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.

Physical activity and cognitive function in adults born very preterm or with very low birth weight-an individual participant data meta-analysis.

OBJECTIVE: Individuals born very preterm (<32 weeks of gestation) or with very low birthweight (<1500g) have lower cognitive function compared with term-born peers. Furthermore, some studies suggest that they are less physically active as young adults than controls, but the relationship between physical activity and cognitive function remains unclear. We performed an individual participant data meta-analysis to examine whether being born preterm/with very low birth weight is associated with physical activity in adulthood and examined if cognitive function mediates this association. STUDY DESIGN: Cohorts with data on physical activity and cognitive function in adults born very preterm/very low birth weight and term-born controls were recruited from the Research on European Children and Adults Born Preterm, and the Adults Born Preterm International Collaboration Consortia. A systematic literature search was performed in PubMed and Embase. RESULTS: Five cohorts with 1644 participants aged 22-28 years (595 very preterm/very low birth weight and 1049 controls) were included. Adults born very preterm/very low birth weight reported 1.11 (95% CI: 0.68 to 1.54) hours less moderate to vigorous physical activity per week than controls, adjusted for cohort, age and sex. The difference between individuals born very preterm/very low birth weight and controls was larger among women than among men. Neither intelligence quotient nor self-reported executive function mediated the association between very preterm/very low birth weight and moderate to vigorous physical activity. Results were essentially the same when we excluded individuals with neurosensory impairments. CONCLUSION: Adults born very preterm/very low birth weight, especially women, reported less moderate to vigorous physical activity than their term-born peers. Cognitive function did not mediate this association. Considering the risk of adverse health outcomes among individuals born preterm, physical activity could be a target for intervention.

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.

Health-Related Quality-of-Life Outcomes of Very Preterm or Very Low Birth Weight Adults: Evidence From an Individual Participant Data Meta-Analysis.

BACKGROUND AND OBJECTIVE: Assessment of health-related quality of life for individuals born very preterm and/or low birthweight (VP/VLBW) offers valuable complementary information alongside biomedical assessments. However, the impact of VP/VLBW status on health-related quality of life in adulthood is inconclusive. The objective of this study was to examine associations between VP/VLBW status and preference-based health-related quality-of-life outcomes in early adulthood. METHODS: Individual participant data were obtained from five prospective cohorts of individuals born VP/VLBW and controls contributing to the 'Research on European Children and Adults Born Preterm' Consortium. The combined dataset included over 2100 adult VP/VLBW survivors with an age range of 18-29 years. The main exposure was defined as birth before 32 weeks' gestation (VP) and/or birth weight below 1500 g (VLBW). Outcome measures included multi-attribute utility scores generated by the Health Utilities Index Mark 3 and the Short Form 6D. Data were analysed using generalised linear mixed models in a one-step approach using fixed-effects and random-effects models. RESULTS: VP/VLBW status was associated with a significant difference in the Health Utilities Index Mark 3 multi-attribute utility score of - 0.06 (95% confidence interval - 0.08, - 0.04) in comparison to birth at term or at normal birthweight; this was not replicated for the Short Form 6D. Impacted functional domains included vision, ambulation, dexterity and cognition. VP/VLBW status was not associated with poorer emotional or social functioning, or increased pain. CONCLUSIONS: VP/VLBW status is associated with lower overall health-related quality of life in early adulthood, particularly in terms of physical and cognitive functioning. Further studies that estimate the effects of VP/VLBW status on health-related quality-of-life outcomes in mid and late adulthood are needed.

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.

Increased Risk of Parental Instability for Children Born Very Preterm and Impacts on Neurodevelopmental Outcomes at Age 12.

Caring for a child born preterm places significant emotional and financial burdens on family relationships. This paper examines (a) the extent to which children born very and extremely preterm are more likely to experience parental change/caregiver instability than children born full term, (b) predictors of parental change/s for preterm infants, and (c) whether exposure to parental change/caregiver instability increases child neurodevelopmental risk. Data were collected as part of a prospective longitudinal study of 110 very preterm and 113 full-term born infants and their parents studied from birth to corrected age 12 years. At ages 2, 4, 6, 9 and 12 years, detailed information was collected about the frequency and nature of all parent/caregiver changes for 3-6 monthly intervals of each child's life. At age 12, all children completed a comprehensive neurodevelopmental evaluation of their emotional and behavioural adjustment, cognition, and educational achievement. Results showed that children born very preterm were at increased risk of experiencing parental/caregiver changes, with this risk being greatest for those born extremely preterm. Neonatal medical complexity, family socioeconomic disadvantage, maternal psychological wellbeing, and child neurodevelopmental impairment were associated with a higher risk of parental change. Preterm birth and exposure to parental change/instability contributed additively to poorer child outcomes. Findings support the need for family-focused neonatal and postnatal care strategies for high-risk infants, to support parents as well as their infants to optimize child health and developmental outcomes.

