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Aims/ Hypothesis: Wolcott- Rallison syndrome (WRS) is a rare autosomal recessively inherited Mendelian disorder. It is characterised by a short trunk compared to arm span, multiple epiphyseal dysplasia, multiple fractures, hepatosplenomegaly and renal insufficiency in addition to insulin dependent diabetes. The onset of diabetes in WRS families is mainly below the age of 6 months and is characterised by permanent severe non-autoimmune insulin deficiency. Mutations of the gene encoding eukaryotic translational initiation factor 2 - alpha kinase 3 (EIF2AK3) were found to account for diabetes in WRS. The aim of our study was to determine whether common polymorphisms in the EIF2AK3 gene (Candidate gene association study) could be associated with type 2 diabetes. Methods: Direct sequencing was performed on all 17 exons/coding regions and intron/exon boundaries of EIF2AK3 gene in 48 diabetes and control subjects. Single Nucleotide Polymorphisms (SNPs) tagging the common haplotypes (tag SNPs) were identified and 11 SNPs were genotyped initially in 2,835 subjects with type 2 diabetes, 3,538 control subjects in the British Irish, Bangladeshi and South Indian Populations and 522 families (n= 1,722) in the British Irish and South Indian Populations. Results: We identified 19 SNPs by direct sequencing. There was no association (all p>0.05) between the SNPs and type 2 diabetes in the case–control study and in the family study. In the one marker, rs7605713, that showed a nominal significance in Warren 2 European samples, further replication studies in the Dundee samples (3,334 diabetes cases and 3,456 controls) proved to be negative thereby avoiding a false positive result. The results also showed several of the SNPs had different minor allele frequencies between the British/Irish Caucasians as compared to the South Asians. Conclusions/interpretation: Common variations in the EIF2AK3 gene were not associated with type 2 diabetes in the British Irish and the South Asian population.

Pregnancy termination for fetal abnormality (TFA) represents 2% of all terminations in England and Wales. In recent years, the number of TFAs has risen (3,099 in 2014 compared to 2,085 in 2009) due to technological developments in prenatal diagnosis and increased maternal age, which have led to a growing number of fetal abnormalities being identified, and this earlier in pregnancy. Research suggests that TFA can have negative, long-lasting psychological consequences for women. These include depression, posttraumatic stress disorder and complicated grief. However, at the inception of the research programme, no research had been conducted on women’s coping processes when dealing with TFA despite clear evidence of a relationship between coping processes and psychological adjustment in other areas of health research. Similarly, although research indicates that some individuals experience positive growth as a result of trauma, no empirical work had been undertaken on potential positive psychological outcomes following TFA. Finally, a dearth of research on health professionals’ understanding of women’s coping with TFA was also identified, despite the likely impact this understanding would have upon women’s experience of care and the way they cope with TFA. This thesis aims to address these knowledge gaps in order to further our understanding of women’s experience of TFA. Specifically, the research had three main objectives: 1) to gain an understanding of women’s coping strategies when dealing with TFA; 2) to examine the relationship between coping and psychological outcomes, as defined by perinatal grief and posttraumatic growth; and 3) to investigate health professionals’ perceptions of women’s coping to identify potential disparities between health professionals’ and women’s accounts. To answer these objectives, a mixed methodology was utilised and five studies were conducted: a systematic review of the qualitative evidence pertaining to women’s experiences of TFA; two qualitative studies: the first one exploring women’s coping strategies when dealing with TFA, and the second one investigating health professionals’ perceptions of women’s coping; and, finally, two quantitative studies: the first one examining the relationship between coping strategies and perinatal grief, and the second one assessing the relationship between coping, perinatal grief and posttraumatic growth. The empirical work relating to the women was carried out online, with participants recruited from a specialist support organisation. The empirical work concerning the health professionals was conducted face-to-face, with participants recruited from three hospitals in England. Ethical approval was obtained for all studies prior to fieldwork commencing. The research generated several important findings, which both build upon existing evidence and further our insights into women’s experience of TFA. Firstly, the research clearly indicates that women regard TFA as a traumatic