Much has been written in recent years of a ‘crisis’ in the recruitment and retention of midwives in the NHS. The crisis has been attributed variously to burnout, a lack of professional autonomy, a bullying culture, and an ideological conflict between the way in which midwives wish to practise and the way they are required to practise within large bureaucratic institutions, such as NHS Trusts. Negotiating these experiences requires a significant amount of emotional labour by midwives, which they may find intolerable. This thesis explores the strategies NHS midwives deploy in order to continue working in NHS maternity services when many of their colleagues are leaving. It examines the extent to which working in a midwife-led service rather than a consultant-led service helps or hinders midwives’ capacity to manage the emotional and ideological demands of their practice. Ethnographic fieldwork was carried out in a consultant unit and an Alongside Midwife-led Unit (AMU) in two NHS Trusts in England. The findings from negotiated interactive observation and in-depth unstructured interviews with eighteen midwives were analysed using inductive ethnographic principles. In order to ameliorate the emotional distress they experienced, the midwives used coping strategies to organise the people and spaces around them. These strategies of organisation and control were part of a personal and professional project which they found almost impossible to articulate because it ran contrary to the ideals of the midwifery discourse. Midwives explained these coping strategies as firstly, necessary in order to deal with institutional constraints and regulations; secondly, out of their control and thirdly, destructive and bad for midwifery. In practice it appeared that the midwives played a role in sustaining these strategies because they formed part of a wider professional project to promote their personal and professional autonomy. These coping strategies were very similar in the Consultant Unit and the Midwifery Unit. A midwife-led service provided the midwives with a space within which to nurture their philosophy of practice. This provided some significant benefits for their emotional wellbeing, but it also polarised them against the neighbouring Delivery Suite. The resulting poor relationships profoundly affected their capacity to provide a service congruent with their professional ideals. This suggests that whilst Alongside Midwife-led Units may attempt to promote a midwifery model of care and a good working environment for midwives, their proximity to consultant-led services compounds the ideological conflict the midwives experience. The strength of their philosophy may have the unintended consequence of silencing open discussion about the negative influence on women of the strategies the midwives use to compensate for ideological conflict and a lack of institutional and professional support.

This thesis examines to what extent women were involved in their own healthcare and that of others, in the late medieval period. It starts from the observation that modem text editing practices often exclude from discussion other widely disseminated texts that formed the 'travelling companions' of a manuscript - in this case particularly the ensemble known as the Trotula. By focusing on one specific text within the manuscript compilations, the diverse and widespread dissemination of women's knowledge of healthcare and the use of vernacular texts have been marginalised. The thesis argues that the consideration of these 'travelling companions' can offer an alternative view of women's involvement in healthcare, despite the seeming female exclusion from the culture of book-learning and the development of professional licensing in the later Middle Ages. The corpus of manuscripts examined is taken from a range of vernacular compilations produced in England, Flanders and Italy, with some discussion of ownership and transmission of these into the Early Modem period. A number of transcriptions and close readings of the contents are used to identify the discrete characteristics of each copy and to track changes that took place during the transmission process. Detailed comparisons demonstrate that conscious, active choices were made in both the adaptation and interpretation of the material being copied. Analysis of these manipulations reveals that the production of vernacular texts enabled easier consultation and use. The manuscripts point to women's continuing engagement with both the texts and the practice of self-care and that, despite the increase in the number of professional male practitioners over the period, women continued to offer advice to others well into the sixteenth century.