Maternal Milk Provision in the Neonatal Intensive Care Unit and Mother-Infant Emotional Connection for Preterm Infants.

Maternal milk (MM) intake during neonatal intensive care unit (NICU) hospitalization is associated with improved neurodevelopment in preterm infants. Underlying mechanisms may include stronger mother-infant emotional connection. This paper examines associations between MM provision in the NICU with maternal connection to her infant using three factors validated in our sample: maternal sensitivity, emotional concern, and positive interaction/engagement. We studied 70 mothers of infants born <1500 g and/or <32 weeks' gestation. Associations between MM provision and mother-infant connection were modeled using median regression adjusted for clustering. Mothers who provided exclusive MM (i.e., 100% MM, no other milk) reported higher levels of maternal sensitivity by a median score of 2 units (ß = 2.00, 95% CI: 0.76, 3.24, p = 0.002) than the mixed group (i.e., MM < 100% days, other milk ≥1 days), as well as greater emotional concern (ß = 3.00, 95% CI: -0.002, 6.00, p = 0.05). Among mothers of very preterm infants, greater milk provision was associated with greater maternal sensitivity, but also with greater emotional concern about meeting the infant's needs. These findings highlight the importance of supporting MM provision and early infant care as an integrated part of lactation support. The findings may also provide insight into links between MM provision in the NICU and infant neurodevelopment.

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.

Psychiatric disorders in individuals born very preterm / very low-birth weight: An individual participant data (IPD) meta-analysis.

BACKGROUND: Data on psychiatric disorders in survivors born very preterm (VP; <32 weeks) or very low birthweight (VLBW; <1500 g) are sparse. We compared rates of psychiatric diagnoses between VP/VLBW and term-born, normal birthweight (term/NBW) control participants. METHODS: This individual participant data (IPD) meta-analysis pooled data from eligible groups in the Adults born Preterm International Collaboration (APIC). Inclusion criteria included: 1) VP/VLBW group (birth weight <1500 g and/or gestational age <32 weeks), 2) normal birth weight/term-born control group (birth weight >2499 g and/or gestational age ≥37 weeks), and 3) structured measure of psychiatric diagnoses using DSM or ICD criteria. Diagnoses of interest were Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Anxiety Disorder, Mood Disorder, Disruptive Behaviour Disorder (DBD), Eating Disorder, and Psychotic Disorder. A systematic search for eligible studies was conducted (PROSPERO Registration Number 47555). FINDINGS: Data were obtained from 10 studies (1385 VP/VLBW participants, 1780 controls), using a range of instruments and approaches to assigning diagnoses. Those born VP/VLBW had ten times higher odds of meeting criteria for ASD (odds ratio [OR] 10·6, 95% confidence interval [CI] 2·50, 44·7), five times higher odds of meeting criteria for ADHD (OR 5·42, 95% CI 3·10, 9·46), twice the odds of meeting criteria for Anxiety Disorder (OR 1·91, 95% CI 1·36, 2·69), and 1·5 times the odds of meeting criteria for Mood Disorder (OR 1·51, 95% CI 1·08, 2·12) than controls. This pattern of findings was consistent within age (<18 years vs. ≥18 years) and sex subgroups. INTERPRETATION: Our data suggests that individuals born VP/VLBW might have higher odds of meeting criteria for certain psychiatric disorders through childhood and into adulthood than term/NBW controls. Further research is needed to corroborate our results and identify factors associated with psychiatric disorders in individuals born VP/VLBW. FUNDING: Australia's National Health & Medical Research Council; CAPES (Coordenação de Aperfeiçoamento de Pessoal deNível Superior) - International Cooperation General Program; Canadian Institutes of Health Research Team Grant; National Council for Scientific and Technological Development (CNPq); Academy of Finland; Sigrid Juselius Foundation; Signe and Ane Gyllenberg Foundation; European Union's Horizon 2020 research and innovation programme: Project RECAP-Preterm; European Commission Dynamics of Inequality Across the Life-course: structures and processes (DIAL); Neurologic Foundation of New Zealand; MRC programme grant; Health Research Council of New Zealand; National Institutes of Health, USA; The Research Council of Norway; Joint Research Committee between St. Olavs Hospital and Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU); Liaison Committee between Central Norway Regional Health Authority and NTNU.

