Pregnancy and children’s development (PRECEDE): how maternal inflammation in pregnancy affects child outcomes

The main research question of this thesis is to examine how maternal inflammatory processes during pregnancy possibly affect a child’s development in domains of cognition, behaviour, and general school readiness. It starts with providing relevant background and basis of Barker’s hypothesis on the developmental origins of health and disease (DoHAD), which postulates effects on fetal and child development if the intrauterine environment is disrupted or compromised during pregnancy. It aims to narrow the gap between animal models and limited human studies through associating maternal inflammation in pregnancy with child outcomes. The predominant focus is using cohorts to examine how gestational biology processes such as infections or maternal metabolic markers are associated with child standardised developmental, cognitive, or socioemotional measures. This thesis also adopts different approaches towards how mother-child outcomes can possibly be affected by other factors, such as analysis of cord blood mediators to further understand mother-child associations during the perinatal period, or synthesis of high-quality evidence on how analgesic drug use during pregnancy affects child neurodevelopment. Overall conclusions will be drawn from quantitative models, seeking to provide careful evaluation and a translational review of previous and current empirical studies. The first empirical chapter, Chapter 2 uses the Avon Longitudinal Study of Parents and Children (ALSPAC) United Kingdom cohort (N= 7,410 mother-child pairs with condition of infections present during pregnancy) to examine associations between maternal prenatal infections occurring in specific pregnancy trimesters and a child’s cognitive outcomes at three timepoints (18 months, 4 years, 8 years) using developmental and intelligence quotient scores. Regression analyses were run, adjusting for maternal and socioeconomic covariates. Results suggest associations between infections occurring at the third pregnancy trimester with verbal IQ at 4 years old, and verbal and performance IQ at 8 years old, however the magnitude of effect appears to be small. Chapter 3 uses the Avon Longitudinal Study of Parents and Children (ALSPAC) United Kingdom cohort (N=15,133 mother-child pairs) to examine associations between maternal metabolic markers and child socio-emotional outcomes over time (4 to 16 years old; 7 timepoints). Growth curve models were fit, adjusting for maternal, child, and environmental covariates. Results showed specific maternal metabolic markers of fasting glucose, HDL, BMI, and triglycerides having differential effects on developmental trajectories of conduct and hyperactivity problems from 4 to 16 years old. Adjusted models also suggest maternal metabolic markers possibly having trimester-specific effects on child development. Chapter 4 uses the Born in Bradford (BiB) United Kingdom cohort (N=10,600 mother-child pairs) to examine associations between maternal metabolic syndrome classification and child development outcomes at age 5, using child cord blood markers as potential mediators. Maternal markers in pregnancy were classified into metabolic syndrome risk, while child cord blood markers were individually measured. Child development outcomes were taken from a national development framework that assesses domains of school readiness. Mediation models were adjusted for maternal, child, and socioeconomic covariates. Mediation results showed no significant effects when looking at individual cord blood markers, however, they suggested significant combined effects of cord blood markers mediating the association between maternal cardiometabolic health and some child outcomes. Chapter 5 consists of a protocol paper and an umbrella review to synthesise evidence on how maternal drug use during pregnancy is linked with child development outcomes. The review examined high-quality evidence on analgesic drug exposure and attention-deficit hyperactivity disorder (ADHD) risk in children. Findings showed significant associations between maternal prenatal acetaminophen (paracetamol) use and ADHD outcomes, with a potential dose-dependent relationship. This review method provides a different perspective on exploring how interventions that are applied to seek to improve a mother’s health may subsequently affect a child’s neurodevelopment. Overall, this thesis uses several different methodologies to combine current literature with empirical data analyses to examine how maternal health affects child outcomes. The discussion chapter of this thesis expands on limitations and future directions, with emphasis on translating results into implications for clinical and educational providers

Examining maternal cardiometabolic markers in pregnancy on child emotional and behaviour trajectories:Using growth curve models on a cohort study

Background Poor maternal cardiometabolic health in pregnancy is associated with negative effects on child health outcomes, but there is limited literature on child and adolescent socio-emotional outcomes. The study aims to investigate associations between maternal cardiometabolic markers during pregnancy with child and adolescence socio-emotional trajectories. Methods Growth curve models were run to examine how maternal cardiometabolic markers in pregnancy affected child socio-emotional trajectories from age 4 to 16. Models were adjusted for all pregnancy trimesters, maternal, child, and socioeconomic covariates. This study used the Avon Longitudinal Study of Parents and Children (United Kingdom) cohort. Participants consisted of mother-child pairs (n=15,133). Maternal predictors of fasting glucose, triglycerides, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and body mass index (BMI) were taken from each pregnancy trimester (T1, T2, T3). Child outcomes included emotional problems, conduct problems, and hyperactivity problems from the Strengths and Difficulties Questionnaire (SDQ). Results Fully adjusted models showed significant associations between elevated T1 fasting glucose and increased conduct problems, higher T1 BMI and increased hyperactivity problems, lowered T1 HDL and decreased hyperactivity problems, and elevated T2 triglycerides and increased hyperactivity problems. Conclusions Maternal cardiometabolic risk is associated with conduct and hyperactivity outcomes from age 4 to 16. This study suggests that maternal markers of fasting glucose, LDL, HDL, and triglycerides during pregnancy could be added as supplements for clinical measures of risk when predicting child and adolescence’s socio-emotional trajectories.peerReviewe

