The impact of maternal inflammation and maternal stress in the regulation of neurodevelopment and physiological function

The mechanisms governing fetal development follow a tightly regulated pattern of progression such that interference at any one particular stage is likely to have consequences for all other stages of development in the physiological system that has been affected thereafter. These disturbances can take the form of many different events but two of the most common and widely implicated in causing detrimental effects to the developing fetus are maternal immune activation (MIA) and maternal stress. MIA has been shown to cause an increase in circulating proinflammatory cytokines in both the maternal and fetal circulation. This increase in proinflammatory mediators in the fetus is thought to occur by fetal production rather than through exchange between the maternal-fetal interface. In the case of maternal stress it is increased levels of stress related hormones such as cortisol/corticosterone which is thought to elicit the detrimental effects on fetal development. In the case of both maternal infection and stress the timing and nature of the insult generally dictates the severity and type of effects seen in affected offspring. We investigated the effect of a proinflammatory environment on neural precursor cells of which exposure resulted in a significant decrease in the normal rate of proliferation of NPCs in culture but did not have any effect on cell survival. These effects were seen to be age dependent. Using a restraint stress model we investigated the effects of prenatal stress on the development of a number of different physiological systems in the same cohort of animals. PNS animals exhibited a number of aberrant changes in cardiovascular function with altered responses to stress and hypertension, modifications in respiratory responses to hypercapnic and hypoxic challenges and discrepancies in gastrointestinal innervation. Taken together these findings suggest that both maternal infection and maternal stress are detrimental to the normal development of the fetus.

Iron status in early life and associations with developmental outcomes

Infants and young children are at particular risk of iron deficiency and its associated consequences for growth and development. The main objectives of this thesis were to quantify iron intakes, status and determinants of status in two year olds; explore determinants of neonatal iron stores; investigate associations between iron status at birth and two years with neurodevelopmental outcomes at two years and explore the influence of growth on iron status in early childhood, using data from the Cork BASELINE (Babies after SCOPE: Evaluating Longitudinal Impact using Neurological and Nutritional Endpoints) Birth Cohort Study (n=2137). Participants were followed prospectively with interviewer-led questionnaires and clinical assessments at day 2 and at 2, 6, 12 and 24 months. At two years, there was a low prevalence of iron deficiency and iron deficiency anaemia in this cohort, representing the largest study of iron status in toddlers in Europe, to date. The increased consumption of iron-fortified products and compliance with recommendations to limit unmodified cows’ milk intakes in toddlers has contributed to the observed improvements in status. Low serum ferritin concentrations at birth, which reflect neonatal iron stores, were shown to track through to two years of age; delivery by Caesarean section, being born small-for-gestational age and maternal obesity and smoking in pregnancy were all associated with significantly lower neonatal iron stores. Despite a low prevalence of iron deficiency in this cohort, both a mean corpuscular volume <74fl and ferritin concentrations <20μg/l were associated with lower neurodevelopmental outcomes at two years. An inverse association between growth in the second year of life and iron status at two years was also observed. This thesis has presented data from one of the largest, extensively-characterised cohorts of young children, to date, to explore iron and its associations with growth and development.

Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.

Surveillance during pregnancy: methods and response rates from a hospital based pilot study of the Pregnancy Risk Assessment Monitoring System in Ireland

Background: Many European countries including Ireland lack high quality, on-going, population based estimates of maternal behaviours and experiences during pregnancy. PRAMS is a CDC surveillance program which was established in the United States in 1987 to generate high quality, population based data to reduce infant mortality rates and improve maternal and infant health. PRAMS is the only on-going population based surveillance system of maternal behaviours and experiences that occur before, during and after pregnancy worldwide.Methods: The objective of this study was to adapt, test and evaluate a modified CDC PRAMS methodology in Ireland. The birth certificate file which is the standard approach to sampling for PRAMS in the United States was not available for the PRAMS Ireland study. Consequently, delivery record books for the period between 3 and 5 months before the study start date at a large urban obstetric hospital [8,900 births per year] were used to randomly sample 124 women. Name, address, maternal age, infant sex, gestational age at delivery, delivery method, APGAR score and birth weight were manually extracted from records. Stillbirths and early neonatal deaths were excluded using APGAR scores and hospital records. Women were sent a letter of invitation to participate including option to opt out, followed by a modified PRAMS survey, a reminder letter and a final survey.Results: The response rate for the pilot was 67%. Two per cent of women refused the survey, 7% opted out of the study and 24% did not respond. Survey items were at least 88% complete for all 82 respondents. Prevalence estimates of socially undesirable behaviours such as alcohol consumption during pregnancy were high [>50%] and comparable with international estimates.Conclusion: PRAMS is a feasible and valid method of collecting information on maternal experiences and behaviours during pregnancy in Ireland. PRAMS may offer a potential solution to data deficits in maternal health behaviour indicators in Ireland with further work. This study is important to researchers in Europe and elsewhere who may be interested in new ways of tailoring an established CDC methodology to their unique settings to resolve data deficits in maternal health.