Association of Very Preterm Birth or Very Low Birth Weight With Intelligence in Adulthood: An Individual Participant Data Meta-analysis.

Importance: Birth before 32 weeks' gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW). Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants. Data Sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]). Study Selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults. Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects. Main Outcomes and Measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group. Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood. Conclusions and Relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Preschool Language Development of Children Born to Women with an Opioid Use Disorder.

Increasing evidence suggests that prenatal exposure to opioids may affect brain development, but limited data exist on the effects of opioid-exposure on preschool language development. Our study aimed to characterize the nature and prevalence of language problems in children prenatally exposed to opioids, and the factors that support or hinder language acquisition. A sample of 100 children born to pregnant women in methadone maintenance treatment and 110 randomly identified non-exposed children were studied from birth to age 4.5 years. At 4.5 years, 89 opioid-exposed and 103 non-exposed children completed the preschool version of the Clinical Evaluation of Language Fundamentals (CELF-P) as part of a comprehensive neurodevelopmental assessment. Children prenatally exposed to opioids had poorer receptive and expressive language outcomes at age 4.5 years compared to non-opioid exposed children. After adjustment for child sex, maternal education, other pregnancy substance use, maternal pregnancy nutrition and prenatal depression, opioid exposure remained a significant independent predictor of children's total CELF-P language score. Examination of a range of potential intervening factors showed that a composite measure of the quality of parenting and home environment at age 18 months and early childhood education participation at 4.5 years were important positive mediators.

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.

Parental use of physical punishment in a birth cohort.

AIM: To document the prevalence of child physical punishment by parents and associated predictors in the Christchurch Health and Development Study (CHDS) birth cohort over a 15-year period. METHOD: A cohort of 1,265 CHDS individuals were followed from birth (1977) to age 40 years. At ages 25 (n=155), 30 (n=337), 35 (n=585) and 40 years (n=636), the cohort members with dependent children (<16 years of age) were interviewed about their use of child physical punishment in the past 12 months using the Parent-Child Conflict Tactics Scale. Parent, child and family predictors were also examined. RESULTS: The most common forms of physical punishment were smacking on bottom and slapping on hand, arm or leg. Rates of all forms of physical punishment declined with age, ranging from 77% reporting any physical punishment at age 25 to 42% at age 40. In multivariable models, significant predictors included parental age, numbers/ages of children in the household, childhood family socioeconomic status, parental history of adolescent mental health problems and concurrent intimate partner violence. CONCLUSION: Use of physical punishment remains a relatively common form of child discipline despite the 2007 anti-smacking legislation and reduced public tolerance for physical violence towards children. Implications for prevention/intervention are discussed.

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.

Emotional and Behavioral Trajectories of 2 to 9 Years Old Children Born to Opioid-Dependent Mothers.

Maternal opioid use in pregnancy has increased dramatically. Knowledge about children's longer-term emotional and behavioral development after prenatal opioid exposure is scarce. A regional sample of 89 opioid-exposed and 104 non-exposed comparison children were studied prospectively at ages 2, 4.5, and 9 years using the Strengths and Difficulties Questionnaire (SDQ) completed by primary caregivers. Across all childhood assessments, opioid-exposed children obtained significantly higher total difficulties scores than non-exposed comparison children. Growth curve modeling revealed that, relative to their same age peers, opioid-exposed children's emotional and behavioral difficulties significantly worsened over time. Moreover, fixed effects estimates showed that total difficulties trajectories were poorer for children subject to higher prenatal risk (Est = 1.78, 95% CI = [0.46, 3.09]) who were born to mothers with high levels of social adversity (1.11 [0.51, 1.71]), and were then raised in families characterized by high levels of psychosocial risk (1.94 [0.90, 2.98]) and unstable caregiving (1.91 [0.33, 3.48]). A complex set of pre- and postnatal processes contribute to opioid-exposed children's emotional and behavioral development. Efforts to mitigate the long-term consequences of opioid use in pregnancy need to consider both children's and their caregivers' biopsychosocial risks.