The association between analgesic drug use in pregnancy and neurodevelopmental disorders: protocol for an umbrella review.

BACKGROUND: Maternal prenatal health has been shown to be an important influence on children's developmental outcomes, which has led to an increased emphasis on providing more information to support clinical decisions in pregnancy. Several systematic reviews suggest that analgesic drug use during pregnancy may have neurodisruptive properties. However, no firm conclusions have yet been drawn on the associations between prenatal analgesic drug use and children's long-term development of neurodevelopmental disorders such as autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD). Therefore, an umbrella review is proposed for the purpose of examining the associations between maternal analgesic drug use during pregnancy and diagnoses of neurodevelopmental disorders. METHODS: Included systematic reviews will consist of studies examining the effect of maternal prenatal analgesic drug use, specifically ibuprofen, acetaminophen, aspirin, naproxen, diclofenac, and ketoprofen, on children's neurodevelopmental disorder status. Examined drugs were restricted to those readily accessible and frequently used by pregnant women, and with characteristics that allow them to cross the placenta and directly affect fetal development. Outcomes will be restricted to formal clinical diagnoses of ASD and/or ADHD. Two reviewers will independently identify eligible reviews from six databases (e.g., PubMed, EMBASE, PsychINFO) from inception dates of databases to the date of data extraction, and conduct manual searches of reference lists, consultation with field experts, and scan of pre-print archives. Extracted data will also include short qualitative summaries by both reviewers. As part of quality assessment, a standardized measurement tool to assess systematic reviews (AMSTAR 2) will be used. A narrative synthesis is proposed to integrate findings from different, potentially methodologically heterogeneous, studies. DISCUSSION: This umbrella review of associations between maternal prenatal use of analgesic drugs and children's neurodevelopmental disorders could allow for firmer conclusions to be drawn through the synthesis of all relevant published research. The synthesis of findings using high-quality evidence could provide more accurate healthcare information on the long-term effects of analgesic drugs on neurodevelopment, to better guide future clinical decisions during pregnancy. This review will also allow gaps and methodological differences in the literature to be identified, informing recommendations for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020179216

Daily life affective dynamics as transdiagnostic predictors of mental health symptoms:An ecological momentary assessment study

BackgroundAffective dynamics have been identified as a correlate of a broad span of mental health issues, making them key candidate transdiagnostic factors. However, there remains a lack of knowledge about which aspects of affective dynamics – especially as they manifest in the course of daily life – relate to a general risk for mental health issues versus specific symptoms. MethodsWe leverage an ecological momentary assessment (EMA) study design with four measures per day over a two-week period to explore how negative affect levels, inertia, lability, and reactivity to provocation and stress in the course of daily life relate to mental health symptoms in young adults (n= 256) in the domains of anxiety, depression, psychosis-like symptoms, behaviour problems, suicidality, and substance use. ResultsDynamic structural equation modelling (DSEM) suggested that negative affect levels in daily life were associated with depression, anxiety, indirect and proactive aggression, psychosis, anxiety, and self-injury; negative affective lability was associated with depression, physical aggression, reactive aggression, suicidal ideation, and ADHD symptoms; negative affective inertia was associated with depression, anxiety, physical aggression, and cannabis use; and emotional reactivity to provocation was related to physical aggression. LimitationsThe cross-sectional design, the limited span of mental health issues included, and the convenience nature and small size of the sample are limitations.ConclusionsFindings suggest that a subset of mental health symptoms have shared negative affective dynamics patterns. Longitudinal research is needed to rigorously examine the directionality of the effects underlying the association between affective dynamics and mental health issues

The Impact of multimorbidity burden, frailty risk scoring, and 3-directional morphological indices vs. testing for CSF responsiveness in normal pressure hydrocephalus

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes.Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer’s Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness.Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008).Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions

DTI Profiles for Rapid Description of Cohorts at the Clinical-Research Interface.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets

DTI Profiles for Rapid Description of Cohorts at the Clinical-Research Interface

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets