Sex and mental health are related to subcortical brain microstructure.

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Visuospatial working memory of children and adults born very preterm and/or very low birth weight.

BACKGROUND: This paper examines the visuospatial working memory (WM) performance of children and adults born very preterm (VPT) and/or very low birth weight (VLBW) relative to their full-term (FT)-born peers. Of interest was the nature and severity of observed impairments, as well associations with educational/occupational functioning at each age point. METHODS: Participants were drawn from two prospective cohort studies: (1) a regional cohort of 110 VPT (<32 weeks' gestation and <1500 g) and 113 FT born children assessed at age 12 years; (2) a national cohort of 229 VLBW (<1500 g) and 100 FT born adults assessed at age 28 years. Visuospatial WM was assessed using a four-span/difficulty-level computerized task. RESULTS: Both children and adults born VPT/VLBW had poorer visuospatial WM than FT controls, with their performance less accurate, slower (correct trials), and less efficient with increasing task difficulty (Cohen's d = 0.27-0.51; p < 0.05). Adults had better visuospatial WM than children, but between-group differences were highly similar across ages, before and after adjustment for confounding social background and individual factors. Poorer WM was associated with lower levels of educational and occupational/socioeconomic achievement. CONCLUSIONS: Visuospatial WM difficulties persist into adulthood raising concerns for the longer-term cognitive and adaptive functioning of VPT survivors. IMPACT: Both children and adults born very preterm have poorer visuospatial working memory than their term-born peers. They are less accurate, take longer to respond correctly and are less efficient, with test performance declining with increasing cognitive demand. Similar differences in visuospatial working memory are observed between VPT/VLBW and full-term individuals during both childhood and adulthood, with these differences remaining even after covariate adjustment. Individuals with poorer visuospatial working memory have lower levels of educational achievement and occupational/socioeconomic success. Visuospatial working memory difficulties persist into adulthood and appear to continue to impact everyday functioning and life-course opportunities.

Self-reported executive function problems in adults born very low birthweight.

BACKGROUND: Executive function difficulties are common among children born very preterm and/or very low birthweight (<1500 g; VLBW), but little is known about whether they persist into adulthood. OBJECTIVES: Examine the nature and pattern of self-reported executive functioning at 23 and 28 years of age using data from a national cohort study of adults born VLBW and a comparison group of same-age full-term (FT) born adults. Also examined were associations between executive function difficulties and socio-economic outcomes. METHODS: All infants born VLBW in New Zealand during 1986 were prospectively included in an audit of retinopathy of prematurity (n = 413), with 250 (77% of survivors) followed to median age 28 years. A comparison group of FT adults was also recruited at age 23 and followed to 28 years (n = 100). Across both adult assessments, executive functioning was assessed using the Behaviour Rating Inventory of Executive Function-Adult Version (BRIEF-A) and analysed with semi-parametric models to examine the effects of age and group on executive function. RESULTS: At 23 and 28 years, VLBW adults had increased risk of executive function impairment compared with FT adults in behaviour regulation (relative risk [CI] 2.37, 95% confidence interval (CI)1.27, 4.45), meta-cognition (RR 6.03, 95% CI 2.18, 16.78) and global functioning (RR 3.20, 95% CI 1.40, 7.28). Impaired global executive functioning was associated with lower socio-economic status (regression estimate [b] = -0.43, 95% CI -0.59, -0.27) and a reduced likelihood of home ownership by age 28 years (RR 0.98, 95% CI 0.96, 1.00), even after controlling for sex, ethnicity and parental socio-economic backgrounds for both groups. CONCLUSION(S): VLBW-born adults continue to experience more executive function difficulties in their everyday life relative to term controls at age 28 years. These difficulties were negatively associated with their socio-economic opportunities as young adults.

Mental health, neurodevelopmental, and family psychosocial profiles of children born very preterm at risk of an early-onset anxiety disorder.

