Brain Injury in Infants Evaluated for, But Not Treated with, Therapeutic Hypothermia.

Defining neonatal encephalopathy clinically to qualify for therapeutic hypothermia is challenging. This study examines magnetic resonance imaging outcomes of 39 infants who were evaluated and not cooled using criteria inclusive of mild encephalopathy. Infants evaluated for therapeutic hypothermia are at risk for brain injury and may benefit from neuroimaging and follow-up.

Associations of Growth and Body Composition with Brain Size in Preterm Infants.

OBJECTIVE: To assess the association of very preterm infants' brain size at term-equivalent age with physical growth from birth to term and body composition at term. STUDY DESIGN: We studied 62 infants born at <33 weeks of gestation. At birth and term, we measured weight and length and calculated body mass index. At term, infants underwent air displacement plethysmography to determine body composition (fat and fat-free mass) and magnetic resonance imaging to quantify brain size (bifrontal diameter, biparietal diameter, transverse cerebellar distance). We estimated associations of physical growth (Z-score change from birth to term) and body composition with brain size, adjusting for potential confounders using generalized estimating equations. RESULTS: The median gestational age was 29 weeks (range, 24.0-32.9 weeks). Positive gains in weight and body mass index Z-score were associated with increased brain size. Each additional 100 g of fat-free mass at term was associated with larger bifrontal diameter (0.6 mm; 95% CI, 0.2-1.0 mm), biparietal diameter (0.7 mm; 95% CI, 0.3-1.1 mm), and transverse cerebellar distance (0.3 mm; 95% CI, 0.003-0.5 mm). Associations between fat mass and brain metrics were not statistically significant. CONCLUSIONS: Weight and body mass index gain from birth to term, and lean mass-but not fat-at term, were associated with larger brain size. Factors that promote lean mass accrual among preterm infants may also promote brain growth.

Thirteen-Year Outcomes in Very Preterm Children Associated with Diffuse Excessive High Signal Intensity on Neonatal Magnetic Resonance Imaging.

OBJECTIVE: To investigate the association between white matter diffuse excessive high signal intensity (DEHSI) on neonatal magnetic resonance imaging in very preterm infants and neurobehavioral outcomes at the age of 13 years. STUDY DESIGN: Magnetic resonance images of very preterm children (<30 weeks gestational age or <1250 g birth weight) were evaluated at term-equivalent age with DEHSI classified into 5 grades. Additionally, visibility of the posterior periventricular crossroads was assessed. General intelligence, memory, attention, executive function, motor abilities, and behavior were examined in 125 children at age 13 years and related to DEHSI grades using linear regression. RESULTS: DEHSI was detected in 93% of infants; 21% grade 1, 22% grade 2, 32% grade 3, and 18% grade 4. Neurobehavioral outcomes were similar for all DEHSI groups. There was weak evidence that higher DEHSI grades related to higher verbal IQ and attention and that lower DEHSI grades related to better planning ability. Adjustment for gestational age, birth weight standard score, and sex further weakened these effects. Only 12 children had invisible posterior crossroads and showed slightly poorer outcomes at 13 years of age. CONCLUSIONS: There was little evidence that neonatal DEHSI serves as a sensitive biomarker for later impairment. Further investigation on the importance of invisible posterior periventricular crossroads in larger samples is needed.

Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children.

OBJECTIVE: To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children. STUDY DESIGN: A total of 223 very preterm infants (<30 weeks of gestation or <1250 g) born at Melbourne's Royal Women's Hospital had a brain MRI scan at term equivalent age. Scans were scored using a standardized system that assessed structural abnormality of cerebral white matter, cortical gray matter, deep gray matter, and cerebellum. Children were assessed at 7 years on measures of general intelligence, motor functioning, academic achievement, and behavior. RESULTS: One hundred eighty-six very preterm children (83%) had both an MRI at term equivalent age and a 7-year follow-up assessment. Higher global brain, cerebral white matter, and deep gray matter abnormality scores were related to poorer intelligence quotient (IQ) (Ps < .01), spelling (Ps < .05), math computation (Ps < .01), and motor function (Ps < .001). Higher cerebellum abnormality scores were related to poorer IQ (P = .001), math computation (P = .018), and motor outcomes (P = .001). Perinatal, neonatal, and social confounders had little effect on the relationships between the MRI abnormality scores and outcomes. Moderate-severe global abnormality on newborn MRI was associated with a reduction in IQ (-6.9 points), math computation (-7.1 points), and motor (-1.9 points) scores independent of the other potential confounders. CONCLUSIONS: Structured evaluation of brain MRI at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors.

