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AIM: To elucidate neurobiological changes underlying motor impairments in adolescents born extremely preterm (gestation <28wks) and/or with extremely low birthweight (ELBW, <1000g), our aims were the following: (1) to compare corticospinal tract (CST) microstructure and primary motor cortex (M1) volume, area, and thickness between extremely preterm/ELBW adolescents and a comparison group with normal birthweight (>2499g); (2) to compare CST microstructure and M1 volume, area, and thickness between extremely preterm/ELBW adolescents with cerebral palsy (CP), motor impairment without CP, and no motor impairment; and (3) to investigate associations between CST microstructure and M1 measures. METHOD: This study used diffusion and structural magnetic resonance imaging to examine the CST and M1 in a geographical cohort of 191 extremely preterm/ELBW adolescents (mean age 18y 2.4mo [SD 9.6mo]; 87 males, 104 females) and 141 adolescents in the comparison group (mean age 18y 1.2mo [SD 9.6mo]; 59 males, 82 females). RESULTS: Extremely preterm/ELBW adolescents had higher CST axial, radial, and mean diffusivities and lower M1 thickness than the comparison group. Extremely preterm/ELBW adolescents with CP had higher CST diffusivities than non-motor-impaired extremely preterm/ELBW adolescents. CST diffusivities correlated with M1 volume and area. INTERPRETATION: Extremely preterm/ELBW adolescents have altered CST microstructure, which is associated with CP. Furthermore, the results elucidate how CST and M1 alterations interrelate to potentially influence motor function in extremely preterm/ELBW adolescents.

OBJECTIVE: To determine if improvements in cognitive outcome detected at 18 months' corrected age (CA) in infants born <33 weeks' gestation receiving a high-docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. DESIGN: Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs ≥1250 g) and hospital. SETTING: Five Australian tertiary hospitals from 2008 to 2013. PARTICIPANTS: 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. INTERVENTIONS: High-DHA (≈1% total fatty acids) enteral feeds compared with standard-DHA (≈0.3% total fatty acids) from age 2-4 days until term CA. PRIMARY OUTCOME: Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. RESULTS: 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard-DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital -0.3, 95% CI -2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high-DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. CONCLUSIONS: Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2-4 until term CA showed no evidence of benefit at 7 years' CA. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinica

AIM: The primary aim of this study was to investigate the accuracy of the Alberta Infant Motor Scale (AIMS) and Neuro-Sensory Motor Developmental Assessment (NSMDA) over the first year of life for predicting motor impairment at 4 years in preterm children. The secondary aims were to assess the predictive value of serial assessments over the first year and when using a combination of these two assessment tools in follow-up. METHOD: Children born <30 weeks' gestation were prospectively recruited and assessed at 4, 8 and 12 months' corrected age using the AIMS and NSMDA. At 4 years' corrected age children were assessed for cerebral palsy (CP) and motor impairment using the Movement Assessment Battery for Children 2nd-edition (MABC-2). We calculated accuracy of the AIMS and NSMDA for predicting CP and MABC-2 scores ≤15th (at-risk of motor difficulty) and ≤5th centile (significant motor difficulty) for each test (AIMS and NSMDA) at 4, 8 and 12 months, for delay on one, two or all three of the time points over the first year, and finally for delay on both tests at each time point. RESULTS: Accuracy for predicting motor impairment was good for each test at each age, although false positives were common. Motor impairment on the MABC-2 (scores ≤5th and ≤15th) was most accurately predicted by the AIMS at 4 months, whereas CP was most accurately predicted by the NSMDA at 12 months. In regards to serial assessments, the likelihood ratio for motor impairment increased with the number of delayed assessments. When combining both the NSMDA and AIMS the best accuracy was achieved at 4 months, although results were similar at 8 and 12 months. INTERPRETATION: Motor development during the first year of life in preterm infants assessed with the AIMS and NSMDA is predictive of later motor impairment at preschool age. However, false positives are common and therefore it is beneficial to follow-up children at high risk of motor impairment at more than one time point, or to use a combinatio