event, which is akin to an existential crisis and which can have negative psychological consequences. Women view TFA as a unique form of bereavement, which can be misunderstood and stigma-bearing. The research also indicates that TFA is an individual as well as a social phenomenon with women’s experiences both shaping and reflecting the political and sociocultural environment within which TFA occurs. Secondly, the research shows that coping with TFA involves four main strategies: ‘support,’ ‘acceptance,’ ‘avoidance,’ and ‘meaning attribution’ which are relevant to both the termination procedure and its aftermath. The findings also reveal that, despite mainly using coping strategies considered to be adaptive, women’s levels of grief are high, and that, for some individuals, distress persists long after the termination. The research also provides evidence of a relationship between coping and psychological adjustment to TFA, with strong associations observed between several coping strategies and psychological adjustment. In particular, the research shows that coping strategies such as ‘acceptance’ and ‘positive reframing’ are closely associated with lower levels of grief, whilst ‘self-blame’ and ‘behavioural disengagement’ relate to higher grief levels. Thirdly, the research offers new insights into the potential for personal growth following TFA. This is particularly manifest in the qualitative investigations and, although it is less evident in the quantitative study, moderate levels of growth were observed for several growth dimensions: ‘relating to others,’ ‘personal strengths’ and ‘appreciation of others.’ The findings also indicate that a relationship exists between coping and posttraumatic growth, with ‘positive reframing’ being a significant predictor of growth. Lastly, the findings reveal that health professionals have a valid understanding of women’s short-term coping strategies when dealing with TFA, but have limited insights into their long-term coping processes. This points to a deficit in aftercare, an issue which was raised by the women in this research. Collectively, these findings have important implications in terms of theory, practice and future research in the area of TFA, which are considered in this thesis. Among the most significant ones are the need to identify women at risk of poor psychological adjustment, the need for a truly women-centred care that continues well beyond the termination, as well as the importance of ‘acceptance’ and ‘positive reframing’ as potential protective factors against distress and of ‘positive reframing’ as a potential foundation for growth. A corollary of the research is the development and implementation of a psychological intervention to support women following TFA. This proposed intervention is underpinned by the reported high levels of grief, the deficit in aftercare, and the potential for growth following TFA, and represents the next step of the research programme.

Maternal obesity has been at the forefront of pregnancy-related research in recent times. The impact of this chronic health condition has been highlighted in reports on maternal mortality (CEMACH, 2007, CEMACH, 2011), where 30% of mothers who died from pregnancy related causes were obese (CEMACH, 2011). The importance of maternal obesity and how it affects maternal adaptation to pregnancy is well documented with obese women exhibiting low grade inflammation, greater coagulability and poorer improvement in vascular function during pregnancy compared to lean women (Stewart et al., 2007a). These findings suggest that obese women display similar characteristics to the non-pregnant adult metabolic syndrome and these attributes may be important in explaining why obese pregnancies have higher rates of obstetric complications including gestational diabetes (GDM) and pre-eclampsia (PET). In non-pregnant adult obesity it has been found that central or truncal adiposity is associated with increased NEFA (non-esterified fatty acids) turnover and ectopic fat (especially liver) deposition. It has been suggested that obese pregnant women may also preferentially gain fat in central depots and this may be the mechanism by which poor vascular improvement and inflammation are initiated. The aims of this thesis were to assess subcutaneous fat accumulation and distribution throughout pregnancy in both lean and OW/OB women. Furthermore this thesis aimed to acquire a better understanding of the impact of anatomical fat deposition on metabolic and vascular function during pregnancy. A final aim was to assess vascular function and evidence of lipotoxicity during pregnancy and test whether the site of fat accumulation and distribution was associated with gestational improvement of vascular function. A longitudinal study was performed and anthropometric data was collected from 26 lean and 16 OW/OB women at three antenatal time points (15, 25 and 35 weeks’ gestation) during pregnancy. Direct measurements of energy metabolism (basal metabolic rate, substrate utilisation, physical