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

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OBJECTIVE: To assess the longitudinal trajectory of cognitive, language, and motor outcomes from 18 months to 4.5 years of age in children born very preterm. STUDY DESIGN: This was a prospective cohort study of 163 infants born very preterm (born 24-32 weeks of gestation) followed longitudinally and assessed with neurodevelopmental scales and magnetic resonance imaging of the brain. Outcomes at 18 months and 3 years were assessed with the Bayley Scales of Infant and Toddler Development, 3rd Edition, and at 4.5 years with the Wechsler Preschool and Primary Scale of Intelligence-III and the Movement Assessment Battery for Children. Cognitive, language, and motor outcomes were categorized as below-average, average, and above-average, and compared across time. Clinical data were analyzed using ANOVA, χ2 tests, and linear regression. RESULTS: Cognitive and language trajectories were stable from 18 months to 4.5 years for all outcome groups. Motor impairment increased over time, with a greater proportion of children having motor deficits at 4.5 years. Children with below-average cognitive and language outcomes at 4.5 years had more clinical risk factors, greater white matter injury, and lower maternal education. Children with severe motor impairment at 4.5 years were born earlier, had more clinical risk factors, and demonstrated greater white matter injury. CONCLUSIONS: Children born preterm have stable cognitive and language trajectories, while motor impairment increased at 4.5 years. These results highlight the importance of continued developmental surveillance for children born preterm into preschool age.

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OBJECTIVE: To evaluate the relationship of quantitative ventricular volume with brain maturation and neurodevelopmental outcomes at age 4.5 years in children born very preterm. STUDY DESIGN: T1-weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy were performed shortly after birth (n = 212) and at term-equivalent age (TEA) (n = 194). Intraventricular hemorrhage (IVH) grade and white matter injury (WMI) volume were measured on early T1-weighted magnetic resonance imaging (MRI) scans. Total cerebral volume and ventricular volume were quantified using the Multiple Automatically Generated Templates-Brain pipeline. At age 4.5 years, 178 children (84%) underwent cognitive and motor assessments. Multivariable linear regression was used to examine the relationships between ventricular volume and neurodevelopmental outcomes. Generalized estimating equations were used to account for repeated measures when analyzing neonatal MRI data. All models accounted for sex, postmenstrual age at scan, WMI volume, IVH grade, and total cerebral volume and were corrected for multiple comparisons. RESULTS: On early MRI, 97 infants had IVH (grade 1, n = 22; grade 2, n = 66; grade 3, n = 9), and 68 had WMI (median, 44 mm3; IQR, 21-296 mm3). IQ at 4.5 years was associated with MRI ventricular volume at the early (ß = -0.64; P < .001) and TEA (ß = -0.44, P < .001) time points. Motor outcomes were associated with ventricular volume at TEA (ß = -0.84, P = .01). Greater ventricular volume independently predicted lower fractional anisotropy in corpus callosum (genu: ß = -0.0008, P = .002; splenium: ß = -0.003, P < .001) and optic radiations (ß = -0.001, P = .004); ventricular volume did not predict the N-acetylaspartate/choline ratio. CONCLUSIONS: In children born very preterm, neonatal ventricular size was associated with 4.5-year neurodevelopmental outcomes. Our findings suggest that white matter maturation may be abnormal in the setting of enlarged ventricular size beyond that expected from concurrent brain injuries.

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OBJECTIVES: To determine, in children born preterm, the association of mechanical ventilation duration with brainstem development, white matter maturation, and neurodevelopmental outcomes at preschool age. STUDY DESIGN: This prospective cohort study included 144 neonates born at <30 weeks of gestation (75 male, mean gestational age 27.1 weeks, SD 1.6) with regional brainstem volumes automatically segmented on magnetic resonance imaging at term-equivalent age (TEA). The white matter maturation was assessed by diffusion tensor imaging and tract-based spatial statistics. Neurodevelopmental outcomes were assessed at 4.5 years of age using the Movement Assessment Battery for Children, 2nd Edition, and the Wechsler Primary and Preschool Scale of Intelligence, 4th Edition, full-scale IQ. The association between the duration of mechanical ventilation and brainstem development was validated in an independent cohort of children born very preterm. RESULTS: Each additional day of mechanical ventilation predicted lower motor scores (0.5-point decrease in the Movement Assessment Battery for Children, 2nd Edition, score by day of mechanical ventilation, 95% CI -0.6 to -0.3, P < .0001). Prolonged exposure to mechanical ventilation was associated with smaller pons and medulla volumes at TEA in 2 independent cohorts, along with widespread abnormalities in white matter maturation. Pons and medulla volumes at TEA predicted motor outcomes at 4.5 years of age. CONCLUSIONS: In neonates born very preterm, prolonged mechanical ventilation is associated with impaired brainstem development, abnormal white matter maturation, and lower motor scores at preschool age. Further research is needed to better understand the neural pathological mechanisms involved.