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy.

OBJECTIVE: To assess and contrast the incidence and severity of abnormalities on cerebral magnetic resonance imaging (MRI) between infants with mild, moderate, and severe neonatal encephalopathy who received therapeutic hypothermia. STUDY DESIGN: This retrospective cohort studied infants with mild, moderate, and severe neonatal encephalopathy who received therapeutic hypothermia at a single tertiary neonatal intensive care unit between 2013 and 2015. Two neuroradiologists masked to the clinical condition evaluated brain MRIs for cerebral injury after therapeutic hypothermia using the Barkovich classification system. Additional abnormalities not included in this classification system were also noted. The rate, pattern, and severity of abnormalities/injury were compared across the grades of neonatal encephalopathy. RESULTS: Eighty-nine infants received therapeutic hypothermia and met study criteria, 48 with mild neonatal encephalopathy, 35 with moderate neonatal encephalopathy, and 6 with severe neonatal encephalopathy. Forty-eight infants (54%) had an abnormality on MRI. There was no difference in the rate of overall MRI abnormalities by grade of neonatal encephalopathy (mild neonatal encephalopathy 54%, moderate neonatal encephalopathy 54%, and severe neonatal encephalopathy 50%; P= .89). Basal ganglia/thalamic injury was more common in those with severe neonatal encephalopathy (mild neonatal encephalopathy 4%, moderate neonatal encephalopathy 9%, severe neonatal encephalopathy 34%; P = .03). In contrast, watershed injury did not differ between neonatal encephalopathy grades (mild neonatal encephalopathy 36%, moderate neonatal encephalopathy 32%, severe neonatal encephalopathy 50%; P = .3). CONCLUSION: Mild neonatal encephalopathy is commonly associated with MRI abnormalities after therapeutic hypothermia. The grade of neonatal encephalopathy during the first hours of life may not discriminate adequately between infants with and without cerebral injury noted on MRI after therapeutic hypothermia.

Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks' Gestation.

OBJECTIVES: To determine the associations of breast milk intake after birth with neurological outcomes at term equivalent and 7 years of age in very preterm infants STUDY DESIGN: We studied 180 infants born at <30 weeks' gestation or <1250 grams birth weight enrolled in the Victorian Infant Brain Studies cohort from 2001-2003. We calculated the number of days on which infants received >50% of enteral intake as breast milk from 0-28 days of life. Outcomes included brain volumes measured by magnetic resonance imaging at term equivalent and 7 years of age, and cognitive (IQ, reading, mathematics, attention, working memory, language, visual perception) and motor testing at 7 years of age. We adjusted for age, sex, social risk, and neonatal illness in linear regression. RESULTS: A greater number of days on which infants received >50% breast milk was associated with greater deep nuclear gray matter volume at term equivalent age (0.15 cc/d; 95% CI, 0.05-0.25); and with better performance at age 7 years of age on IQ (0.5 points/d; 95% CI, 0.2-0.8), mathematics (0.5; 95% CI, 0.1-0.9), working memory (0.5; 95% CI, 0.1-0.9), and motor function (0.1; 95% CI, 0.0-0.2) tests. No differences in regional brain volumes at 7 years of age in relation to breast milk intake were observed. CONCLUSION: Predominant breast milk feeding in the first 28 days of life was associated with a greater deep nuclear gray matter volume at term equivalent age and better IQ, academic achievement, working memory, and motor function at 7 years of age in very preterm infants.

Neonatal Infection and Later Neurodevelopmental Risk in the Very Preterm Infant.

OBJECTIVES: To document associations between confirmed and suspected neonatal infection and motor, cognitive, educational, and mental health outcomes of very preterm (VPT)-born children at 9 years of age; to examine the potential intervening role of cerebral white matter abnormalities (WMAs) and structural development on term magnetic resonance imaging. STUDY DESIGN: A regional cohort of 110 infants born VPT in Christchurch, New Zealand were studied from birth to age of 9 years. Confirmed infection was defined as positive blood, cerebrospinal fluid or urine culture, and/or necrotizing enterocolitis ≥ stage 2. Suspected infection was defined as ≥ 5 days of antibiotics with evidence of clinical correlates. At term gestational equivalence, infants underwent structural magnetic resonance imaging. At age 9 years, neuromotor function, IQ, educational achievement, and mental health were assessed. RESULTS: During hospitalization, 25% of VPT infants had confirmed and 23% had suspected infection. Longer-term neurodevelopmental impairments were largely confined to infants with confirmed infection (relative risk 1.4-3.1, vs uninfected). After accounting for other neonatal factors, these infants were at increased risk of severe motor impairment (OR 3.3, 95% CI 1.3-8), attention deficit hyperactivity disorder (ADHD) (OR 3.6, 95% CI 1.6-8), and IQ delay (OR 2.0, 95% CI 1-3.9). Cerebral WMAs contributed to associations between confirmed infection and motor and IQ impairments but not to ADHD (P = .005). CONCLUSIONS: Confirmed neonatal infection heightens VPT infants' risk for neurodevelopmental impairment. WMA appears to be an important intervening factor linking infection and severe motor and IQ impairments. Further analysis of the neurologic mechanism accounting for ADHD in infants with infection is needed.

Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Age 2 Years.

OBJECTIVE: To examine the association of difficult feeding behaviors in very preterm infants at age 2 years with growth and neurodevelopmental outcomes and family factors and functioning. STUDY DESIGN: Eighty children born ≤30 weeks gestation were studied from birth until age 2 years. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age 2 years, along with growth measurement and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and χ(2) analyses were performed to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics. RESULTS: Twenty-one children (26%) were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age 2 years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems, including impaired cognition (P = .02), language (P = .04), motor (P = .01), and socioemotional (P < .007) skills. Compared with the parents of children with fewer feeding difficulties, parents of the children with feeding difficulties had higher parenting stress (P = .02) and reported more difficulty managing their child's behavior (P = .002) and more frequent parent-child interaction problems (P = .002). No associations were found between difficult feeding behaviors and growth, maternal mental health, or family factors. CONCLUSION: Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes.

Impaired language abilities and white matter abnormalities in children born very preterm and/or very low birth weight.

OBJECTIVES: To investigate language abilities in children born very preterm (VPT; <32 weeks' gestational age) or very low birth weight (VLBW; <1500 g) at 7 years of age and compare their performances with children born at term, and to determine whether group differences could be explained by cerebral white matter abnormality on neonatal magnetic resonance imaging. STUDY DESIGN: A cohort of 198 children born <30 weeks' gestational age and/or <1250 g, and 70 term controls were examined. White matter abnormalities were rated quantitatively on brain magnetic resonance imaging at term-equivalent age. Language was assessed at age 7 years using standardized language tests. Differences between groups were tested in the 5 language subdomains of phonological awareness, semantics, grammar, discourse, and pragmatics. A mediation effect was tested between birth group, white matter abnormality, and language subdomains. RESULTS: The VPT/VLBW group performed significantly worse than controls on all language subdomains (all P < .001). White matter abnormality mediated the effect of group differences on phonological awareness, and partly mediated this effect for semantics, grammar, and discourse. White matter abnormality was not significantly associated with pragmatics (P = .13). CONCLUSIONS: Language is an important area of concern in children born VPT/VLBW. Neonatal white matter abnormality is an important predictor of outcome; however, different language abilities are differentially associated with neonatal white matter abnormality.

Neurologic outcomes in very preterm infants undergoing surgery.

OBJECTIVE: To investigate the relationship between surgery in very preterm infants and brain structure at term equivalent and 2-year neurodevelopmental outcome. STUDY DESIGN: A total of 227 infants born at <30 weeks gestation or at a birth weight of <1250 g were prospectively enrolled into a longitudinal observational cohort for magnetic resonance imaging and developmental follow-up. The infants were categorized retrospectively into either a nonsurgical group (n=178) or a surgical group (n=30). Nineteen infants were excluded because of incomplete or unsuitable data. The surgical and nonsurgical groups were compared in terms of clinical demographic data, white matter injury, and brain volume at term. Neurodevelopmental outcome was assessed at age 2 years. RESULTS: Compared with the nonsurgical group, the infants in the surgical group were smaller and more growth-restricted at birth, received more respiratory support and oxygen therapy, and had longer hospital stays. They also had smaller brain volumes, particularly smaller deep nuclear gray matter volumes. Infants who underwent bowel surgery had greater white matter injury. Mental Developmental Index scores were lower in the surgical group, whereas Psychomotor Developmental Index scores did not differ between the groups. The Mental Developmental Index difference became nonsignificant after adjustment for confounding variables. CONCLUSION: Preterm infants exposed to surgery and anesthesia had greater white matter injury and smaller total brain volumes, particularly smaller deep nuclear gray matter volumes. Surgical exposure in the preterm infant should alert the clinician to an increased risk for adverse cognitive outcome.

