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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 (β = -0.64; P < .001) and TEA (β = -0.44, P < .001) time points. Motor outcomes were associated with ventricular volume at TEA (β = -0.84, P = .01). Greater ventricular volume independently predicted lower fractional anisotropy in corpus callosum (genu: β = -0.0008, P = .002; splenium: β = -0.003, P < .001) and optic radiations (β = -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. [ABSTRACT FROM AUTHOR]

Objective: To assess whether Family Integrated Care (FICare) in the neonatal intensive care unit improves maternal chronic physiological stress and child behavior at 18 months of corrected age for infants born preterm.Study Design: Follow-up of a multicenter, prospective cluster-randomized controlled trial comparing FICare and standard care of children born at <33 weeks of gestation and parents, stratified by tertiary neonatal intensive care units, across Canada. Primary outcomes at 18 months of corrected age were maternal stress hormones (cortisol, ie, hair cumulative cortisol [HCC], dehydroepiandrosterone [DHEA]) assayed from hair samples. Secondary outcomes included maternal reports of parenting stress, child behaviors (Internalizing, Externalizing, Dysregulation), and observer-rated caregiving behaviors. Outcomes were analyzed using multilevel modeling.Results: We included 126 mother-child dyads from 12 sites (6 FICare sites, n = 83; 6 standard care sites, n = 43). FICare intervention significantly lowered maternal physiological stress as indicated by HCC (B = -0.22 [-0.41, -0.04]) and cortisol/DHEA ratio (B = -0.25 [-0.48, -0.02]), but not DHEA (B = 0.01 [-0.11, 0.14]). Enrollment in FICare led to lower child Internalizing (B = -0.93 [-2.33, 0.02]) and Externalizing behavior T scores (B = -0.91 [-2.25, -0.01]) via improvements to maternal HCC (mediation). FICare buffered the negative effects of high maternal HCC on child Dysregulation T scores (B = -11.40 [-23.01, 0.21]; moderation). For mothers reporting high parenting stress at 18 months, FICare was related to lower Dysregulation T scores via maternal HCC; moderated mediation = -0.17 (-0.41, -0.01).Conclusions: FICare has long-term beneficial effects for mother and child, attenuating maternal chronic physiological stress, and improving child behavior in toddlerhood.Clinical Trial Registration: NCT01852695. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that the diurnal cortisol secretion rhythm of children who as neonates had been hospitalized differs from that of children without a history of neonatal hospital admission and that this rhythm differs between these hospitalized children treated with either continuous morphine infusion or placebo. Study design: A follow-up cohort study was performed with 5-year-old children who as neonates participated in a randomized controlled trial of continuous morphine infusion (born 24-42 weeks' gestation), and a control group of healthy term born (≥37 weeks' gestation) children. Five saliva samples over a school day were assayed for cortisol concentrations. The diurnal cortisol rhythm was analyzed with random regression analysis for repeated measurements. Results: Compared with the healthy controls, the trial participants had greater cortisol levels (P = .002) after adjustment for sex and socioeconomic status. The administration of morphine did not affect the cortisol concentrations (P = .66) after adjustment for sex, socioeconomic status, and gestational age at birth. Conclusions: The finding that former trial participants had greater cortisol levels at 5 years of age supports the concept of long-lasting programming of the hypothalamic-pituitary-adrenal axis. Morphine infusion in the neonatal period did not alter cortisol secretion at 5 years of age. [ABSTRACT FROM AUTHOR]

Objective To determine the effect of neonatal caffeine treatment on rates of developmental coordination disorder (DCD). Study design Children in the Caffeine for Apnea of Prematurity trial were assessed for motor performance (Movement Assessment Battery for Children [MABC]), clinical signs of cerebral palsy, and Full-Scale IQ at 5 years of age by staff who were unaware of the children's treatment group. DCD was defined as MABC <5th percentile in children with a Full-Scale IQ >69 who did not have a diagnosis of cerebral palsy. Results There were 1433 children with known MABC corrected-age percentile as well as known Full-Scale IQ at 5 years and cerebral palsy status, of whom 735 had been randomly assigned to caffeine and 698 to placebo therapy. The rate of DCD was lower in those treated with caffeine (11.3%) than in the placebo group (15.2%) (OR adjusted for center and baseline covariates, 0.71, 95% CI, 0.52-0.97; P = .032). Conclusions Neonatal caffeine therapy for apnea of prematurity reduces the rate of DCD at 5 years of age. As more children have DCD than have cerebral palsy, this is an important additional benefit from neonatal caffeine treatment. [ABSTRACT FROM AUTHOR]

Objective: Little is known about the developmental trajectory of cortisol levels in preterm infants after hospital discharge. Study design: In a cohort of 225 infants (gestational age at birth <33 weeks) basal salivary cortisol levels were compared in infants born at extremely low gestational age (ELGA, 23-28 weeks), very low gestational age (29-32 weeks), and term (37-42 weeks) at 3, 6, 8, and 18 months corrected age (CA). Infants with major neurosensory or motor impairment were excluded. Results: At 3 months CA, salivary cortisol levels were lower in both preterm groups compared with the term infants (P = .003). Conversely, at 8 and 18 months CA, the ELGA infants had significantly higher basal cortisol levels than the very low gestational age and term infants (P = .016 and P = .006, respectively). Conclusions: In ELGA infants, the shift from low basal cortisol levels at 3 months to significantly high levels at 8 and 18 months CA suggests long-term “resetting” of endocrine stress systems. Multiple factors may contribute to these higher cortisol levels in the ELGA infants, including physiological immaturity at birth, cumulative stress related to multiple procedures, and mechanical ventilation during lengthy hospitalization. Prolonged elevation of the cortisol “set-point” may have negative implications for neurodevelopment and later health. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA).Study Design: A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes.Results: A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth.Conclusions: Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. [ABSTRACT FROM AUTHOR]