Monitoring behaviours and experiences before, during and after pregnancy in Ireland

Background: On-going surveillance of behaviours during pregnancy is an important but overlooked population health activity that is particularly lacking in Ireland. Few, if any, nationally representative estimates of most maternal behaviours and experiences are available. While on-going surveillance of maternal behaviours has not been a priority thus far in European countries including Ireland, on-going surveillance was identified as a key priority in the United States (US) during the 1980’s when the Pregnancy Risk Assessment Monitoring System (PRAMS), was established. Today, PRAMS is the only surveillance programme of maternal behaviours and experiences world-wide. Although on-going prevalence estimates are required in Ireland, studies which examine the offspring health effects of maternal behaviours are also required, since various questions regarding maternal exposures and their offspring health effects remain unanswered. Gestational alcohol consumption is one such important maternal exposure which is common in pregnancy, though its offspring health effects are unclear, particularly at lower or moderate levels. Thus, guidelines internationally have not reached consensus on safe alcohol recommendations for pregnant women. The aims of this thesis are to implement the PRAMS in Ireland (PRAMS Ireland), to describe the prevalence of health behaviours around the time of pregnancy in Ireland and to examine the effect of health behaviours on pregnancy and child outcomes (specifically the relationship between alcohol use during pregnancy and infant and child growth). Structure: In Chapter 1, a brief background and rationale for the work, as well as the thesis aims and objective is provided. A detailed description of the design and implementation of PRAMS Ireland is described in Chapter 2. Chapter 3 and Chapter 4 describe the methodological results of the implementation of the PRAMS Ireland pilot study and PRAMS Ireland main study. In Chapter 5, a comparison of alcohol prevalence in two Irish studies (PRAMS Ireland and Growing up in Ireland (GUI)) and one multi-centre prospective cohort study, Screening for Pregnancy Endpoints (SCOPE) Study is detailed. Chapter 6 describes findings on adherence to National Clinical Guidelines on health behaviours and nutrition around the time of pregnancy in PRAMS Ireland. Findings on exposure to alcohol use in pregnancy and infant growth outcomes are described in Chapter 7 and Chapter 8. The results of analysis conducted to examine the impact of gestational alcohol use on offspring growth trajectories to age ten are described in Chapter 9. Finally, a discussion of the findings, strengths and limitations of the thesis, direction for future research, policy, practice and public health implications are discussed in Chapter 10.Results: Implementation of PRAMS: PRAMS may be an effective system for the surveillance of health behaviours around the time of pregnancy in the Irish context. PRAMS Ireland had high response rates (67% and 61% response rates in the pilot and main study respectively), high item completion rates and valid prevalence estimates for many health behaviours. Examining prevalence of health behaviours: We found high levels of alcohol consumption before and during pregnancy, poor adherence to healthy diets and high levels of smoking before and during pregnancy among women in Ireland. Socially disadvantaged women had higher rates of deleterious health behaviours before pregnancy, although women with the most deleterious behaviour profiles before pregnancy appeared to experience the greatest gain in protective health behaviours during pregnancy. The impact of alcohol use on infant and offspring growth: We found that low and moderate levels of alcohol use did not impact on birth outcomes or offspring growth whereas heavy alcohol consumption resulted in reduced birth length and birth weight; however, this finding was not consistently observed across all studies. Selection, reporting and confounding biases which are common in observational research could be masking harmful effects. Conclusion: PRAMS is a valid and feasible method of surveillance of health behaviours around the time of pregnancy in Ireland. A surveillance program of maternal behaviours and experiences is immediately warranted due to high levels of deleterious health behaviours around the time of pregnancy in Ireland. Although our results do not indicate any evidence of harm, given the quality of evidence available, abstinence and advice of abstinence from alcohol may be the most prudent choice for patients and healthcare professionals respectively. Further studies of the effects of gestational alcohol use are required; particularly those which can reduce selection bias, reporting bias and confounding.