AIM: To compare the mental health and neurodevelopmental profiles of school-age children born very preterm, with and without an anxiety disorder, and to identify neonatal medical, psychosocial, and concurrent neurodevelopmental correlates. METHOD: A regional cohort of 102 (51 males, 51 females) children born very preterm (mean [SD] gestation at birth=28wks [2], range=23-31wks) was studied from birth to age 9 years alongside a comparison group of 109 (58 males, 51 females) children born at term (mean [SD] gestation at birth=40wks [1], range=38-41wks). At age 9 years, all children underwent a neurodevelopmental evaluation while parents were interviewed using the Development and Well-Being Assessment to diagnose a range of DSM-IV childhood psychiatric disorders. Detailed information was also available about the children's neonatal medical course and postnatal psychosocial environment, including maternal mental health and parenting. RESULTS: At age 9 years, 21% (n=21) of very preterm and 13% (n=14) of term-born children met diagnostic criteria for an anxiety disorder. Clinically-anxious children born very preterm were characterized by higher rates of comorbid mental health (odds ratio [OR]=11.5, 95% confidence interval [CI]=3.8-34.7), social (OR=6.2, 95% CI=2.1-18.4), motor (OR=4.4, 95% CI=1.6-12.2), and cognitive (OR=2.6, 95% CI=1.0-7.0) problems than those without an anxiety disorder. Concurrent maternal mental health and child social difficulties were the strongest independent correlates of early-onset child anxiety disorders. INTERPRETATION: Children born very preterm who developed an early-onset anxiety disorder were subject to high rates of comorbid problems. Findings highlight the importance of addressing both maternal and child mental health issues to optimize outcomes in this high-risk population. What this paper adds One out of five school-age children born very preterm are likely to meet DSM-IV diagnostic criteria for an anxiety disorder. Half of these children born very preterm with an early-onset anxiety disorder have comorbid attention-deficit/hyperactivity disorder. Other neurodevelopmental correlates of early-onset anxiety disorders include lower cognitive ability, motor problems, and peer social difficulties. Concurrent maternal mental health and child social adjustment problems were the strongest correlates of early-onset anxiety disorder risk among children born very preterm.

Prenatal methadone exposure and child developmental outcomes in 2-year-old children.

AIM: To examine the developmental outcomes of children born to opioid-dependent females enrolled in methadone maintenance and identify pre- and postnatal factors that place these children at developmental risk. METHOD: Ninety-nine methadone-maintained females and their 100 infants (42 females, 58 males, mean gestational age 38.8wks) were recruited during pregnancy/at birth and studied to age 2 years alongside a regionally representative comparison group of 108 non-methadone-maintained females and their 110 infants (62 females, 48 males, mean gestational age 39.2wks). Information about perinatal exposure was collected from medical records, maternal urine and infant meconium toxicological analysis, maternal interviews (at birth and at 18mo), and a home visit (at 18mo). At age 2 years, child neuromotor function, cognition, language, and emotional/behavioral dysregulation were assessed. RESULTS: Opioid-exposed children achieved lower motor, cognitive, and language scores and had poorer self, emotional, eating/feeding, and sensory processing regulation than unexposed children. After adjustment for maternal education and other substance use in pregnancy, between-group differences in child motor, cognitive, and overall dysregulation remained. Postnatal parental and family factors explained a further 40% to 52% of between-group differences in child outcomes. INTERPRETATION: These children and families are extremely high-risk and need antenatal and postnatal support. Children exposed to opioids during pregnancy have pervasive developmental difficulties by age 2 years. These challenges are largely explained by adverse pregnancy and socio-environmental exposures, emphasizing the importance of specialist prenatal care and postnatal intervention support. What this paper adds Children born to opioid-dependent females are at high risk of pervasive developmental problems. These problems span a range of functional domains, including motor, cognitive, language, and behavioral/emotional dysregulation. Contributing factors include other adverse pregnancy exposures, postnatal environmental factors, and the direct effects of prenatal opioid exposure.

Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial.

BACKGROUND: Human milk is recommended for very preterm infants, but its variable macronutrient content may contribute to undernutrition during a critical period in development. We hypothesize that individually targeted human milk fortification is more effective in meeting macronutrient requirements than the current standard of care. METHODS: We designed a single-center randomized, controlled trial enrolling 130 infants born < 31 completed weeks' gestation. Participants will receive fortified maternal and/or pasteurized donor milk but no formula. For participants in the intervention group, milk will be individually fortified with protein and fat modulars to achieve target levels based on daily point-of-care milk analysis with mid-infrared spectroscopy, in addition to standard fortification. The study diet will continue through 36 weeks' postmenstrual age (PMA). Clinical staff and parents will be masked to study group. Primary outcomes include: 1) body length and lean body mass by air displacement plethysmography at 36 weeks' PMA; 2) quantitative magnetic resonance imaging-based measures of brain size and microstructure at term equivalent age; and 3) Bayley-IV scales at 2 years' corrected age. DISCUSSION: We expect this trial to provide important data regarding the effectiveness of individually targeted human milk fortification in the neonatal intensive care unit (NICU). TRIAL REGISTRATION: NCT03977259 , registered 6 June, 2019.

Perinatal and childhood predictors of general cognitive outcome at 28 years in a very-low-birthweight national cohort.

AIM: To determine IQ at 26 to 30 years in very-low-birthweight (VLBW) adults compared with term-born controls; and to examine the stability of IQ in VLBW individuals between 7 to 8 years and 26 to 30 years, identify perinatal and social predictors of IQ, and assess the contribution of brain volume to IQ. METHOD: At 26 to 30 years, 229 VLBW adults (71% survivors of prospectively enrolled national cohort) and 100 term-born controls were tested on the Wechsler Abbreviated Scale of Intelligence. For VLBW, IQ at 7 to 8 years, perinatal and social data were extracted from the data set, and 150 adults underwent volumetric cranial magnetic resonance imaging (MRI). RESULTS: At 26 to 30 years, the mean adjusted difference between VLBW and controls for total IQ was 9.4 (95% CI 6.5-12.4) points. In VLBW individuals the correlation between IQ scores at 7 to 8 years and 26 to 30 years was 0.78. On multiple regression analysis, parental education was the strongest predictor of verbal and total IQ at both ages. Birthweight was a strong predictor of perceptual and total IQ. In VLBW individuals with MRI scans, the addition of brain volume as a variable increased the variance explained for perceptual and total IQ. INTERPRETATION: VLBW adults have mean IQ scores 9 to 11 points below controls. Parental education and birthweight are the strongest predictors of IQ.

Peer Relationship Outcomes of School-Age Children Born Very Preterm.

OBJECTIVES: To characterize the friendship networks, peer relationships, and bullying experiences of 12-year-old children born extremely preterm (EPT; 23-27 weeks of gestation), very preterm (VPT; 28-32 weeks of gestation), and full term (FT; 38-41 weeks of gestation), and to identify child characteristics placing children at risk of peer problems. STUDY DESIGN: A regional cohort of 44 EPT, 60 VPT, and 109 FT born children were followed prospectively to 12 years of age. The nature of children's close friendships, peer relations, and bullying experiences were assessed using a multimethod approach, including parent, teacher, and child report. RESULTS: Across all measures, children born EPT had more peer social difficulties than children born VPT and FT. They were more likely to report no close friendships (5%-14% EPT vs 0%-3% VPT/FT), dissatisfaction with their peer network (16% vs 1%-2%), and less time interacting face-to-face with friends (16%-23% vs 5%-8%). They were also 3 times more likely to be rated by their parents and teachers as experiencing problems relating to peers (P ≤ .001). In contrast, rates of chronic bullying (≥2 times/week) were similar for EPT and VPT children (12%-14% vs 4% FT). Emotional problems, inattention/hyperactivity, and motor deficits were associated with an increased risk of peer relationship problems, whereas higher body mass index, delayed pubertal development, vision problems, and inattention/hyperactivity problems were associated with frequent bullying. CONCLUSIONS: With the exception of bullying, risks of peer social difficulties were greatest among children born EPT. Peer social relationships should be monitored as part of longer term developmental surveillance and support.

Exposure to parental separation in childhood and later parenting quality as an adult: evidence from a 30-year longitudinal study.

BACKGROUND: Previous research has documented that exposure to parental separation/divorce during childhood can be associated with long-term consequences into adulthood. This study sought to extend this literature by examining associations between childhood exposure to parental separation/divorce and later parenting behavior as an adult in a New Zealand birth cohort. METHODS: Data were drawn from the Christchurch Health and Development Study (CHDS), a longitudinal study of a birth cohort of 1,265 children born in 1977 in Christchurch, New Zealand. Information about exposure to parental separation and divorce was gathered annually from birth to 15 years. At the 30-year follow-up, all cohort members who had become parents (biological or nonbiological) were assessed on several parenting dimensions (sensitivity, warmth, overreactivity, inconsistency, quality of child management, and physical punishment). RESULTS: The analyses showed that exposure to more frequent parental separation in childhood and adolescence was associated with lower levels of parental sensitivity and warmth, greater overreactivity, and an increased use of physical punishment as a parent, after controlling for a wide range of family socioeconomic and psychosocial factors, and individual child characteristics. CONCLUSIONS: The findings suggest that as exposure to parental separation increases, so does the likelihood of experiencing multiple developmental challenges in childhood and adolescence. As an adult, these life-course experiences can have small but significant associations with the quality of parenting behavior.

Attention and Regional Gray Matter Development in Very Preterm Children at Age 12 Years.

