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OBJECTIVE: To explore the associations between nutrition in the first 28 days after birth with somatic growth from birth to term-equivalent age, brain volumes at term-equivalent age, and neurodevelopment at 24 months of corrected age. STUDY DESIGN: Prospective cohort study of 149 infants born from 2011 to 2014 at <30 weeks of gestation in a tertiary neonatal nursery in Australia. The following data were collected: average daily energy, protein, fat, and carbohydrate intakes from birth until 28 days, and the difference in weight and head circumference z scores between birth and term-equivalent. Total brain tissue volumes were calculated from brain magnetic resonance imaging at term-equivalent age. Children were assessed at 2 years of corrected age with the Bayley Scales of Infant and Toddler Development-Third Edition. Relationships of nutritional variables with growth, brain volumes, and cognitive, language, and motor development were explored using linear regression. RESULTS: Complete nutritional data were available for 116 (78%) of the cohort. A 1 g/kg/day higher mean protein intake was associated with a mean increase in weight z score per week of 0.05 (95% CI 0.05, 0.10; P = .04). There was a lack of evidence for associations of any nutritional variables with head circumference growth, with brain volumes at term-equivalent age, or with 2-year neurodevelopment. CONCLUSIONS: Only higher protein intakes in the first 28 days after birth were associated with better weight growth between birth and term-equivalent age in very preterm infants. Nutrition in the first 28 days was otherwise not substantially related to brain size or to neurodevelopmental outcomes.

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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.

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OBJECTIVE: To assess the effectiveness of Cogmed Working Memory Training compared with a placebo program in improving academic functioning 24 months post-training in extremely preterm/extremely low birth weight 7-year-olds. STUDY DESIGN: A multicenter double-blind, placebo-controlled randomized controlled trial was conducted across all tertiary neonatal hospitals in the state of Victoria, Australia. Participants were 91 extremely preterm/extremely low birth weight 7-year-old children born in Victoria in 2005. Children were randomly assigned to either the Cogmed or placebo arm and completed the Cogmed or placebo program (20-25 sessions of 35-40 minutes duration) at home over 5-7 weeks. Academic achievement (word reading, spelling, sentence comprehension, and mathematics) was assessed 24 months post-training, as well as at 2 weeks and 12 months post-training, via standardized testing inclusive of working memory, attention, and executive behavior assessments. Data were analyzed using an intention-to-treat approach with mixed-effects modeling. RESULTS: There was little evidence of any benefits of Cogmed on academic functioning 24 months post-training, as well as on working memory, attention, or executive behavior at any age up to 24 months post-training compared with the placebo program. CONCLUSIONS: We currently do not recommend administration of Cogmed for early school-aged children born extremely preterm/extremely low birth weight to improve academic functioning. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12612000124831.

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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.

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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.

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OBJECTIVE: To explore the association between brain maturation, injury, and volumes at term-equivalent age with 2-year development in moderate and late preterm children. STUDY DESIGN: Moderate and late preterm infants were recruited at birth and assessed at age 2 years using the Bayley Scales of Infant and Toddler Development, Third Edition. Brain magnetic resonance imaging (MRI) was performed at term-equivalent age and qualitatively assessed for brain maturation (myelination of the posterior limb of the internal capsule and gyral folding) and injury. Brain volumes were measured using advanced segmentation techniques. The associations between brain MRI measures with developmental outcomes were explored using linear regression analyses. RESULTS: A total of 197 children underwent MRI and assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Larger total brain tissue volumes were associated with higher cognitive and language scores (adjusted coefficients per 10% increase in brain size; 95% CI of 3.2 [0.4, 5.6] and 5.6 [2.4, 8.8], respectively). Similar relationships were documented for white matter volumes with cognitive and language scores, multiple cerebral structures with language scores, and cerebellar volumes with motor scores. Larger cerebellar volumes were independently associated with better language and motor scores, after adjustment for other perinatal factors. There was little evidence of relationships between myelination of the posterior limb of the internal capsule, gyral folding, or injury with 2-year development. CONCLUSIONS: Larger total brain tissue, white matter, and cerebellar volumes at term-equivalent age are associated with better neurodevelopment in moderate and late preterm children. Brain volumes may be an important marker for neurodevelopmental deficits described in moderate and late preterm children.

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OBJECTIVES: To compare brain volumes in adolescents who were born extremely preterm (<28 weeks gestation) who had received postnatal dexamethasone, and to determine if there was a postnatal dexamethasone dose-response effect on brain volumes. STUDY DESIGN: Geographical cohort study of extremely preterm adolescents born in 1991-1992 in Victoria, Australia. T1-weighted magnetic resonance imaging was performed at 18 years of age. Segmented and parcellated brain volumes were calculated using an automated segmentation method (FreeSurfer) and compared between groups, with and without adjustment for potential confounders. The relationships between total postnatal dexamethasone dose and brain volumes were explored using linear regression. RESULTS: Of the 148 extremely preterm participants, 55 (37%) had received postnatal dexamethasone, with a cumulative mean dose of 7.7 mg/kg. Compared with participants who did not receive postnatal dexamethasone, those who did had smaller total brain tissue volumes (mean difference -3.6%, 95% CI [-7.0%, -0.3%], P value = .04) and smaller white matter, thalami, and basal ganglia volumes (all P < .05). There was a trend of smaller total brain and white matter volumes with increasing dose of postnatal dexamethasone (regression coefficient -7.7 [95% CI -16.2, 0.8] and -3.2 [-6.6, 0.2], respectively). CONCLUSIONS: Extremely preterm adolescents who received postnatal dexamethasone in the newborn period had smaller total brain tissue volumes than those who did not receive postnatal dexamethasone, particularly white matter, thalami, and basal ganglia. Vulnerability of brain tissues or structures associated with postnatal dexamethasone varies by structure and persists into adolescence.

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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.

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