Prenatal Predictors of Child and Adolescent Mental Health

Background: The foetal period is characterised by rapid growth, epigenetic fine-tuning, and adaptation to the foetal-maternal environment. Prenatal factors such as low birth weight have been acknowledged as correlates of subsequent mental illness for many decades. However, much of the literature has focused on group differences (e.g., “Normal” Vs “Low” birth weight) in the risk for subsequent mental disorder, and it is unclear whether prenatal variables such as birth weight can be used for individual-level prediction. In this thesis, we modelled the dose-response association between birth weight and a range of mental health outcomes in large samples of children. We explored a range of prenatal variables— birth weight, gestational age at birth, prenatal testosterone levels, obstetric complications, and maternal substance-use during pregnancy— as risk factors for subsequent mental health problems, with particular focus on age and sex as potential moderators. Methods: Secondary analysis was performed on existing cohort studies: (1) the Adolescent Brain Cognitive Development (ABCD) study based in the United States of America, (2) the Growing Up in Ireland (GUI) study, for which two cohorts were recruited born around 1998 and 2008 respectively, and (3) the Cambridge Child Development Project, based in the United Kingdom. The ABCD and GUI are large nationally representative studies of US and Irish children, respectively. Our statistical methods mostly consisted of general and generalised linear models, including random effects and interactions were necessary to model clustering and interdependencies within the data. Results: Birth weight was most strongly linked with attention problems around age 9. This dose-response association was significant after controlling for gestational age at birth, suggesting that variation in foetal growth drove the association (Chapters 2-3). Foetal growth variation had long-lasting associations with mental health from ages 9 to 17. Associations with ADHD-type issues were stable and pervasive across this period, but associations between foetal growth and emotional problems only became apparent in the later adolescent years (Chapter 3). Across two independent cohorts, we showed that the association between foetal growth restriction and ADHD-type issues could be statistically decomposed into that explained by familial background factors (income, education, demographics; 26-30%) and potentially modifiable prenatal factors (pregnancy complications, maternal substance-use; 13-26%; Chapter 4). Eight percent of the variance in age 9 ADHD symptoms could be explained using pre/perinatal factors alone (R2 95% CI = 5.6-11.5%), many of which were modifiable (Chapter 5). Throughout, sex differences were identified regarding the strength of association between prenatal factors and child mental health. Chapter 6 found that prenatal testosterone was not correlated with autistic traits in adolescence, and therefore could not alone explain the sex difference in this construct. Conclusions: The association between birth weight and subsequent mental health issues in childhood is small but significant and highly replicable across cohorts. The strength and specificity of this association to certain aspects of mental health depend in part on age and sex of the child. Males may be a particularly vulnerable group when it comes to restricted foetal growth and certain obstetric complications. Our ability to predict mental health outcomes from prenatal data is modest, however interactions between prenatal factors and existing familial/social vulnerabilities may improve predictive capacity. Birth weight is a widely available and generalisable predictor of childhood mental health issues. Conversely, the specific prenatal factors underlying this association (e.g. maternal smoking, nutrition level, infection) may be context-specific, and therefore should be identified and targeted in a context-specific manner.</p

Birth weight and childhood psychopathology in the ABCD cohort: association is strongest for attention problems and is moderated by sex

Many studies have shown low birth weight is associated with psychopathology later in life, particularly attention-deficit/hyperactivity disorder (ADHD). The association is well-replicated, independent from a variety of potential familial confounds, and follows a dose–response curve (decreasing birth weight linked with increasing odds of disorder). However, the specificity of the association to attention problems is called into question by the extent of comorbidity in ADHD, and recent findings that the association is stronger for autism than ADHD. We test the relative dose–response strength of birth weight on multiple aspects of behavior to explore specificity of the effect to attention problems. We also test recent suggestions that the association between birth weight and attention problems is driven by males. Our sample consisted of 9,076 children aged 9–10 from the United States (Adolescent Brain Cognitive Development study). Outcomes included 9 problem-scales and the total problems scale from the Child Behavior Checklist (CBCL). Attention problems were the most strongly associated with birth weight after controlling for gestational age, potential familial confounds, and multiple testing, supporting the outcome-specificity of this association. Contrary to recent registry-based findings, an association between birth weight and an autism scale was not observed. Sex moderated the effect of birth weight on total problems, attention problems and aggressive behavior such that these inverse associations were strongly driven by males. Our findings have strong implications for sex-specific prediction and etiological models of childhood psychopathology.</p