This retrospective cohort study, examined pregnancy and birth related outcomes for 32,895 births between 1st January 1992 and 31st December 2001 in two maternity units in the East Midlands. The study compared seven outcomes in younger teenagers (<16 year), older teenagers (17-19 years) and a comparison group (20-25 year olds). The sample included 1105 births to younger teenagers, 6923 to older teenagers and 24867 to the comparative group. 14824 were to primiparous women and 18071 were to multiparous women of which 1711 births to multiparous women were rapid repeat births (<18 months of a previous birth). Results showed that compared to those in their early 20s, primiparous teenagers had an increased risk of antepartum haemorrhage (APH) (<16, OR=1.67,95% CI 1.262 to 2.227; 17-19, OR=1.48,95% CI 1.253 to 1.751) and low Apgar score (<16, OR=1.36,95% CI 1.102 to 1.669; 17-19, OR=1.15, 95% CI 1.023 to 1.297) but were less likely to have an instrumental birth (<16, 0R=0.64,95% CI 0.499 to 0.819; 17-19, OR=0.708,95% CI 0.622 to 0.807) or perineal trauma (<16, OR=0.63,95% CI 0.534 to 0.745; 17-19, OR=0.667, 95% CI 0.608 to 0.734). Teenagers had a similar statistical risk as the comparative group for lower segment Caesarean section (LSCS), low birth weight (LBW) and premature birth. Compared to those in their early 20s multiparous older teenagers had a reduced risk of both instrumental (OR= 0.711, 95% CI 0.555 to 0.912) and perineal trauma (OR=0.863, 95% CI 0.752 to 0.99 1) but in younger teenagers there was a similar risk. Multiparous teenagers were at an increased risk of premature birth (<16, OR=1.934,95% CI 1.153 to 3.243; 17-19, OR=1.227,95% CI 1.043 to 1.442) but for LSCS, low Apgar score and low birth weight a similar statistical risk was found as the comparative group. When comparing multiparous teenagers with primiparous teenagers, multiparous teenagers had a reduced risk of instrumental birth (OR=0.429, 95% CI 0.339 to 0.541), perineal trauma (OR=0.668, 95% CI 0.595 to 0.750), low Apgar score (OR=0.782,95% CI 0.664 to 0.921) and LBW (OR=0.760, 95% CI 0.587 to 0.982) but an increased risk of premature birth (OR=1.269, 95% CI 1.061 to 1.517). For the remaining outcomes both primiparous and multiparous teenagers had a similar statistical risk. Teenagers having a rapid repeat birth had a reduced risk of instrumental birth (OR=0.32, 0.110 to 0.931) but an increased risk for premature birth (OR=1.617 95% CI 1.150 to 2.272). For APH, Apgar score and LBW teenagers having a rapid repeat birth had a similar statistical risk to those who had not. In conclusions teenagers should not be treated as a homogenous group and outcomes should be investigated separately for age groupings and parity as teenagers birth well and only APII and neonatal complications are worse in some groups of teenagers.

Increasing the uptake of elective single embryo transfer is necessary to achieve the 10% HFEA limit for multiple IVF births in 2011. This thesis aims to explore patients’ and clinicians’ attitudes to eSET and to promote effective decision making regarding embryo transfer. Study 1 compared neurobehavioural outcomes between twins and singletons in a prospective study of infants born very preterm (n=233). Despite having older (p=0.025) and higher social class (p=0.023) mothers, twins had the same risk of cognitive impairment at 2 years as singletons. In study 2, a 44 item Attitudes to Twin Pregnancy scale (ATIPS) was developed and administered to a sample of clinicians, medical students and conference delegates (n=411). Item analysis reduced ATIPS to 2 short subscales. A-Twin (12 items) assessed perceptions of risks and benefits associated with a twin birth (α=0.7). A-SET (8 items) assessed attitudes to eSET (α=0.53). Study 3 explored the reliability and validity of ATIPS-R in IVF patients. Exclusion of 2 A-SET items increased alpha to 0.8. Female patients (n=100) had more positive attitudes to a twin birth than clinicians (p=<0.001). Less than a third of patients felt that a twin birth was risky for infants and over 80% of doctors agreed that a twin birth was worth any risks to infants. First cycle IVF patients were more positive about eSET (p=<0.001) than women undergoing repeat cycles. Study-4 developed a decision aid and evaluated its impact in a pilot randomised controlled trial (n=8). Lower decisional conflict in patients at embryo transfer was associated with more positive attitudes to twins at baseline (p=0.024) and less positive attitudes to eSET, (p=0.04). Although the attitudes of patients receiving the DA did not change, partners became more positive towards eSET (p=0.024). Conclusion: Patients and clinicians underestimate the risk of a twin birth for infants and would benefit from educational interventions to promote eSET. The ATIPS-R is a useful measure for assessing the effectiveness of such interventions. Abbreviations: SET- single embryo transfer; HFEA- Human fertility and embryology authority; IVF- In vitro fertilisation; A-Twin- attitude to risks and benefits of twins; ATIP- attitude to twin IVF pregnancy; A-SET attitude to single embryo transfer; eSET- elective single embryo transfer; DET- double embryo transfer; RCT – randomised control trial; DA- decision aid.