OBJECTIVES: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. METHODS: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. RESULTS: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected p<.05). Poorer sustained auditory attention was associated with increased gray matter in the anterior cingulate cortex (p=.04). Poor executive shifting attention was associated with reduced gray matter in the right superior temporal cortex (p=.04) and bilateral thalami (p=.05). Poorer executive divided attention was associated with reduced gray matter in the occipital (p=.001), posterior cingulate (p=.02), and left temporal (p=.01) cortices; and increased gray matter in the anterior cingulate cortex (p=.001). CONCLUSIONS: Disturbances in regional gray matter development appear to contribute, at least in part, to the poorer attentional performance of VPT children at school age. (JINS, 2017, 23, 539-550).

Cognitive Development Trajectories of Very Preterm and Typically Developing Children.

Cognitive impairment is common among children born very preterm (VPT), yet little is known about how this risk changes over time. To examine this issue, a regional cohort of 110 VPT (≤ 32 weeks gestation) and 113 full-term (FT) born children was prospectively assessed at ages 4, 6, 9, and 12 years using the Wechsler Preschool and Primary Scale of Intelligence-Revised and then Wechsler Intelligence Scale for Children, 4th ed. At all ages, VPT children obtained lower scores than their FT born peers (p < .001). Growth curve modeling revealed stable cognitive trajectories across both groups. Neonatal white matter abnormalities and family socioeconomic adversity additively predicted cognitive risk. Despite some intraindividual variability, cognitive functioning of typically developing and high-risk VPT children was stable and influenced by early neurological development and family rearing context.

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.

Relation of perinatal risk and early parenting to executive control at the transition to school.

Executive control (EC) develops rapidly during the preschool years and is central to academic achievement and functional outcome. Although children with perinatal adversity are at known risk for EC impairments, little is known about the underlying nature of these impairments or the mechanisms that contribute to their development over time. Drawing on a cohort of 110 high-risk children born very preterm (VPT; < 33 weeks / < 1500 g) and 113 healthy full-term children, this study examined the implications of perinatal adversity and early parenting for children's EC as they transitioned to formal schooling. Parent supportive presence, intrusiveness, and parent-child synchrony were observed during a series of problem-solving tasks at ages 2 and 4 years. At age 6, children completed a comprehensive battery of EC tasks. Academic outcomes were assessed at age 9. The VPT group showed global EC impairments at age 6, although the unitary factor that best characterized the structure of EC was the same in both groups. High-risk dyads were characterized by more intrusive and less synchronous parent-child interactions in early childhood, which in turn predicted poorer child EC at age 6. EC partially mediated the relation of risk status to poorer academic achievement at age 9. Findings demonstrate the cumulative effects of perinatal adversity on children's EC in the crucial transition to schooling. They also highlight the importance of the parent-child relationship as a target for intervention efforts to help mitigate these effects.

Social development of children born very preterm: a systematic review.

AIM: To review systematically studies examining the development of social competence in children born very preterm (VPT) (gestation <33 wks) and identify neonatal and family predictors. METHOD: Peer-reviewed original articles were extracted from PubMed and PsycINFO following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Selection criteria included children born VPT and comparison children born at term, sample born after 1990, and children assessed between 0 and 17 years on at least one measure of social competence spanning social adjustment, performance, and/or social skills. RESULTS: Twenty-three studies were included. Seven focused on social competence and another 16 examined social competence within a range of outcomes. Study quality was low. Limitations included reliance on single informant data, cross-sectional measurement, use of brief screening tools, absence of child or peer report, and no conceptual model. In terms of social adjustment, 16 out of 21 studies found children born VPT had more peer problems and social withdrawal. Findings of social performance were mixed, with some studies suggesting differences in prosocial behavior (4/14) and others not. Social skills were assessed in four studies and showed children born VPT had poorer skills than children born at term. Predictors of social competence included gestational age, neonatal brain abnormalities, and family socio-economic status. INTERPRETATION: Children born VPT have poorer social competence. These difficulties emerge early and persist throughout childhood.

The New Zealand 1986 very low birth weight cohort as young adults: mapping the road ahead.