Mental health of Irish adolescents following the COVID-19 pandemic: results from a population-based cross-sectional survey

Objectives: This study provides data on the prevalence of mental health problems among adolescents in Ireland in 2021, toward the end of the COVID-19 pandemic. The importance of having recent, large-scale, mental health data for adolescents has been heightened by COVID-19, the increased demand for child and adolescent mental health services, and the rapidly changing adolescent environment. Methods: As part of the Planet Youth study, a cross-sectional survey of adolescents (N = 4,404), mostly aged 15-16, was conducted between September and December 2021. Participants were recruited from 40 schools and non-traditional educational centres across 3 regions in Ireland, one predominantly urban (North Dublin) and two predominantly rural (Cavan, Monaghan). A range of mental health outcomes were self-reported: a single-item question on mental health; the Strengths & Difficulties Questionnaire (SDQ); depressive and anxiety symptoms from the Symptom Check List 90; the Adolescent Psychotic-like Symptom Screener; and lifetime self-harm, suicidal ideation, and attempt. Results: Over a quarter of adolescents described their mental health as 'bad' or 'very bad' (29%), and had SDQ total problem scores over 20 (26%). Over a third (39%) reported self-harming, 42% reported suicidal ideation, and 11% reported attempting suicide, in their lifetime. Gender-diverse youth (non-binary, trans, and undisclosed) had higher rates of poor mental health outcomes compared to cis-gendered youth (male/female), and females had higher rates of most mental health outcomes compared to males. Conclusions: Many of these estimates suggest a deterioration from previous epidemiological studies. While our findings do not definitively prove youth mental health has worsened over time, these findings are highly concerning. We propose a close monitoring of mental health in future surveys of this population and encourage initiatives to improve the capacity and quality of youth mental health services.</p

Predicting childhood ADHD-linked symptoms from prenatal and perinatal data in the ABCD cohort

This study investigates the capacity of pre/perinatal factors to predict attention-deficit/hyperactivity disorder (ADHD) symptoms in childhood. It also explores whether predictive accuracy of a pre/perinatal model varies for different groups in the population. We used the ABCD (Adolescent Brain Cognitive Development) cohort from the United States (N = 9975). Pre/perinatal information and the Child Behavior Checklist were reported by the parent when the child was aged 9-10. Forty variables which are generally known by birth were input as potential predictors including maternal substance-use, obstetric complications and child demographics. Elastic net regression with 5-fold validation was performed, and subsequently stratified by sex, race/ethnicity, household income and parental psychopathology. Seventeen pre/perinatal variables were identified as robust predictors of ADHD symptoms in this cohort. The model explained just 8.13% of the variance in ADHD symptoms on average (95% CI = 5.6%-11.5%). Predictive accuracy of the model varied significantly by subgroup, particularly across income groups, and several pre/perinatal factors appeared to be sex-specific. Results suggest we may be able to predict childhood ADHD symptoms with modest accuracy from birth. This study needs to be replicated using prospectively measured pre/perinatal data. </p

The persistent effects of foetal growth on child and adolescent mental health: longitudinal evidence from a large population-based cohort

Low birth weight for one's gestational age is associated with higher rates of child psychopathology, however, most studies assess psychopathology cross-sectionally. The effect of such foetal growth restriction appears to be strongest for attention problems in childhood, although adult studies have found associations with a range of outcomes, from depression to psychosis. We explore how associations between foetal growth and psychopathology change across age, and whether they vary by sex. We used a large nationally representative cohort of children from Ireland (N ~ 8000). Parents completed the Strengths and Difficulties Questionnaire (SDQ) at 3 time points (age 9, 13 and 17). Outcomes included a total problems scale and subscales measuring attention/hyperactivity, peer, conduct and emotional problems. Foetal growth had significant associations with all problem scales, even after controlling for sex, socioeconomic factors and parental mental health. The magnitude of these effects was small but relatively stable across ages 9-17. In males, foetal growth had the strongest associations with attention/hyperactivity and peer problems, whereas females showed more widespread associations with all four subscales. There was a trend for the association between foetal growth and emotional problems to increase with advancing age, approaching the borderline-abnormal threshold by age 17. Reduced foetal growth predicted persistently higher scores on all measured aspects of child and adolescent psychopathology. Associations with child attention/hyperactivity may generalize to a wider array of adult psychopathologies via adolescent-onset emotional problems. Future studies should explore potential age-dependent effects of foetal growth into the early 20s. </p