The research within this thesis concerns the monitoring of the fetus during labour, using the fetal electrocardiogram (FECG). A versatile FECG analysis system was developed for the Microsoft Windows environment, to allow various FECG parameters to be extracted. Algorithms, currently used in other FECG analysis systems, were implemented using Object Oriented Programming, thus allowing new algorithms to be easily added at a later stage. Although these current algorithms have been demonstrated by several authors, it was felt that they had been used with only partial investigation of their limitations, and with failure to fully determine their accuracy in controlled conditions. These factors are fully addressed within this thesis. By developing a FECG simulator, in which heart-rate, morphology, and noise levels could be varied, the ability of the analysis algorithms to extract the parameters, and the accuracy of these parameters under different noise conditions, were thoroughly checked. Both ability and accuracy were shown to be very good in ideal noiseless conditions; but, with the addition of noise, there exists a compromise between parameter accuracy when the morphology is static, and parameter accuracy when the morphology is changing. The accuracies of the most common indices in this field (the Conduction Index, and the T/QRS ratio) were determined for different levels of simulated noise, and their values demonstrated for data previously recorded from the fetal scalp. Errors as large as 0.3 in the CI and 0.05 in the T/QRS suggested that in the clinical environment, an indication of the accuracy of each index ought to be displayed, and this may be estimated from the measured level of noise. Furthermore, this analysis system allows the direct comparison of both indices. Finally, in order to design a more effective front-end filter, it is important to be aware of the frequency content of the underlying FECG. The Integral Pulse Frequency Modulation (IPFM) model, combined with Pulse Amplitude Modulation (PAM), was used to estimate realistic frequency components within the FECG signal. The effects of filtering could then easily be modelled to show the distortion of both the FECG and any parameters taken from it. For a FECG frontend filter, distortion was found to be insignificant provided that, above 1 Hz, both the gain remained constant and there was no phase-distortion.

A method for measuring human platelet Angiotensin II (All) binding was validated, and characterisation studies involving 67 non-pregnant subjects were performed. Platelets were found to possess high affinity binding sites with many of the characteristics of receptors. No correlation was found between platelet All binding and the rise in intracellular free calcium after ex vivo All infusion, thus formal validation of the binding sites as receptors was not achieved. In 25 non-pregnant subjects, there was an inverse correlation between platelet All binding and simultaneously measured plasma All (P<0.02). In 10 ovulatory subjects, platelet All binding diminished in the luteal phase of the menstrual cycle (P<0.02). In a pilot cross-sectional study of platelet All in normotensive pregnancy, incorporating 125 pregnant/postnatal patients, platelet All binding was significantly lower in 1st trimester patients as compared to non-pregnant subjects (P<0.001). Platelet All binding remained low throughout pregnancy. Higher values, approximating to the non-pregnant level, were found 6 weeks postnatally. These findings were confirmed in a longitudinal study .of 30 pregnant women, with a diminution in platelet All binding being suggested by 5-8 weeks gestation (p= 0.02). Inverse correlations in pregnancy between platelet All binding and the components of the renin-angiotensin system were found (P<0.01). There were also significant correlations between platelet All binding and the levels of serum sodium, urea and osmolality (P<0.01). When platelet All binding was measured in 67 patients with established hypertension in pregnancy, binding in patients with pregnancy induced hypertension (PIH) was significantly higher than in normotensive primigravidae (P<0.0001). No differences in binding were found in the puerperium. In a prospective comparison of platelet All binding and the All sensitivity test in predicting the development of PIH, involving 34 subjects, platelet All binding was a more effective discriminant than any of the parameters derived from the All sensitivity test. There was a significant correlation between platelet All binding and the slope of the curve relating the diastolic pressor response to infused All (P<0.01).

Hypothesis: This thesis set out to test the hypothesis first proposed by Baker et al (1995) that Vascular Endothelial Growth Factor (VEGF) may be involved in the alteration in endothelial function that is observed in the disease of pre-eclampsia. Aims: To investigate concentrations of VEGF in plasma from non-pregnant, and normal pregnant women and women with pre-eclampsia. To investigate uterine and placental expression of VEGF in non-pregnant, normal pregnant women and women with pre-eclampsia. To investigate some of the vascular adaptations that occur in pregnancy and pre-eclampsia within the uterine and systemic circulations. To investigate the effect of plasma from women with PE and VEGF on i) An in vitro endothelial cell culture model. ii) An in vitro isolated vessel model. To characterise the mechanism whereby VEGF causes any alteration in vascular function.