BACKGROUND: Moderate-to-severe white matter abnormality (WMA) in the newborn has been shown to produce persistent disruptions in cerebral connectivity but does not universally result in neurodevelopmental disability in very preterm (VPT) children. The aims of this hypothesis-driven study were to apply diffusion imaging to: (i) examine whether bilateral WMA detected in VPT children in the newborn period can predict microstructural organization at the age of 7 y and (ii) compare corticospinal tract and corpus callosum (CC) measures in VPT children at the age of 7 y with neonatal WMA with normal vs. impaired motor functioning. METHODS: Diffusion parameters of the corticospinal tract and CC were compared between VPT 7-y olds with (n = 20) and without (n = 42) bilateral WMA detected in the newborn period. For those with WMA, diffusion parameters were further examined. RESULTS: Microstructural organization of corticospinal tract and CC tracts at the age of 7 y were altered in VPT children with moderate-to-severe WMA detected at term equivalent age as compared with those without injury. Furthermore, diffusion parameters differed in the CC for children with WMA categorized by motor outcome (n = 8). CONCLUSION: WMA on conventional magnetic resonance imaging at term equivalent age is associated with altered microstructural organization of the corticospinal tract and CC at 7 y of age.

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.

BACKGROUND AND OBJECTIVES: Preterm infants commonly have transient hypothyroxinemia of prematurity after birth, which has been associated with deficits in general intellectual functioning, memory, attention, and academic achievement. However, research has predominantly focused on thyroxine levels in the first 2 weeks of life and outcomes are limited to the preschool period. Our objective was to evaluate the relationships between free thyroxine (fT₄) levels over the first 6 weeks after very preterm (VPT) birth with cognitive functioning and brain development at age 7 years. METHODS: A total of 83 infants born VPT (<30 weeks' gestation) had fT₄ concentrations measured postnatally and 2- and 6-week area under the curve (AUC) summary measures were calculated. Follow-up at age 7 years included a neuropsychological assessment and brain MRI. Univariable and multivariable regression modeling was used where AUC for fT₄ was the main predictor of neurodevelopmental outcome at age 7 years. RESULTS: Multivariable modeling revealed that higher, not lower, postnatal fT₄ levels (2-week AUC) were associated with poorer cognitive performances at age 7 years on tasks of verbal learning (P = .02), verbal memory (P = .03), and simple reaction time (P < .001). A similar pattern of results was found when the 6-week AUC was examined. No significant associations between postnatal fT₄ levels and brain volumes at age 7 years were identified. CONCLUSIONS: Results are contradictory to previous observations and suggest that after adjustment for confounders, higher postnatal fT₄ levels in VPT infants, rather than lower levels, may be a marker of adverse neuropsychological development in childhood.

Children born very preterm (VPT) are at risk for visual impairments, the main risk factors being retinopathy of prematurity and cerebral white matter injury, however these only partially account for visual impairments in VPT children. This study aimed to compare optic radiation microstructure and volume between VPT and term-born children, and to investigate associations between 1) perinatal variables and optic radiations; 2) optic radiations and visual function in VPT children. We hypothesized that optic radiation microstructure would be altered in VPT children, predicted by neonatal cerebral white matter abnormality and retinopathy of prematurity, and associated with visual impairments. 142 VPT children and 32 controls underwent diffusion-weighted magnetic resonance imaging at 7 years of age. Optic radiations were delineated using constrained spherical deconvolution tractography. Tract volume and average diffusion tensor values for the whole optic radiations and three sub-regions were compared between the VPT and control groups, and correlated with perinatal variables and 7-year visual outcome data. Total tract volumes and average diffusion values were similar between VPT and control groups. On regional analysis of the optic radiation, mean and radial diffusivity were higher within the middle sub-regions in VPT compared with control children. Neonatal white matter abnormalities and retinopathy of prematurity were associated with optic radiation diffusion values. Lower fractional anisotropy in the anterior sub-regions was associated with poor visual acuity and increased likelihood of other visual defects. This study presents evidence for microstructural alterations in the optic radiations of VPT children, which are largely predicted by white matter abnormality or severe retinopathy of prematurity, and may partially explain the higher rate of visual impairments in VPT children.