Objective: To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. Study Design: Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. Results: Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. Conclusions: In very preterm children, exposure to painful procedures, as well as additional neonatal risk factors such as infection, were associated with reduced cerebellar volumes in specific subregions and poorer outcomes at school age. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the mortality and long-term morbidity rates of extremely low birth weight (ELBW) infants admitted to neonatal intensive care units (NICUs). Study design: This was a longitudinal cohort study of all admissions born between 1983 and 2003 with birth weight ≤ 800 g at a single tertiary NICU. Trends in survival and neurodevelopmental outcome rates at school entry in four 5-year epochs were analyzed. Results: Of 917 admissions, 552 survived to NICU discharge, with significantly increasing survival rates from 46% in epoch 1 to 71% in epoch 4 (P < .0001). Although the overall impairment rate of 30% did not change, the pattern of impairments did. Cognitive (P = .017) and hearing (P = .014) impairment rates increased. Visual impairment rates decreased (P = .042), with a trend toward decreasing cerebral palsy from 20% to 12% (P = .061). Conclusions: Improved survival of low birth weight preterm infants has been associated with different types of neurodevelopmental impairments, including increased cognitive impairment rates. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of early brain injury and neonatal illness on corticospinal tract (CST) development in premature newborns serially studied with diffusion tensor tractography. Study design: Fifty-five premature newborns (median 27.6 weeks postmenstrual age) were scanned with magnetic resonance imaging (MRI) early in life and at term-equivalent age. Moderate-severe brain abnormalities (abnormal-MRI) were characterized by moderate-severe white matter injury or ventriculomegaly. Diffusion tensor tractography was used to measure CST diffusion parameters which reflect microstructural development: fractional anisotropy (FA) and average diffusivity (Dav). The effect of abnormal-MRI and neonatal illness on FA and Dav were assessed with multivariate regression for repeated measures adjusting for age at scan. Results: Twenty-one newborns (38%) had abnormal-MRI on either scan. FA increased with age significantly slower in newborns with abnormal-MRI (0.008/week) relative to newborns without these MRI abnormalities (0.011/wk) (interaction term P = .05). Dav was higher in newborns with abnormal-MRI (1.5 × 10−5 mm2/sec; P < .001) for any given age at scan. In the 23 newborns (42%) with postnatal infection, FA increased more slowly (interaction term P = .04), even when adjusting for the presence of abnormal-MRI. Conclusions: CST microstructural development is significantly impaired in premature newborns with abnormal-MRI or postnatal infection, with a pattern of diffusion changes suggesting impaired glial cell development. [Copyright &y& Elsevier]

Objective: To examine sex differences in neurodevelopmental outcomes and brain development from early life to 8 years in males and females born preterm., Study Design: This was a prospective cohort study of infants born very preterm (24-32 weeks' gestation) and followed to 8 years with standardized measures of neurodevelopment. Brain magnetic resonance imaging (MRI) scans were performed soon after birth, term-equivalent age, and 8 years. The relationship between sex, severe brain injury, early pain exposure, fractional anisotropy (FA), and neurodevelopmental outcomes were assessed using multivariable generalized estimating equations., Results: Males (N=78) and females (N=66) were similar in clinical risk factors. Male sex was associated with lower cognitive scores (β=-3.8, P=0.02) and greater motor impairment (OR=1.8, P=0.04) across time. Male sex was associated with lower superior white matter FA across time (β=-0.01, P=0.04). Sex moderated the association between severe brain injury, early pain, and neurodevelopmental outcomes. With severe brain injury, males had lower cognitive scores at 3 years (P<0.001). With increasing pain, females had lower cognitive scores at 8 years (P=0.008), and males had greater motor impairment at 4.5 years (P=0.001) and 8 years (P=0.05)., Conclusions: Males born preterm had lower cognitive scores and greater motor impairment compared with females, which were associated with differences in white matter maturation. The association between severe brain injury, early pain exposure, and neurodevelopmental outcomes was moderated by sex, indicating a differential response to early-life adversity in males and females born preterm., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate the mortality and long-term morbidity rates of extremely low birth weight (ELBW) infants admitted to neonatal intensive care units (NICUs)., Study Design: This was a longitudinal cohort study of all admissions born between 1983 and 2003 with birth weight ≤ 800 g at a single tertiary NICU. Trends in survival and neurodevelopmental outcome rates at school entry in four 5-year epochs were analyzed., Results: Of 917 admissions, 552 survived to NICU discharge, with significantly increasing survival rates from 46% in epoch 1 to 71% in epoch 4 (P < .0001). Although the overall impairment rate of 30% did not change, the pattern of impairments did. Cognitive (P = .017) and hearing (P = .014) impairment rates increased. Visual impairment rates decreased (P = .042), with a trend toward decreasing cerebral palsy from 20% to 12% (P = .061)., Conclusions: Improved survival of low birth weight preterm infants has been associated with different types of neurodevelopmental impairments, including increased cognitive impairment rates., (Copyright © 2010 Mosby, Inc. All rights reserved.)