Sodium bicarbonate administration and outcome in preterm infants.

The short-term outcomes of sodium bicarbonate therapy in preterm infants were investigated by retrospective analysis of 165 of 984 infants who received sodium bicarbonate. The infants treated with sodium bicarbonate were more immature and had greater severity of illness and more adverse outcomes. Sodium bicarbonate therapy did not improve the blood pH.

Neurobehavior at term and white and gray matter abnormalities in very preterm infants.

OBJECTIVE: To examine the relationship between very preterm infant neurobehavior at term and concurrent magnetic resonance-defined cerebral abnormalities. STUDY DESIGN: 168 very preterm infants (birth weight <1250 g or gestation <30 weeks) were examined at term with 2 standardized neurobehavioral assessments, the Revised Hammersmith Neonatal Neurological Examination and the Neonatal Intensive Care Unit Network Neurobehavioral Scale. The relationship between composite neurobehavioral scores and qualitative white and gray matter abnormalities on magnetic resonance imaging was determined. RESULTS: Poorer neurobehavioral performance related to magnetic resonance-defined cerebral abnormalities. Composite neurobehavioral scores related to the total grade of white matter abnormality, and worse neurobehavior related most strongly to 2 components of this grade: white matter signal abnormalities and reduction in white matter volumes. Neurobehavior was not related to the total grade of gray matter abnormality. However, delayed gyral maturation, a component of the total gray matter grade, was related to poorer performance on both neurobehavioral scales. CONCLUSION: Very preterm infant neurobehavior at term is related to concurrent cerebral abnormalities in both white and gray matter defined by qualitative magnetic resonance imaging.

Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term.

OBJECTIVES: To test the hypothesis that the impact of postnatal sepsis/necrotizing enterocolitis (NEC) on neurodevelopment may be mediated by white matter abnormality (WMA), which can be demonstrated with magnetic resonance imaging (MRI). STUDY DESIGN: A prospective cohort of 192 unselected preterm infants (gestational age <30 weeks), who were evaluated for sepsis and NEC, underwent imaging at term-equivalent age and neurodevelopmental outcome at 2 years corrected age with the Bayley Scales of Infant Development. RESULTS: Sixty-eight preterm (35%) infants had 100 episodes of confirmed sepsis, and 9 (5%) infants had confirmed NEC. Coagulase-negative staphylococci accounted for 73% (73/100) of the episodes of confirmed sepsis. Infants with sepsis/NEC had significantly more WMA on MRI at term compared with infants in the no-sepsis/NEC group. They also had poorer psychomotor development that persisted after adjusting for potential confounders but which became nonsignificant after adjusting for WMA. CONCLUSIONS: Preterm infants with sepsis/NEC are at greater risk of motor impairment at 2 years, which appears to be mediated by WMA. These findings may assist in defining a neuroprotective target in preterm infants with sepsis/NEC.

Neonatal hypoglycemia and occipital cerebral injury.

Occipital brain injury associated with neonatal hypoglycemia can result in long-term disability, epilepsy, and visual impairment. The etiology of this pattern of injury is unclear; however, transient hyperinsulinism may be an independent risk factor. Magnetic resonance brain imaging can delineate the extent of brain injury and guide follow-up.

Randomized trial of systemic hypothermia selectively protects the cortex on MRI in term hypoxic-ischemic encephalopathy.

Twenty-six infants with hypoxic-ischemic encephalopathy (HIE) were randomized to normothermia or to systemic hypothermia. The hypothermia group had less cortical gray matter signal abnormality on magnetic resonance imaging (MRI) (1/12 vs 7/14 infants in the normothermic group; P = .036), which may indicate differing regional benefit from systemic hypothermia.