The aims of this study were to investigate regional white matter microstructural differences between very preterm (VPT) (<30 weeks' gestational age and/or <1250 g) and full term (FT) (≥37 weeks' gestational age) infants at term corrected age with diffusion tensor imaging, and to explore perinatal predictors of diffusion measures, and the relationship between regional diffusion measures and neurodevelopmental outcomes at age 7 years in VPT children. Mean (MD) (p = .003), axial (AD) (p = .008), and radial diffusivity (RD) (p = .003) in total white matter were increased in VPT compared with FT infants, with similar fractional anisotropy (FA) in the two groups. There was little evidence that group-wise differences were specific to any of the 8 regions studied for each hemisphere. Perinatal white matter abnormality and intraventricular hemorrhage (grade III or IV) were associated with increased diffusivity in the white matter of VPT infants. Higher white matter diffusivity measures of the inferior occipital and cerebellar region at term-equivalent age were associated with increased risk of impairments in motor and executive function at 7 years in VPT children, but there was little evidence for associations with IQ or memory impairment. In conclusion, myelination is likely disrupted or delayed in VPT infants, especially those with perinatal brain abnormality (BA). Altered diffusivity at term-equivalent age helps explain impaired functioning at 7 years. This study defines the nature of microstructural alterations in VPT infant white matter, assists in understanding the associated risk factors, and is the first study to reveal an important link between inferior occipital and cerebellar white matter disorganization in infancy, and executive and motor functioning 7 years later.

PURPOSE: To compare the size of multiple brain structures, maturation in terms of both brain myelination and gyral development, and evidence of brain injury between moderate and late preterm (MLPT) and term-born infants at term-equivalent age. MATERIALS AND METHODS: The study was approved by the human research ethics committees of the participating hospitals, and informed parental consent was obtained for all infants. One hundred ninety-nine MLPT and 50 term-born infants underwent 3-T magnetic resonance (MR) imaging brain examinations at 38-44 weeks of corrected gestational age. T1- and T2-weighted MR images were compared between groups for size of multiple cerebral structures, degree of myelination in the posterior limb of the internal capsule, gyral maturation, signal intensity abnormalities, and presence of cysts by a single assessor who was blinded to the gestational group and perinatal course of the infants. Group differences were compared by using linear regression for continuous variables and logistic regression for categorical variables, and interrater and intrarater reliability was assessed by using intraclass correlation coefficients. RESULTS: Compared with those in the term-born control group, measurements of brain biparietal diameter, corpus callosum, basal ganglia and thalami, and cerebellum were smaller in infants in the MLPT group (all P ≤ .01), while extracerebral space was larger (P < .0001). Myelination of the posterior limb of the internal capsule was less developed, and gyral maturation was delayed in the MLPT group (both P < .001). Signal intensity abnormalities and cysts were uncommon in both groups, with 13 (6.5%) MLPT infants and one (2%) term infant having abnormalities. Inter- and intrarater reliability was good for most measures, with intraclass correlation coefficients generally greater than 0.68. CONCLUSION: MLPT birth is associated with smaller brain size, less-developed myelination of the posterior limb of the internal capsule, and mor

BACKGROUND: Most babies are born healthy and grow and develop normally through childhood. There are, however, clearly identifiable high-risk groups of survivors, such as those born preterm or with ill-health, who are destined to have higher than expected rates of health or developmental problems, and for whom more structured and specialised follow-up programs are warranted. DISCUSSION: This paper presents the results of a two-day workshop held in Melbourne, Australia, to discuss neonatal populations in need of more structured follow-up and why, in addition to how, such a follow-up programme might be structured. Issues discussed included the ages of follow-up, and the personnel and assessment tools that might be required. Challenges for translating results into both clinical practice and research were identified. Further issues covered included information sharing, best practice for families and research gaps. SUMMARY: A substantial minority of high-risk children has long-term medical, developmental and psychological adverse outcomes and will consume extensive health and education services as they grow older. Early intervention to prevent adverse outcomes and the effective integration of services once problems are identified may reduce the prevalence and severity of certain outcomes, and will contribute to an efficient and effective use of health resources. The shared long-term goal for families and professionals is to work toward ensuring that high risk children maximise their potential and become productive and valued members of society.