activity and diet) were also collected to assess the impact of energy metabolism on fat accumulation and distribution. A comprehensive panel of plasma markers of carbohydrate and lipid metabolism (fasting glucose, fasting insulin, total cholesterol [TC], total triglyceride [TG], high density lipoprotein [HDL] and NEFA) and inflammatory (C-reactive protein [CRP], interleukin-6 [IL6] and tumour necrosis factor alpha [TNF]) were quantitated at each study appointment. Endothelial function was measured using laser Doppler imaging (LDI). Measurement of plasma and urinary biomarkers of endothelial function and lipotoxicity including soluble intracellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), oxidised low density lipoprotein (oxLDL), plasma superoxide and urinary isoprostanes were undertaken. Lean and OW/OB women gained similar amounts of total body weight and fat mass during pregnancy. Only in lean women was there an anatomical preference for site of fat storage and this was in the upper peripheral subcutaneous depots. In healthy OW/OB pregnancy no such anatomical preference of fat deposition was found. The study of energy metabolism found that OW/OB women had higher basal metabolic rate and higher fat oxidation than lean women, whilst lean women had higher rates of carbohydrate oxidation and physical activity than OW/OB women. In the lean and OW/OB groups dietary macronutrient intakes were similar. Overall the parameters of energy metabolism were not associated with overall fat mass accumulation or distribution. During pregnancy, OW/OB women were more insulin resistant and pro-inflammatory (CRP and TNFα) than lean women and lean women had higher concentrations of plasma HDL. Interestingly the lean group had higher plasma concentrations of IL6 which may be a result of higher rates of vascular remodelling and may reflect a physiological rather than pathological process. In both lean and OW/OB pregnancies the gestational increase in subcutaneous adipose depots was not associated with the gestational changes in markers of carbohydrate, lipid or inflammatory profiles. Both lean and OW/OB women exhibited similar gestational improvement in endothelial microvascular function. During pregnancy both groups showed an increase in markers of lipotoxicity but levels were not associated with vascular function. Changes in anatomical subcutaneous fat distribution were also not associated with the changes in vascular function during pregnancy. In conclusion, in pregnancy, only lean women exhibit an anatomical site-specific fat accumulation. Although the OW/OB group displayed some aspects of the metabolic syndrome in general the OW/OB women studied here adapted to pregnancy in a similar way to lean women in terms of vascular function and levels of lipotoxicity. However, visceral adiposity was not assessed and OW/OB women with larger visceral adipose stores may exhibit a more lipotoxic phenotype and more pathological adaptation to pregnancy that may make them susceptible to metabolic complications of pregnancy. This study highlights the heterogeneity of maternal obesity and suggests that further studies into ‘metabolically healthy’ and ‘metabolically unhealthy’ lean and OW/OB women is warranted.

Since the discovery of cell-free fetal DNA in the circulation of pregnant women fetal-specific DNA biomarkers for non-invasive prenatal diagnosis of fetal aneuploidy have been sought. A model system assessing the DNA methylation of placental DNA and adult peripheral leukocyte DNA has been developed previously to represent fetal and maternal plasma DNA. To use DNA methylation to detect specific DNA molecules it is desirable that cellfree plasma DNA maintains the methylation profile of its tissue source. Using the imprinted gene GNAS1, a test has been developed to assess, for the first time the relative abundance of methylated and unmethylated DNA circulating in plasma. Methylated and unmethylated DNA sequences were found in equal abundance. If this finding is applicable to all plasma DNA sequences, we conclude that the steadystate concentration of DNA in methylated and unmethylated form is a reliable indicator of its input into the circulation. We have also investigated whether the abundances of different single copy gene sequences in cell-free plasma DNA are equal. Using real-time PCR, the relative abundances of six unique genomic DNA sequences in plasma were assessed. We find that plasma DNA from different sequences is not present in equal abundance in normal healthy individuals. The relative abundance of sequences tested differed by as much as 12.3 fold. We present a panel of novel candidate epigenetic biomarkers which have been identified using the model system. Of 366 DNA regions tested 3% were found to be differential. Further characterisation of these candidate epigenetic biomarkers has revealed limitations of the model system. In view of these results, future epigenetic biomarker development should be achieved by a direct assessment of first trimester plasma DNA.