Explaining the association between fetal growth and childhood ADHD symptoms: cross-cohort replication

The association between restricted fetal growth and symptoms of attention deficit/hyperactivity disorder (ADHD) in childhood is well-replicated and robust. However, fetal growth is determined by many prenatal factors and associations with mental health may be confounded by familial and social context. In this study, we sought to quantify the relative contributions of prenatal factors and familial confounds to the association between fetal growth and ADHD symptoms. Two independent cohorts were analyzed, the Adolescent Brain Cognitive Development study (ABCD; United States) and the Growing Up in Ireland (GUI) study. ADHD symptoms were measured by the Child Behavior Checklist (ABCD) and the Strengths & Difficulties questionnaire (GUI) at age 9-10. Using sequential regression models, we assessed the change-in-association between fetal growth and ADHD symptoms after controlling for sex, familial factors (socioeconomic/demographic factors & family psychiatric history) and prenatal factors (pregnancy complications & maternal substance-use during pregnancy). Converging findings from cohorts suggested that over a quarter of the association between fetal growth and ADHD symptoms is attributable to familial confounds. The degree to which the association was explained by prenatal factors differed by cohort-pregnancy complications explained a larger proportion of the effect in ABCD (7.9%) than GUI (2.7%), and maternal substance-use explained a larger proportion of the effect in GUI (22.7%) compared to ABCD (4.8%). Different explanations of the fetal growth-ADHD association across cohorts suggests cohort-specific, and potentially nationally-specific, risk factors for fetal growth and related neurodevelopmental outcomes. The evidence suggests early prevention of ADHD in Ireland should focus on minimizing maternal smoking during pregnancy. In the US, prevention and treatment of pregnancy complications are highlighted as viable targets for intervention. </p

Childhood and adolescent psychotic experiences and risk of mental disorder: a systematic review and meta-analysis.

BACKGROUND: Psychotic experiences (PEs) are common in childhood and adolescence and their association with mental disorders is well-established. We aim to conduct a quantitative synthesis the literature on the relationship between childhood and adolescent PEs and (i) any mental disorder; and (ii) specific categories of mental disorder, while stratifying by study design.METHOD: Three electronic databases (PUBMED, PsycINFO and EMBASE) were searched from inception to August 2017 for all the published literature on childhood and adolescent PEs and mental disorder (outcome) in non-help-seeking community samples. Study quality was assessed using a recognised quality assessment tool for observational studies. Two authors conducted independent data extraction. Pooled odds ratios were calculated for mental disorders using random-effects models. Additional analyses were conducted investigating different categories of mental disorder while stratifying by study design.RESULTS: Fourteen studies from 13 community samples (n = 29 517) were identified with 9.8% of participants reporting PEs. PEs were associated with a three-fold increased risk of any mental disorder [odds ratio (OR) 3.08, confidence interval (CI) 2.26-4.21, k = 12]. PEs were associated with four-fold increase risk of psychotic disorder (OR 3.96, CI 2.03-7.73, population-attributable-fraction: 23.2%, k = 5). In addition, PEs were associated with an increased risk of affective disorders, anxiety disorders, behavioural disorders and substance-use disorders. Few longitudinal studies have investigated childhood and adolescent PEs and subsequent non-psychotic disorders which limited a meaningful synthesis and interpretation of these results.CONCLUSION: This meta-analysis confirms that PEs are prevalent in childhood and adolescent community samples and are associated with a variety of mental disorders beyond psychotic disorders. Further longitudinal research is necessary to fully determine the longitudinal relationship between PEs and non-psychotic disorders.</div

Fine motor skill and processing speed deficits in young people with psychotic experiences: A longitudinal study.