BACKGROUND: Adolescents born extremely preterm (EP; <28 weeks' gestation) and/or extremely low birthweight (ELBW; <1000 g) experience high rates of visual impairments, however the potential neural correlates of visual impairments in EP/ELBW adolescents require further investigation. This study aimed to: 1) compare optic radiation and primary visual cortical structure between EP/ELBW adolescents and normal birthweight controls; 2) investigate associations between perinatal factors and optic radiation and primary visual cortical structure in EP/ELBW adolescents; 3) investigate associations between optic radiation and primary visual cortical structure in EP/ELBW adolescents and the odds of impaired vision. METHODS: 196 EP/ELBW adolescents and 143 controls underwent magnetic resonance imaging at a mean age of 18 years. Optic radiations were delineated using constrained spherical deconvolution based probabilistic tractography. Primary visual cortices were segmented using FreeSurfer software. Diffusion tensor variables and tract volume of the optic radiations, as well as volume, surface area and thickness of the primary visual cortices, were estimated. RESULTS: Axial, radial and mean diffusivities within the optic radiations, and primary visual cortical thickness, were higher in the EP/ELBW adolescents than controls. Within EP/ELBW adolescents, postnatal corticosteroid exposure was associated with altered optic radiation diffusion values and lower tract volume, while decreasing gestational age at birth was associated with increased primary visual cortical volume, area and thickness. Furthermore, decreasing optic radiation fractional anisotropy and tract volume, and increasing optic radiation diffusivity in EP/ELBW adolescents were associated with increased odds of impaired vision, whereas primary visual cortical measures were not associated with the odds of impaired vision. CONCLUSIONS: Optic radiation and primary visual cortical structure are altered in EP/ELBW adolescen

BACKGROUND: Infants born <30 weeks' gestation are at increased risk of long term neurodevelopmental problems compared with term born peers. The predictive value of neurobehavioural examinations at term equivalent age in very preterm infants has been reported for subsequent impairment. Yet there is little knowledge surrounding earlier neurobehavioural development in preterm infants prior to term equivalent age, and how it relates to perinatal factors, cerebral structure, and later developmental outcomes. In addition, maternal psychological wellbeing has been associated with child development. Given the high rate of psychological distress reported by parents of preterm children, it is vital we understand maternal and paternal wellbeing in the early weeks and months after preterm birth and how this influences the parent-child relationship and children's outcomes. Therefore this study aims to examine how 1) early neurobehaviour and 2) parental mental health relate to developmental outcomes for infants born preterm compared with infants born at term. METHODS/DESIGN: This prospective cohort study will describe the neurobehaviour of 150 infants born at <30 weeks' gestational age from birth to term equivalent age, and explore how early neurobehavioural deficits relate to brain growth or injury determined by magnetic resonance imaging, perinatal factors, parental mental health and later developmental outcomes measured using standardised assessment tools at term, one and two years' corrected age. A control group of 150 healthy term-born infants will also be recruited for comparison of outcomes. To examine the effects of parental mental health on developmental outcomes, both parents of preterm and term-born infants will complete standardised questionnaires related to symptoms of anxiety, depression and post-traumatic stress at regular intervals from the first week of their child's birth until their child's second birthday. The parent-child relationship will be assessed at one

OBJECTIVES: Extremely preterm (EP) survivors have smaller brains, lower IQ, and worse educational achievement than their term-born peers. The contribution of smaller brain size to the IQ and educational disadvantages of EP is unknown. This study aimed (i) to compare brain volumes from multiple brain tissues and structures between EP-born (< 28 weeks) and term-born (≥ 37 weeks) control adolescents, (ii) to explore the relationships of brain tissue volumes with IQ and basic educational skills and whether this differed by group, and (iii) to explore how much total brain tissue volume explains the underperformance of EP adolescents compared with controls. METHODS: Longitudinal cohort study of 148 EP and 132 term controls born in Victoria, Australia in 1991-92. At age 18, magnetic resonance imaging-determined brain volumes of multiple tissues and structures were calculated. IQ and educational skills were measured using the Wechsler Abbreviated Scale of Intelligence (WASI) and the Wide Range Achievement Test(WRAT-4), respectively. RESULTS: Brain volumes were smaller in EP adolescents compared with controls (mean difference [95% confidence interval] of -5.9% [-8.0, -3.7%] for total brain tissue volume). The largest relative differences were noted in the thalamus and hippocampus. The EP group had lower IQs(-11.9 [-15.4, -8.5]), spelling(-8.0 [-11.5, -4.6]), math computation(-10.3 [-13.7, -6.9]) and word reading(-5.6 [-8.8, -2.4]) scores than controls; all p-values<0.001. Volumes of total brain tissue and other brain tissues and structures correlated positively with IQ and educational skills, a relationship that was similar for both the EP and controls. Total brain tissue volume explained between 20-40% of the IQ and educational outcome differences between EP and controls. CONCLUSIONS: EP adolescents had smaller brain volumes, lower IQs and poorer educational performance than controls. Brain volumes of multiple tissues and structures are related to IQ and educational outcome