Haemolytic Disease of the Foetus and Newborn (HDFN) and Foetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) are the most clinically relevant alloimmune disorders of pregnancy caused by maternal alloimmunisation to paternally derived foetal red blood cell (RhD) and platelet antigens (HPA-1a) respectively. Recombinant Fc-modified antibodies have been designed as inert potential biotherapeutics to compete with maternal alloantibodies and reduce foetal mortality. Fc-modified anti-D (Fog1G1 Δnab) and anti-HPA-1a (B2G1Δnab & B2G1Δnac) have been evaluated for their materno-foetal transport capacity using human placental models. For future in vivo efficacy, Fc-modified antibodies should transport at similar rates to wild-type antibodies (Fog1G1 and B2G1). The placental perfusion model showed that the Δnab mutation appeared to lower the transport capability of anti-D and anti-HPA-1a across the placenta. In a Human Umbilical Endothelial Vein Cell (HUVEC-c) cell culture model, transport of HPA-1a was favoured in a basal to apical direction and was statistically significant at hours 12 and 24 (p=0.002 & p=0.010 respectively). The relative order of transport was B2G1Δnac > B2G1 > B2G1Δnab implying the Δnac mutation enhances transport across the foetal endothelium. Since approximately 40% of RhD negative women give birth to RhD negative babies, these women currently receive anti-D prophylaxis unnecessarily. Foetal DNA was successfully extracted from maternal plasma and genotyped for foetal RhD status using Real-Time PCR. Foetal genotyping results revealed 96% and 98% concordance with cord blood serology for maternal blood samples taken at booking (~16 weeks) and at 28 weeks gestation respectively. Two-dimensional Difference in Gel Electrophoresis (2-D DiGE) was used to evaluate the normal placental proteome of syncytiotrophoblast membrane particles (STBMs) generated from placental perfusion. Eleven differentially expressed protein species were identified when comparing different STBM samples. Future work aims to compare the normal placental proteome with the proteome of placentas from complicated pregnancies (e.g. PE, IUGR, PTL and Trisomies 13, 18 and 21) to discover potential biomarkers for screening.

This thesis examines the use of alcohol in pregnancy amongst women in Scotland, post the introduction of a recommendation for abstinence in 2007 from alcohol during pregnancy. There is an ongoing debate over this recommendation, with some researchers highlighting abstinence as the safest choice but others indicating that such advice may generate excess fear and stress to mothers and can also be a way of stigmatising and controlling women. I argue that an increase in women’s alcohol consumption has also initiated a marked increase in attention towards the role of alcohol in women’s lives and the risks of drinking alcohol during pregnancy. This growing emphasis of the concern towards women drinking during pregnancy has come from the extension of the medicalisation of motherhood and the perception that the maternal-foetal relationship is strained. Biographical narrative interviews with 22 women in Edinburgh and Inverness are used to explore women's alcohol consumption during pregnancy in Scotland. Primarily with the aim to further the understanding of the social and cultural context of women’s alcohol consumption during pregnancy by examining women’s attitudes towards drinking during pregnancy and their awareness of the risks of consuming alcohol during pregnancy. It is my contention that there are many complex themes involved in women’s choices around drinking during pregnancy and that the change to abstinence has further led to the messages women receive being inconsistent, which leaves women in a state of confusion. I maintain that it is important that we recognise that women have different attitudes towards alcohol. Women cannot associate themselves with generalised statements about harm and risk. I explore how women respond to health interventions and their attitudes towards existing public health campaigns and health interventions. Consequently, I contend that women in this study reveal mixed attitudes towards these interventions as they often feel they gloss over the individuality of these decisions and their complexity within women’s lives by using a ‘one size fits all’ approach. Women therefore challenged the notion of harm and the evidence base behind the guidance, leading to a lack of confidence in the medical profession and an increasing reliance on lay health beliefs. It also draws upon the often overlooked importance of pleasure in women’s choices around alcohol consumption. The study highlights the importance of women’s experience, and the necessity of talking to women to further understand what influences their decision making around alcohol consumption during pregnancy. I argue that an attempt to trigger concern in pregnant women is inappropriate because of the lack of evidence into the risks caused by even moderate alcohol consumption.

