Preterm Sex Differences in Neurodevelopment and Brain Development From Early Life to 8 years.

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 (ß=-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 (ß=-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.

Neuroimaging to guide neuroprognostication in the neonatal intensive care unit.

PURPOSE OF REVIEW: Neurological problems are common in infants admitted to the neonatal intensive care unit (NICU). Various neuroimaging modalities are available for neonatal brain imaging and are selected based on presenting problem, timing and patient stability. RECENT FINDINGS: Neuroimaging findings, taken together with clinical factors and serial neurological examination can be used to predict future neurodevelopmental outcomes. In this narrative review, we discuss neonatal neuroimaging modalities, and how these can be optimally utilized to assess infants in the NICU. We will review common patterns of brain injury and neurodevelopmental outcomes in hypoxic-ischemic encephalopathy, perinatal arterial ischemic stroke and preterm brain injury. SUMMARY: Timely and accurate neuroprognostication can identify infants at risk for neurodevelopmental impairment and allow for early intervention and targeted therapies to improve outcomes.

Preterm Neurodevelopmental Trajectories from 18 Months to 4.5 Years.

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.

Cerebral Venous Sinus Thrombosis in Preterm Infants.

BACKGROUND: Neonatal cerebral venous sinus thrombosis (CVST) can lead to brain injury and neurodevelopmental impairments. Previous studies of neonatal CVST have focused on term infants, and studies of preterm infants are lacking. In this study, we examined the clinical and radiological features, treatment and outcome of CVST in preterm infants. METHODS: This was a retrospective, consecutive cohort study of preterm infants (gestational age <37 weeks) with radiologically confirmed CVST. All magnetic resonance imaging/MRV and CT/CTV scans were re-reviewed to study thrombus characteristics and pattern of brain injury. Outcome was assessed by the validated pediatric stroke outcome measure at the most recent clinic visit. RESULTS: Twenty-six preterm infants with CVST were studied. Of these, 65% were moderate-late preterm (32-37 weeks), 27% very preterm (28-32 weeks), and 8% extreme preterm (<28 weeks). Most (73%) were symptomatic at presentation with seizures or abnormal exam. Transverse (85%) and superior sagittal (42%) sinuses were common sites of thrombosis. Parenchymal brain injury was predominantly periventricular (35%) and deep white matter (31%) in location. Intraventricular hemorrhage occurred in 46%. Most infants (69%) were treated with anticoagulation. No treated infant (including eleven with pretreatment hemorrhage) had new or worsening post-treatment hemorrhage. Outcomes ranged from no deficits (50%), mild-moderate (25%), and severe (25%) impairment. CONCLUSIONS: In our sample of preterm infants with CVST, more than one-quarter were asymptomatic. White matter brain lesions predominated and one-half had neurological deficits at follow-up. Anticoagulation of preterm CVST in this small cohort appeared to be safe. Larger studies of preterm CVST are needed.

Longitudinal neurodevelopmental outcomes in preterm twins.

BACKGROUND: Several factors contribute to neurodevelopmental outcomes in preterm infants. The aim of this study was to examine the genetic and environmental influences on long-term outcomes in preterm twins. METHODS: From a prospective cohort of 225 preterm neonates studied with MRI, 24 monozygotic and 52 dizygotic twins were included. Neurodevelopmental outcomes at 1.5 and 3 years were assessed with the Bayley-III and at 4.5 years with The Movement Assessment Battery for Children and The Wechsler Preschool and Primary Scale of Intelligence-III. RESULTS: Preterm monozygotic and dizygotic twin pairs (N = 76 neonates) had similar neurodevelopmental outcomes at all time points. Monozygotic twins (N = 24) did not show greater agreement for outcomes relative to dizygotic twins (N = 52). Twin pairs who were discordant in development (N = 12) were born at a lower gestational age and had a higher incidence of bronchopulmonary dysplasia and retinopathy of prematurity. Discordant twins become more similar in cognitive and language outcomes over time. CONCLUSIONS: Neurodevelopmental outcomes in preterm twins may relate more strongly to environmental factors than genetics. Discordant twins were born earlier and had more perinatal morbidities. Despite the initial discordance, these twin pairs become similar in outcomes over time, which may reflect the positive impact of home environment or early intervention programs. IMPACT: Neurodevelopmental outcomes in preterm twins relate more strongly to environmental factors than genetics. Monozygotic twins did not show greater agreement in outcomes relative to dizygotic twins suggesting a stronger environmental, rather than genetic, influence on development. Twin pairs who were discordant in development were born at a lower gestational age and had a higher incidence of perinatal morbidities. Despite the initial discordance, these twin pairs become more similar in cognitive and language outcomes over time, which may reflect the positive impact of early intervention programs or home environment. Neurodevelopmental outcomes in preterm twins are influenced by exposure to early-life insults or environmental stressors. The initial variability in outcomes among preterm infants is not fixed, and efforts made post-discharge from the neonatal intensive care unit can have a substantial impact on long-term outcomes.

Change in pain status in children with cerebral palsy.

AIM: To identify factors associated with a change in pain over time in children with cerebral palsy (CP). METHOD: Pain was assessed at two time-points by physicians and caregiver-rated Health Utilities Index 3 (HUI3) pain scores. RESULTS: One hundred and forty-eight children out of 179 approached from outpatient clinics (83% response; 104 males, 44 females mean age 8y 8mo, range 3y-16y) across all Gross Motor Function Classification System (GMFCS) levels were included. Fifty-five percent had changes in caregiver-reported HUI3 pain. A backward stepwise multiple linear regression retained HUI3 pain score at visit 1 and GMFCS level (F[2,144] =23.40, R2 =0.35; p<0.001) as variables associated with a change in pain status (HUI3 pain at visit 1: ß=0.61, p<0.001; GMFCS level: ß=-0.17, p<0.015). The association between HUI3 pain at visit 1 and GMFCS level was significant (ß=-0.15, p<0.036). There was an association between pain etiology and pain trajectory (F[3,144] =5.39, p=0.002). Post-hoc testing revealed musculoskeletal pain had the greatest improvements compared with the no pain group (p=0.006). INTERPRETATION: Children with CP with more severe initial pain and higher gross motor function have lower pain at follow-up indicating an improvement in pain status over time.

Increased activity of frontal and limbic regions to emotional stimuli in children at-risk for anxiety disorders.

Neuroimaging studies of children with anxiety disorders are limited, and no study has examined children who are at increased risk for developing anxiety disorders based on parental anxiety. The objective of this study was to examine the function of frontal and limbic brain regions using functional magnetic resonance imaging (fMRI) in children at risk for anxiety disorders. Study participants included high-risk children (n=20) who had at least one parent with a primary diagnosis of social anxiety disorder and normal-risk control children (n=19). Using fMRI, we measured the blood oxygenation level dependent response while high-risk and normal-risk children were exposed to different emotional facial stimuli. We found greater activation of frontal, temporal and limbic regions in high-risk children relative to normal-risk children during the presentation of emotional stimuli (angry and happy). These regions included the prefrontal cortex, anterior cingulate, hippocampus and insula. Our within-group analysis revealed similar patterns of hyperactivity in high-risk children with and without current anxiety symptoms. To our knowledge, this is the first study to demonstrate functional alterations in emotion-processing brain regions in children who are at risk for anxiety disorders based on parental anxiety. These findings are consistent with previous fMRI studies of pediatric anxiety and behaviorally inhibited children, and they contribute to our understanding of the neural correlates of risk for anxiety disorders.