BACKGROUND: Very preterm children exhibit difficulties in working memory, a key cognitive ability vital to learning information and the development of academic skills. Previous research suggests that an adaptive working memory training intervention (Cogmed) may improve working memory and other cognitive and behavioural domains, although further randomised controlled trials employing long-term outcomes are needed, and with populations at risk for working memory deficits, such as children born preterm.In a cohort of extremely preterm (<28 weeks' gestation)/extremely low birthweight (<1000 g) 7-year-olds, we will assess the effectiveness of Cogmed in improving academic functioning 2 years' post-intervention. Secondary objectives are to assess the effectiveness of Cogmed in improving working memory and attention 2 weeks', 12 months' and 24 months' post-intervention, and to investigate training related neuroplasticity in working memory neural networks 2 weeks' post-intervention. METHODS/DESIGN: This double-blind, placebo-controlled, randomised controlled trial aims to recruit 126 extremely preterm/extremely low birthweight 7-year-old children. Children attending mainstream school without major intellectual, sensory or physical impairments will be eligible. Participating children will undergo an extensive baseline cognitive assessment before being randomised to either an adaptive or placebo (non-adaptive) version of Cogmed. Cogmed is a computerised working memory training program consisting of 25 sessions completed over a 5 to 7 week period. Each training session takes approximately 35 minutes and will be completed in the child's home. Structural, diffusion and functional Magnetic Resonance Imaging, which is optional for participants, will be completed prior to and 2 weeks following the training period. Follow-up assessments focusing on academic skills (primary outcome), working memory and attention (secondary outcomes) will be conducted at 2 weeks', 12 months' and 24 mon

OBJECTIVE: Although ~50% of very preterm (VP) children have neurodevelopmental impairments, early prediction of infants who will experience problems later in life remains a challenge. This study evaluated the predictive value of general movements (GM; spontaneous and endogenous movements) at 1 and 3 months' corrected age for neurodevelopment at 2 and 4 years of age in VP children. METHODS: At 1 and 3 months' corrected age, infants born <30 weeks' gestation had GM assessed as normal or abnormal. Motor, cognitive, and language development at 2 years was assessed by using the Bayley Scales of Infant and Toddler Development, Third Edition. At 4 years, cognitive and language outcomes were assessed by using the Differential Ability Scale-Second Edition and motor outcomes with the Movement Assessment Battery for Children-Second Edition; a diagnosis of cerebral palsy was documented. RESULTS: Ninety-nine VP infants were recruited, with 97% and 88% of survivors followed up at age 2 and 4 years, respectively. Abnormal GM at 1 month were associated with worse motor outcomes at 2 and 4 years but not language or cognitive outcomes. Abnormal GM at 3 months were associated with worse motor, cognitive, and language outcomes at both 2 and 4 years. Overall, GM at 1 month demonstrated better sensitivity to impairments at 2 and 4 years, whereas GM at 3 months had better specificity and were more accurate overall at distinguishing between children with and without impairment. CONCLUSIONS: Abnormal GM in VP infants, particularly at 3 months postterm, are predictive of worse neurodevelopment at ages 2 and 4 years.

AIM: To assess the predictive validity of the Bayley Scales of Infant and Toddler Development - Third Edition (Bayley-III) for later motor outcome. METHOD: Ninety-six infants (49 males, 47 females) born at less than 30 weeks' gestation admitted to two tertiary hospitals in Melbourne, Australia, were assessed with the Bayley-III Motor Scale at 2 years' corrected age and were classified as suspect or definite motor impairment if they scored less than -1 or -2 standard deviations respectively, relative to the test mean. At 4 years' corrected age, children completed Movement Assessment Battery for Children - Second Edition (MABC-2); for the total motor score, cut-offs of not more than the 15th were used to classify motor development and cut-offs of not more than the 15th centile were classified as having a significant movement difficulty. RESULTS: Of the 96 children assessed at both ages, at 2 years 9% had suspect and 4% had definite motor impairment; however, by 4 years, rates had increased to 22% and 19% respectively. The specificity of the Bayley-III for motor impairments for later motor outcome was excellent (ranging from 94 to 100% for cerebral palsy [CP] and 97 to 100% for motor impairment), although the sensitivity was low (ranging from 67 to 83% for CP and 18 to 37% for motor impairment); many children with later impairment were not identified by the Bayley-III. INTERPRETATION: The Bayley-III Motor Scale at 2 years underestimates later rates of motor impairment, particularly in the absence of CP at 4 years on the MABC-2 total motor score in children born at less than 30 weeks' gestational age.

BACKGROUND: Preterm birth confers a high risk of adverse long term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18 years comparing survivors of extremely preterm birth with infants born at term. METHODS: Using 12 extreme preterm birth cases and 12 matched, term controls, we extracted DNA from archived neonatal blood spots and blood collected in a similar way at 18 years of age. DNA methylation was measured at 347,789 autosomal locations throughout the genome using Infinium HM450 arrays. Representative methylation differences were confirmed by Sequenom MassArray EpiTYPER. RESULTS: At birth we found 1,555 sites with significant differences in methylation between term and preterm babies. At 18 years of age, these differences had largely resolved, suggesting that DNA methylation differences at birth are mainly driven by factors relating to gestational age, such as cell composition and/or maturity. Using matched longitudinal samples, we found evidence for an epigenetic legacy associated with preterm birth, identifying persistent methylation differences at ten genomic loci. Longitudinal comparisons of DNA methylation at birth and 18 years uncovered a significant overlap between sites that were differentially-methylated at birth and those that changed with age. However, we note that overlapping sites may either differ in the same (300/1,555) or opposite (431/1,555) direction during gestation and aging respectively. CONCLUSIONS: We present evidence for widespread methylation differences between extreme preterm and term infants at birth that are largely resolved by 18 years of age. These results are consistent with methylation changes associated with blood cell development, cellular composition, immune induc

OBJECTIVE: Research is required to monitor changes in the nature of neurobehavioral deficits in extremely preterm (EP) or extremely low birth weight (ELBW) survivors. This study examines cognitive, academic, and behavioral outcomes at age 8 years for a regional cohort of EP/ELBW children born in 1997. METHODS: The EP/ELBW cohort comprised all live births with a gestational age <28 weeks (EP) or birth weight <1000 g (ELBW) born in the state of Victoria, Australia, in 1997. Of 317 live births, 201 (63.4%) survived to 2 years of age.A term/normal birth weight (T/NBW) cohort was recruited comprising 199 infants with birthweights ≥2500 g or gestational age ≥37 weeks [corrected]. Measures of intellectual ability, educational achievement, and behavior were administered at age 8. RESULTS: Retention was 94% for the EP/ELBW group and 87% for the T/NBW group. The EP/ELBW group performed poorer than the T/NBW group on measures of IQ, educational achievement, and certain behavioral domains, even after adjustment for sociodemographic factors and exclusion of children with neurosensory impairment. The rate of any neurobehavioral impairment was elevated in the EP/ELBW group (71% vs 42%), and one-half of subjects had multiple impairments. The outcomes for those with <750 g birth weight or <26 weeks' gestational age were similar to those with a birth weight of 750 to 999 g or a gestational age of 26 to 27 weeks, respectively. CONCLUSIONS: Despite ongoing improvements in the management of EP/ELBW infants, the rate of neurobehavioral impairment at school-age remains too high relative to controls.

BACKGROUND AND OBJECTIVES: Ocular growth and development differs between preterm and term-born infants and may cause long-term negative consequences for visual function, but contemporary data on long-term visual outcomes in representative samples of the highest risk extremely low birth weight (ELBW, <1000 g birth weight) or extremely preterm (EP, <28 weeks' gestation) survivors are lacking. Our objective was to compare visual functioning between ELBW/EP and normal birth weight (NBW, >2499 g birth weight) control adolescents. METHODS: Geographically determined cohort study of 228 consecutive ELBW/EP survivors born in the state of Victoria in 1991 and 1992, and 166 randomly selected NBW controls assessed between 14 and 20 years of age. Visual acuity, stereopsis, convergence, color perception, and visual perception were assessed and contrasted between groups. RESULTS: ELBW/EP subjects had significantly worse visual acuity with habitual correction in both the left and right eyes, and for the best eye (P < .001). The ELBW/EP adolescents also exhibited poorer stereopsis, odds ratio (OR) 3.22 (95% confidence interval [CI] 1.78 to 5.84), and convergence, OR 2.76 (CI 1.32 to 5.75) than controls, and more problems with visual perception, OR 3.09 (CI 1.67 to 5.71) after habitual correction. CONCLUSIONS: Despite advances in medical care improving the survival rate of high-risk ELBW/EP infants, visual morbidity is still relatively high compared with controls in late adolescence.

The hippocampus undergoes rapid growth and development in the perinatal months. Infants born very preterm (VPT) are vulnerable to hippocampal alterations, and can provide a model of disturbed early hippocampal development. Hippocampal shape alterations have previously been associated with memory impairment, but have never been investigated in infants. The aims of this study were to determine hippocampal shape differences between 184 VPT infants (<30 weeks' gestation or <1250 g at birth) and 32 full-term infants, effects of perinatal factors, and associations between infant hippocampal shape and volume, and 7 year verbal and visual memory (California Verbal Learning Test - Children's Version and Dot Locations). Infants underwent 1.5 T magnetic resonance imaging at term equivalent age. Hippocampi were segmented, and spherical harmonics-point distribution model shape analysis was undertaken. VPT infants' hippocampi were less infolded than full-term infants, being less curved toward the midline and less arched superior-inferiorly. Straighter hippocampi were associated with white matter injury and postnatal corticosteroid exposure. There were no significant associations between infant hippocampal shape and 7 year memory measures. However, larger infant hippocampal volumes were associated with better verbal memory scores. Altered hippocampal shape in VPT infants at term equivalent age may reflect delayed or disrupted development. This study provides further insight into early hippocampal development and the nature of hippocampal abnormalities in prematurity.

BACKGROUND: Uncertainty remains about the rate of specific psychiatric disorders and associated predictive factors for very preterm (VPT) children. The aims of this study were to document rates of psychiatric disorders in VPT children aged 7 years compared with term born children, and to examine potential predictive factors for psychiatric diagnoses in VPT children. METHODS: Participants were 177 VPT and 65 term born children. Perinatal medical data were collected, which included brain abnormalities detected using magnetic resonance imaging. The Infant-Toddler Social-Emotional Assessment (ITSEA) and Strengths and Difficulties Questionnaire (SDQ) were administered at 2 and 5 years respectively. At 7 years of age, the Developmental and Well-being Assessment (DAWBA) was used to indicate psychiatric diagnoses. RESULTS: Compared with term born children, VPT children had three times the odds of meeting criteria for any psychiatric diagnosis at age 7 years (odds ratio 3.03; 95% confidence interval 1.23, 7.47, p = .02). The most common diagnoses were anxiety disorders (11% VPT, 8% term), attention-deficit/hyperactivity disorder (10% VPT, 3% term) and autism spectrum disorder (4.5% VPT, 0% term). For VPT children, those with severe global brain abnormalities (p = .02), those who displayed social-emotional problems at age 5 (p = .000) and those with higher social risk at age 7 (p = .001) were more likely to meet criteria for a psychiatric illness at age 7. CONCLUSIONS: Compared with term born children, VPT children have higher rates of psychiatric diagnoses at early school age, predicted by neonatal brain abnormalities, prior social-emotional problems and social factors.