This portfolio thesis contains three separate parts: a systematic literature review, an empirical study and corresponding appendices. Part one is a systematic literature review, which uses meta-ethnography to synthesise qualitative empirical studies investigating the female experience of living and coping with Type 1 Diabetes mellitus and the impact on identity. A systematic database search identified nine articles which were included. The synthesis of findings resulted in seven subthemes and four super-ordinate themes: ‘Identity shaped by the grip of blood glucose levels’, ‘The influence of others’, ‘Resistance against a ‘diabetic’ identity’ and ‘Creating Stability: integrating diabetes’. The quality of included studies was reviewed and the overall strength of literature considered. Results are discussed in relation to implications for clinical practice in diabetes care and areas for future research. Part two is an empirical study exploring the experience of discussing risk from the perspective of midwives and pregnant women with Type 1 diabetes mellitus. Five midwives and eight women with Type 1 diabetes were interviewed. Data was analysed using Interpretative Phenomenological Analysis. Twelve subthemes and four super-ordinate themes were identified: ‘Understanding and responding to risk’, ‘Talking about risk’, ‘Negotiating choice and control’ and ‘The relationship buffer’. Results are discussed in relation to relevant theory, implications for clinical practice in maternity care and suggestions for future research. Part three includes appendices which support the meta-ethnography and empirical study. This contains an epistemological statement and a reflective statement detailing the research processes and underpinnings.

Obstetric anal sphincter injuries (OASIS) are serious complications of vaginal birth with a reported average worldwide incidence of 4%-6%. They are a recognised major risk factor for anal incontinence resulting in concern amongst women who sustain such injuries when considering the most suitable mode of birth in a subsequent pregnancy. This thesis contains three studies; a systematic review and meta-analysis of the published literature exploring the impact of a subsequent birth and it’s mode on bowel function and/or QoL for women with previous OASIS, a follow-up study on the long-term effects of OASIS on bowel function and QoL and finally a prospective cohort study of women with previous OASIS to assess the impact of subsequent birth and its mode on change in bowel function. The work in this thesis demonstrated an increase in incidence of bowel symptoms in women with previous OASIS over time and that short-term bowel symptoms were significantly associated with bowel symptoms and QoL. This thesis also showed that the mode of subsequent birth was not significantly associated with bowel symptoms or QoL and for women with previous OASIS who have normal bowel function and no anal sphincter disruption a subsequent vaginal birth is a suitable option.

This thesis included a systematic literature review, yielding studies on three employment categories: hairdressers, cosmetologists and laboratory workers. The original research examined pregnancy outcomes for Finnish singleton births between 1990 and 2010. The parameters were increased male gender, low birth-weight, high birth-weight, pre-term delivery, post-term delivery, small for gestational age, large for gestational age, stillbirth and early neonatal death. Finnish Birth Registry data included 507,659 prima gravida women who delivered singletons with at least 22 weeks’ gestation 1990- 2010. There were 12,854 hairdressers, 1841 cosmetologists and 3587 laboratory workers. Control populations: 40,405 teachers, 1968 musicians and 447,004 women-general population. When hairdressers were compared to the general public, there were three marginally statistically significant results for new-borns: SGA, (OR 1.01, 95% CI 1.00 - 1.02), LGA, (OR 1.02, 95% CI 1.00 - 1.03) and post-term delivery (OR 1.06, 95% CI 1.02 -1.11). Marginal increased statistically significant results for pooled effect size (ES) from the meta-analysis were found for LBW among hairdressers ES 1.083 (95% CI, 1.017-1.153) and SGA infants among hairdressers ES 1.077 (95% CI, 1.006-1.153). Hairdressers may be at a marginally increased risk of low birth weight and small size for gestational age. This may be due to occupational exposure.