OBJECTIVE: To identify neuropsychological and motor changes from adolescence to early adulthood in young people with psychotic experiences (PE). METHODS: A community-based sample of 56 young people attended the study over a 9 year follow-up period. Participants were assessed over 3 time-points at T1, T2 and T3 aged x¯ = 11.69, x¯ = 15.80 and x¯ = 18.80 years respectively. PE were assessed using the Kiddie Schedule for Affective and Depressive Symptoms (K-SADS). Neuropsychological assessments, including subtests of the MATRICS battery, and motor assessments were examined at T2 and T3. Two groups were compared: those who ever reported PE during their adolescence or early adulthood (n = 21) and a healthy control group (n = 35). Further group analysis was conducted within the PE group subdividing into those with transient PE (n = 10) and those with persistent PE (n = 11). RESULTS: At T3, a significant group difference was found between the PE and control groups in the fine motor skill task, the Pegboard task (F = 4.8, p = .03) and the processing speed task, the Digit-Symbol Coding task (F = 5.36, p = .03). Furthermore, a significant group difference was found between the transient PE and control groups on the Digit-Symbol Coding task (F = 5.61, p = .02), while a significant group difference was found between the persistent PE and control groups on the Pegboard task (F = 7.84, p = .01). CONCLUSION: This study shows that fine motor skill and processing speed deficits persist in young people who report PE, even in those with transient PE. The current research advances the knowledge about the trajectory and precursors of sub-clinical symptoms of psychosis in young people.</p

Longitudinal Gray Matter Development Associated With Psychotic Experiences in Young People

Background: Grey matter abnormalities are observed across the psychosis spectrum. The trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) may provide insight into the neural mechanisms underlying psychotic symptoms. The risk of psychosis and additional psychopathology is even higher amongst these individuals who also report childhood adversity/DSM5 diagnoses. Thus, the aims of this longitudinal study are to investigate PE related volumetric changes in young people, noting any effects of childhood adversity/DSM5 diagnosis. Methods: 211 young people aged 11-13 participated in the initial Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 76 participants with at least one scan were included in the final sample; 34 who met criteria for PE at least once across all the timepoints (PE group), and 42 controls. Data from 20 bilateral regions of interest were extracted for Linear Mixed Effects analyses. Results: Right hippocampal volume increased over time in the control group, with no increase in the PE group (p = 0.00352). DSM5 diagnosis and childhood adversity were not significantly associated with right hippocampal volume. There was no significant effect of group or interaction in any other region. Conclusions: These findings further implicate right hippocampal volumetric abnormalities in the pathophysiology underlying psychotic experiences. Furthermore, as suggested by previous studies in those at clinical high risk for psychosis and those with first episode psychosis, it is possible that these deficits may be a marker for later clinical outcomes.</p

Multiple Network Dysconnectivity in Adolescents with Psychotic Experiences: a longitudinal population-based study

Background: Functional dysconnectivity amongst neural networks is well established in psychosis, and has been implicated in the psychopathology associated with the disorder. However, little is known about functional connectivity (FC) in individuals, particularly adolescents, who experience sub-threshold psychotic experiences (PE), and their trajectory over time. Thus, the aim of this study was to investigate large and small-scale network FC in adolescents with PE.Methods: A population-based case-control study of 24 adolescents (mean age 13.58) who met criteria for PE were drawn from a sample of 211 young people recruited for a neuroimaging study, followed up 2 years later (n=18, mean age = 15.78), and compared to matched controls drawn from the same sample. Functional seed networks included the default mode (DMN), salience (SN), central executive (CEN), motor (MN), and auditory networks (AN). Whole-brain FC analyses were performed using the CONN functional connectivity toolbox.Results: At both timepoints, the PE group generally displayed significant hypoconnectivity, with specific instances of hyperconnectivity, compared to controls. At baseline, FC in the PE group was decreased between regions in the MN and DMN, and the AN and visual regions. At follow up, FC in the PE group was decreased between regions in the SN and DMN, the AN and visual regions, and also within the MN.Conclusions: Significant hypoconnectivity across multiple networks reflects findings in established psychosis, supporting a prominent role for the default mode network in the dysfunctional information processing and integration thought to underlie psychotic experiences.</div