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OBJECTIVES: To determine prevalence and risk factors for brain injury in infants with critical congenital heart disease (CHD) from 2 sites with different practice approaches who were scanned clinically. STUDY DESIGN: Prospective, longitudinal cohort study (2016-2017) performed at Hospital for Sick Children Toronto (HSC) and Wilhelmina Children's Hospital Utrecht (WKZ), including 124 infants with cardiac surgery ≤60 days (HSC = 77; WKZ = 47). Magnetic resonance imaging was performed per clinical protocol, preoperatively (n = 100) and postoperatively (n = 120). Images were reviewed for multifocal (watershed, white matter injury) and focal ischemic injury (stroke, single white matter lesion). RESULTS: The prevalence of ischemic injury was 69% at HSC and 60% at WKZ (P = .20). Preoperative multifocal injury was associated with low cardiac output syndrome (OR, 4.6), which was equally present at HSC and WKZ (20% vs 28%; P = .38). Compared with WKZ, HSC had a higher prevalence of balloon-atrioseptostomy in transposition of the great arteries (83% vs 53%; P = .01) and more frequent preoperative focal injury (27% vs 6%; P = .06). Postoperatively, 30% of new multifocal injury could be attributed to postoperative low cardiac output syndrome, which was equally present at HSC and WKZ (38% vs 28%; P = .33). Postoperative focal injury was associated with intraoperative selective cerebral perfusion in CHD with arch obstruction at both sites (OR, 2.7). Compared with HSC, WKZ had more arch obstructions (62% vs 35%; P < .01) and a higher prevalence of new focal injury (36% vs 16%; P = .01). CONCLUSIONS: Brain injury is common in clinical cohorts of infants with critical CHD and related to practice approaches. This study confirms that the high prevalence of brain injury in critical CHD is a clinical concern and does not simply reflect the inclusion criteria of published research studies.

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OBJECTIVES: To evaluate whether the number of postnatal infections is associated with abnormal white matter maturation and poorer motor neurodevelopmental outcomes at 36 months of corrected age. STUDY DESIGN: A prospective longitudinal cohort study was undertaken of 219 newborns born preterm at 24-32 weeks of gestational age recruited between 2006 and 2013 with magnetic resonance imaging of the brain both early in life and at term-equivalent age. Postnatal infection was defined as any clinical infection or positive culture ≥72 hours after birth. White matter maturation was assessed by magnetic resonance spectroscopic imaging, magnetic resonance diffusion tensor imaging, and tract-based spatial statistics. Neurodevelopmental outcomes were assessed in 175 (82% of survivors) infants with Bayley Scales of Infant and Toddler Development-III composite scores and Peabody Developmental Motor Scales at 35 months of corrected age (IQR 34-37 months). Infection groups were compared via the Fisher exact test, Kruskal-Wallis test, and generalized estimating equations. RESULTS: Of 219 neonates born preterm (median gestational age 27.9 weeks), 109 (50%) had no postnatal infection, 83 (38%) had 1 or 2 infections, and 27 (12%) had ≥3 infections. Infants with postnatal infections had more cerebellar hemorrhage. Infants with ≥3 infections had lower N-acetylaspartate/choline in the white matter and basal ganglia regions, lower fractional anisotropy in the posterior limb of the internal capsule, and poorer maturation of the corpus callosum, optic radiations, and posterior limb of the internal capsule on tract-based spatial statistics analysis as well as poorer Bayley Scales of Infant and Toddler Development-III (P = .02) and Peabody Developmental Motor Scales, Second Edition, motor scores (P < .01). CONCLUSIONS: In newborns born preterm, ≥3 postnatal infections predict impaired development of the motor pathways and poorer motor outcomes in early childhood.

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OBJECTIVE: To identify clinical risk factors for punctate white matter lesions (PWML) on early magnetic resonance imaging (MRI) in 2 cohorts of newborns born extremely preterm in different neonatal centers. STUDY DESIGN: A total of 250 newborns born preterm at less than 28 weeks of gestation (mean 26.4 ± 1.1 weeks) with an early MRI were identified from 2 neonatal centers, in Vancouver, Canada (cohort A, n = 100) and Utrecht, the Netherlands (cohort B, n = 150). Cohort A was imaged as part of a prospective research study and cohort B was imaged as part of routine clinical care. PWML were defined as cluster type foci of hyperintensity on T1-weighted imaging and were identified at a mean postmenstrual age of 31.1 (±1.9) weeks. Multivariable analysis was used to identify clinical factors predictive of PWML. RESULTS: Cluster type PWML were found in 47 newborns born extremely preterm (18.8%) and were more common in cohort A (32%) than in cohort B (10%). Newborns in cohort A generally were sicker than those in cohort B. Multivariable analyses revealed that greater birth weight (B = 0.002; P < .02), grade II-III intraventricular hemorrhage (B = 0.83; P < .02), and cohort A (B = 1.34; P < .0001) were independent predictors of PWML. CONCLUSION: Several risk factors for PWML on early MRI were identified. The interaction among birth weight, intraventricular hemorrhage, and other aspects of postnatal illness as risk factors for PWML warrants further investigation in newborns born extremely preterm and may help to identify modifiable risk factors for PWML.

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OBJECTIVES: To evaluate patterns of narcotic and sedative use in neonatal intensive care units (NICUs) across Canada using data collected by the Canadian Neonatal Network. STUDY DESIGN: We conducted a retrospective observational cohort study of preterm neonates at <33 weeks' gestation and admitted to a participating Canadian Neonatal Network NICU. The proportion of all neonates who received sedative(s), narcotic(s), or either sedative(s), narcotic(s), or both during their NICU stay was calculated for each year. Because opioids are used for premedication before intubation, only continuous infusions of a narcotic drug were included. Variation in narcotics and sedative usage between sites in 2014 was determined using logistic regression analysis, with adjustment for gestational age, surgery, and mechanical ventilation. RESULTS: Of 20 744 neonates, 29% of neonates received a narcotic, a sedative, or both; 23% received a narcotic and 17% a sedative. Although no clinically significant changes in drug exposure were documented during the 5-year period, there were statistically significant differences in narcotic and sedative use between sites, ranging from 3% to 41% for narcotic and 2% to 48% for sedative use (aORs 0.2-5.7 and 0.1-15, respectively, P < .05). CONCLUSIONS: Exposure to narcotic or sedative agents is highly variable in preterm neonates across Canada despite concerns of adverse outcomes associated with these drugs. The tremendous variation in practice suggests that further research on their current usage, as well as identifying optimal practice procedures is warranted.

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