Measured parental weight status and familial socio-economic status correlates with childhood overweight and obesity at age 9

Background: Parental obesity is a predominant risk factor for childhood obesity. Family factors including socio-economic status (SES) play a role in determining parent weight. It is essential to unpick how shared family factors impact on child weight. This study aims to investigate the association between measured parent weight status, familial socio-economic factors and the risk of childhood obesity at age 9. Methodology/Principal Findings: Cross sectional analysis of the first wave (2008) of the Growing Up in Ireland (GUI) study. GUI is a nationally representative study of 9-year-old children (N = 8,568). Schools were selected from the national total (response rate 82%) and age eligible children (response rate 57%) were invited to participate. Children and their parents had height and weight measurements taken using standard methods. Data were reweighted to account for the sampling design. Childhood overweight and obesity prevalence were calculated using International Obesity Taskforce definitions. Multinomial logistic regression examined the association between parent weight status, indicators of SES and child weight. Overall, 25% of children were either overweight (19.3%) or obese (6.6%). Parental obesity was a significant predictor of child obesity. Of children with normal weight parents, 14.4% were overweight or obese whereas 46.2% of children with obese parents were overweight or obese. Maternal education and household class were more consistently associated with a child being in a higher body mass index category than household income. Adjusted regression indicated that female gender, one parent family type, lower maternal education, lower household class and a heavier parent weight status significantly increased the odds of childhood obesity. Conclusions/Significance: Parental weight appears to be the most influential factor driving the childhood obesity epidemic in Ireland and is an independent predictor of child obesity across SES groups. Due to the high prevalence of obesity in parents and children, population based interventions are required.

Learning to 'understand backwards' in time: children's temporal cognition and the primary history curriculum

This study examines children’s temporal ways of knowing and it highlights the centrality of temporal cognition in the development of children’s historical understanding. It explores how young children conceptualise time and it examines the provision for temporal cognition at the levels of the intended, enacted and received history curriculum in the Irish primary school context. Positioning temporality as a prerequisite second-order concept, the study recognises the essential role of both first-order and additional second-order concepts in historical understanding. While the former can be defined as the basic, substantive content to be taught, the latter refers to a number of additional key concepts that are deemed fundamental to children's capacity to make meaningful sense of history. The study argues for due recognition to be given to temporality, in the belief that both sets of knowledge, the content and skills, are required to develop historical thinking (Lévesque, 2011). The study addresses a number of key research questions, using a mixed methods research design, comprising an analysis of history textbooks, a survey among final year student teachers about their teaching of history, and school-based interviews with primary school children: What opportunities are available for children to develop temporal ways of knowing? How do student teachers experience being apprenticed into the available culture for teaching history and understanding temporality at primary level? What insights do the cognitive-developmental and sociocultural perspectives on learning provide for understanding the dynamics of children’s temporal ways of knowing? The study argues that the skill of developing a deeper understanding of time is a key prerequisite in connecting with, and constructing, understandings and frameworks of the past. The study advances a view of temporality as complex, multi-faceted and developmental. The findings have a potential contribution to make in influencing policy and pedagogy in establishing an elaborated and well-defined curriculum framework for developing temporal cognition at both national and international levels.

Using parent report to assess early lexical production in children exposed to more than one language

Limited expressive vocabulary skills in young children are considered to be the first warning signs of a potential Specific Language Impairment (SLI) (Ellis & Thal, 2008). In bilingual language learning environments, the expressive vocabulary size in each of the child’s developing languages is usually smaller compared to the number of words produced by monolingual peers (e.g. De Houwer, 2009). Nonetheless, evidence shows children’s total productive lexicon size across both languages to be comparable to monolingual peers’ vocabularies (e.g. Pearson et al., 1993; Pearson & Fernandez, 1994). Since there is limited knowledge as to which level of bilingual vocabulary size should be considered as a risk factor for SLI, the effects of bilingualism and language-learning difficulties on early lexical production are often confounded. The compilation of profiles for early vocabulary production in children exposed to more than one language, and their comparison across language pairs, should enable more accurate identification of vocabulary delays that signal a risk for SLI in bilingual populations. These considerations prompted the design of a methodology for assessing early expressive vocabulary in children exposed to more than one language, which is described in the present chapter. The implementation of this methodological framework is then outlined by presenting the design of a study that measured the productive lexicons of children aged 24-36 months who were exposed to different language pairs, namely Maltese and English, Irish and English, Polish and English, French and Portuguese, Turkish and German as well as English and Hebrew. These studies were designed and coordinated in COST Action IS0804 Working Group 3 (WG3) and will be described in detail in a series of subsequent publications. Expressive vocabulary size was measured through parental report, by employing the vocabulary checklist of the MacArthur-Bates Communicative Development Inventory: Words and Sentences (CDI: WS) (Fenson et al., 1993, 2007) and its adaptations to the participants’ languages. Here we describe the novelty of the study’s methodological design, which lies in its attempt to harmonize the use of vocabulary checklist adaptations, together with parental questionnaires addressing language exposure and developmental history, across participant groups characterized by different language exposure variables. This chapter outlines the various methodological considerations that paved the way for meaningful cross-linguistic comparison of the participants’ expressive lexicon sizes. In so doing, it hopes to provide a template for and encourage further research directed at establishing a threshold for SLI risk in children exposed to more than one language.