BACKGROUND: The aim of this individual participant data (IPD) meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol. METHODS/DESIGN: The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant); severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores). For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse)). For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics

BACKGROUND: The primary aim of this study is to assess, using individual participant data (IPD) meta-analysis, the effects of administration of antenatal magnesium sulphate given to women at risk of preterm birth on important clinical outcomes for their child such as death and neurosensory disability. The secondary aim is to determine whether treatment effects differ depending on important pre-specified participant and treatment characteristics, such as reasons at risk of preterm birth, gestational age, or type, dose and mode of administration of magnesium sulphate. DESIGN: The Antenatal Magnesium Individual Participant Data (IPD) International Collaboration: assessing the benefits for babies using the best level of evidence (AMICABLE) Group will perform an IPD meta-analysis to answer these important clinical questions. SETTING/TIMELINE: The AMICABLE Group was formed in 2009 with data collection commencing late 2010. INCLUSION CRITERIA: Five trials involving a total 6,145 babies are eligible for inclusion in the IPD meta-analysis. PRIMARY STUDY OUTCOMES: For the infants/children: Death or cerebral palsy. For the women: Any severe maternal outcome potentially related to treatment (death, respiratory arrest or cardiac arrest). DISCUSSION: Results are expected to be publicly available in 2012.

Preterm children are at risk for a number of visual impairments which can be important for a range of other more complex visuocognitive tasks reliant on visual information. Despite the relatively high incidence of visual impairments in this group there are no good predictors that would allow early identification of those at risk for adverse outcomes. Several lines of evidence suggest that docosahexaenoic acid (DHA) supplementation for preterm infants may improve outcomes in this area. For example, diets deficient in the long-chain polyunsaturated fatty acid DHA have been shown to reduce its concentration in the cerebral cortex and retina, which interferes with physiological processes important for cognition and visual functioning. Further, various studies with pregnant and lactating women, as well as formula-fed infants, have demonstrated a general trend that supplementation with dietary DHA is associated with better childhood outcomes on tests of visual and cognitive development over the first year of life. However, research to date has several methodological limitations, including concentrations of DHA supplementation that have been too low to emulate the in utero accretion of DHA, using single measures of visual acuity to make generalised assumptions about the entire visual system, and little attempt to match what we know about inadequate DHA and structural ramifications with how specific functions may be affected. The objective of this review is to consider the role of DHA in the context of visual processing with a specific emphasis on preterm infants and to illustrate how future research may benefit from marrying what we know about structural consequences to inadequate DHA with functional outcomes that likely have far-reaching ramifications. Factors worth considering for clinical neuropsychological evaluation are also discussed.

BACKGROUND: Early developmental interventions to prevent the high rate of neurodevelopmental problems in very preterm children, including cognitive, motor and behavioral impairments, are urgently needed. These interventions should be multi-faceted and include modules for caregivers given their high rates of mental health problems. METHODS/DESIGN: We have designed a randomized controlled trial to assess the effectiveness of a preventative care program delivered at home over the first 12 months of life for infants born very preterm (<30 weeks of gestational age) and their families, compared with standard medical follow-up. The aim of the program, delivered over nine sessions by a team comprising a physiotherapist and psychologist, is to improve infant development (cognitive, motor and language), behavioral regulation, caregiver-child interactions and caregiver mental health at 24 months' corrected age. The infants will be stratified by severity of brain white matter injury (assessed by magnetic resonance imaging) at term equivalent age, and then randomized. At 12 months' corrected age interim outcome measures will include motor development assessed using the Alberta Infant Motor Scale and the Neurological Sensory Motor Developmental Assessment. Caregivers will also complete a questionnaire at this time to obtain information on behavior, parenting, caregiver mental health, and social support. The primary outcomes are at 24 months' corrected age and include cognitive, motor and language development assessed with the Bayley Scales of Infant and Toddler Development (Bayley-III). Secondary outcomes at 24 months include caregiver-child interaction measured using an observational task, and infant behavior, parenting, caregiver mental health and social support measured via standardized parental questionnaires. DISCUSSION: This paper presents the background, study design and protocol for a randomized controlled trial in very preterm infants utilizing a preventative care progra