Recruitment and retention of participants in longitudinal studies after a natural disaster.

Climate change and population growth will increase vulnerability to natural and human-made disasters or pandemics. Longitudinal research studies may be adversely impacted by a lack of access to study resources, inability to travel around the urban environment, reluctance of sample members to attend appointments, sample members moving residence and potentially also the destruction of research facilities. One of the key advantages of longitudinal research is the ability to assess associations between exposures and outcomes by limiting the influence of sample selection bias. However, ensuring the validity and reliability of findings in longitudinal research requires the recruitment and retention of respondents who are willing and able to be repeatedly assessed over an extended period of time. This study examined recruitment and retention strategies of 11 longitudinal cohort studies operating during the Christchurch, New Zealand earthquake sequence which began in September 2010, including staff perceptions of the major impediments to study operations during/after the earthquakes and respondents' barriers to participation. Successful strategies to assist recruitment and retention after a natural disaster are discussed. With the current COVID-19 pandemic, longitudinal studies are potentially encountering some of the issues highlighted in this paper including: closure of facilities, restricted movement of research staff and sample members, and reluctance of sample members to attend appointments. It is possible that suggestions in this paper may be implemented so that longitudinal studies can protect the operation of their research programmes.

Neurobehavior of newborn infants exposed prenatally to methadone and identification of a neurobehavioral profile linked to poorer neurodevelopmental outcomes at age 24 months.

The abuse of prescription opioids and heroin by women of childbearing age over the past decade has resulted in a five-fold increase in the number of infants born opioid-dependent. Daily opioid substitution treatment with methadone is associated with less maternal illicit opioid use and improved antenatal care. However, research on the neurobehavioral effects of daily prenatal exposure to methadone on the infant is limited. Using the NICU Network Neurobehavioral Scale (NNNS), we compared the neurobehavior at birth of 86 infants born to opioid-dependent mothers receiving methadone treatment (MMT) with 103 infants unexposed to methadone. Generalized linear models, adjusted for covariates, showed methadone exposed infants had significantly poorer attention, regulation, and quality of movement. They were also significantly more excitable, more easily aroused, exhibited more non-optimal reflexes, hypertonicity, and total signs of stress abstinence. Maternal MMT was also associated with more indices of neonatal abstinence, including: CNS, visual, genitourinary (GI), and state. Latent profile analysis of the NNNS summary scores revealed four distinct neurobehavioral profiles with infants characterized by the most disturbed neurobehavior at birth having the poorest clinical outcomes at birth, and poorer cognitive and motor development at 24 months of age.

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.

Predicting School-Aged Cognitive Impairment in Children Born Very Preterm.

BACKGROUND AND OBJECTIVES: Children born very preterm (VPT) are at high risk of cognitive impairment that impacts their educational and social opportunities. This study examined the predictive accuracy of assessments at 2, 4, 6, and 9 years in identifying preterm children with cognitive impairment by 12 years. METHODS: We prospectively studied a regional cohort of 103 children born VPT (≤32 weeks' gestation) and 109 children born term from birth to corrected age 12 years. Cognitive functioning was assessed by using age-appropriate, standardized measures: Bayley Scales of Infant Development, Second Edition (age 2); Wechsler Preschool and Primary Scale of Intelligence (ages 4 and 6); and Wechsler Intelligence Scale for Children, Fourth Edition (ages 9 and 12). RESULTS: By 12 years, children born VPT were more likely to have severe (odds ratio 3.9; 95% confidence interval 1.1-13.5) or any (odds ratio 3.2; 95% confidence interval 1.8-5.6) cognitive impairment compared with children born term. Adopting a severe cognitive impairment criterion at age 2 under-identified 44% of children born VPT with later severe impairment, whereas a more inclusive earlier criterion identified all severely affected children at 12 years. Prediction improved with age, with any delay at age 6 having the highest sensitivity (85%) and positive predictive value (66%) relative to earlier age assessments. Inclusion of family-social circumstances further improved diagnostic accuracy. CONCLUSIONS: Cognitive risk prediction improves with age, with assessments at 6 years offering optimal diagnostic accuracy. Intervention for children with early mild delay may be beneficial, especially for those raised in socially disadvantaged family contexts.