BACKGROUND: Very low birth weight (less than 1500 g) is associated with increased morbidity and costs of health care in childhood. Emerging evidence suggests these infants face a range of health and social problems as young adults. We studied all New Zealand very low birth weight infants born in 1986 (when 58% were exposed to antenatal corticosteroids) in infancy, with later follow-up at 7 to 8 years and 23 to 24 years. We now aim to assess the cohort at 26-28 years compared with controls. METHODS/DESIGN: The case sample will comprise a minimum of 250 members of the 1986 New Zealand national very low birth weight cohort (77% of survivors). Outcomes will be compared with a control group of 100 young adults born at term in 1986. Following written informed consent, participants will travel to Christchurch for 2 days of assessments undertaken by experienced staff. Medical assessments include growth measures, vision, respiratory function, blood pressure and echocardiogram, renal function, dental examination and blood tests. Cognitive and neuropsychological functioning will be assessed with standard tests, and mental health and social functioning by participant interview. A telephone interview will be conducted with a parent or significant other person nominated by the respondent to gain a further perspective on the young person's health and functioning. All those born at less than 28 weeks' gestation, plus a random subset of the cohort to a total of 150 cases and 50 controls, will be offered cranial magnetic-resonance imaging. Statistical analysis will examine comparison with controls and long-term trajectories for the very low birth weight cohort. DISCUSSION: The research will provide crucial New Zealand data on the young adult outcomes for very low birth weight infants and address gaps in the international literature, particularly regarding cardiovascular, respiratory, visual and neurocognitive outcomes. These data will inform future neonatal care, provide evidence-based guidelines for care of preterm graduates transitioning to adult care, and help shape health education and social policies for this high risk group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000995875 . Registered 1 October 2012.

Early electrographic seizures, brain injury, and neurodevelopmental risk in the very preterm infant.

BACKGROUND: Previous studies of very preterm (VPT) infants have shown a wide range of seizure prevalence and association with intraventricular hemorrhage (IVH), white matter injury (WMI), and death. However, the impact of seizures on neurodevelopment is not well known. We hypothesized that seizures in the first 3 d after VPT birth would be associated with increased radiographic brain injury and later neurodevelopmental risk. METHODS: For 72 h after birth, 95 VPT infants underwent amplitude-integrated electroencephalogram monitoring. High and low seizure burdens were related to radiographic brain injury, death in the neonatal period, and children's Bayley III (Bayley Scales of Infant Development) performance at 2 y corrected age in a subgroup of 59 infants. RESULTS: The overall incidence of seizures in this sample was 48%. High seizure burden was associated with increased risk of IVH on day 1; IVH, WMI, and death on day 2; and high-grade IVH on day 3. The presence of seizures on any day was associated with decreased language performance at age 2, even after controlling for family social risk. CONCLUSION: Seizures during the first 3 d after birth are common and are associated with an increased risk of IVH, WMI, and death. They were also associated with poorer early language development.

Neonatal cerebral morphometry and later risk of persistent inattention/hyperactivity in children born very preterm.

BACKGROUND: Attention problems are among the most prevalent neurobehavioral morbidities affecting very preterm (VPT) born children. The first study aim was to document rates of persistent attention/hyperactivity problems from ages 4 to 9 years in a regional cohort of VPT born children. The second aim was to examine the extent to which persistent problems were related to cerebral white matter abnormality and structural development on neonatal MRI. METHODS: Data were drawn from a prospective longitudinal study of 110 VPT (≤32 weeks gestation) and 113 full-term (FT) children born from 1998 to 2000. At term equivalent, all VPT and 10 FT children underwent cerebral structural MRI, with scans analyzed qualitatively for white matter abnormalities and quantitatively for cortical and subcortical gray matter, myelinated and unmyelinated white matter, and cerebrospinal fluid volumes. At ages 4, 6, and 9 years, each child's parent and teacher completed the Inattention/Hyperactivity subscale of the Strengths and Difficulties Questionnaire. RESULTS: VPT born children had a fivefold increased risk of persistent attention/hyperactivity problems compared with FT children (13.1% vs. 2.8%; p = .002). No association was found between neonatal white matter abnormalities and later persistent inattention/hyperactivity risk (p ≥ .24). In contrast, measures of cerebral structural development including volumetric estimates of total cerebral tissue and cerebrospinal fluid relative to intracranial volume were associated with an increased risk of persistent attention/hyperactivity problems in VPT born children (p = .001). The dorsal prefrontal region showed the largest volumetric reduction (↓3.2-8.2 mL). These brain-behavior associations persisted and in some cases, strengthened after covariate adjustment for postmenstrual age at MRI, gender, and family socioeconomic status. CONCLUSIONS: Just over one in 10 VPT born children are subject to early onset and persistent attention/hyperactivity problems during childhood. These problems appear to reflect, at least in part, neonatal disturbances in cerebral growth and development rather than the effects of white matter injury.

Long term follow up of high risk children: who, why and how?

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.