Preeclampsia and fetal growth restriction (FGR) are common and costly obstetric complications. Both conditions are associated with immediate and remote mortality and morbidity for the mother and the offspring. Impaired placentation and aberrant maternal systemic responses are implicated as pathophysiological mechanisms in preeclampsia and FGR. Both preeclampsia and FGR are known to have a clear genetic basis. This study has investigated the roles of several candidate genes including those previously associated with diabetes (TCF7L2, FTO, PPAR-g, CDKN2B-AS1 and KCNJ11), and epidermal growth factor (EGF). Functional consequences of variants within the EGF gene were also investigated. A bidirectional association between type 2 diabetes (T2D) and preeclampsia is consistently reported, whereby each condition is associated with an increased risk of the other. Furthermore, fetal growth restriction, which complicates 30% of preeclamptic pregnancies, predisposes the offspring to an increased risk of type 2 diabetes and coronary artery disease (CAD) later in life. 11 single nucleotide polymorphisms (SNPs) reproducibly associated with T2D in the TCF7L2, FTO, PPAR-y, CDKN2B-AS1 and KCNJ11 genes were investigated as susceptibility loci for preeclampsia and fetal growth restriction in a maternal case control study. The study group consisted of 448 white western European women with preeclampsia, 673 controls with no evidence of preeclampsia, 243 women with pregnancies complicated by FGR, and 570 controls with no evidence of growth restriction. A maternal haplotype on the T2D region of the CDKN2BAS1 gene on chromosome 9p21 was found to be a risk variant for fetal growth restriction (P=O.005).The other 9 investigated SNPs in TCF7L2, FTO, PPAR-y, and KCNJ11 showed no association with growth restricted pregnancies. None of the SNPs investigated showed an association with preeclampsia. These findings suggest that some maternal diabetogenic risk variants are associated with an altered risk of FGR pregnancy but not preeclampsia. The results require replication in a larger sample and fetal-maternal gene interactions merit investigation. Epidermal growth factor (EGF) is described as a major regulator of the placentation process. It also helps to maintain an adequate blood supply to the growing fetus through its effects on umbilical vessel tone. Investigating the role of two genetic variants of the EGF gene in susceptibility to preeclampsia and FGR showed that the maternal variants, rs4444903 in the 5'UTR and rs2237051 in exon 14 of the EGF gene has no effect on the risk of preeclampsia or FGR pregnancy. The G allele of the SNP rs4444903 was associated with higher systolic blood pressure measures in the control group. The G allele of the rs4444903 and the A allele of rs2237051 have been associated with increased risk for FGR and lower birth weight in a previous study from our laboratory. This led to investigations to characterize the functional consequences of the two SNPs in the EGF gene on transcription, translation and ribonucleic acid (RNA) splicing using a variety of methods. These experiments have shown that the G allele of rs4444903 was transcriptionally more active than the A allele in hepatocellular carcinoma (HepG2) and more active than EGFP on its own in choriocarcinoma (Jeg-3) cell lines using a luciferase reporter gene assay. There was no effect of this variant on translational efficiency in the cell lines investigated using reporter gene assays, or in a cell free environment using an in vitro translation assay. DNA-protein interaction was investigated using nuclear extract from HepG2 cells to further define the mechanism by which the G allele exerts its higher transcriptional activity. Initial experiments suggest that the Sp1 transcription factor interacts with and represses the A allele of the rs4444903 SNP. The study also demonstrated no evidence of higher activity of the G allele on EGF expression in vivo using term placental tissues. It was expected that higher EGF expression as a function of genotype at rs4444903 SNP may lead to down regulation of the EGFR in the placenta, which was not confirmed in this study. SNP rs2237051 in exon 14 of the EGF gene is in strong linkage disequilibrium with rs4444903, and disrupts a predicted exon splicing enhancer region. This polymorphism was investigated using a minigene assay, but there was no evidence that it affected splicing of exon 14. Taken together, these findings provide no evidence that EGF genetic variants alter the risk of preeclampsia or FGR though functioning.

Chorionic plate (CPA) and stem villous (SVA) arteries located at the fetal and maternal interface of the placenta respond to stimuli including hypoxia and acidic pH which can be the result of an intermittent blood supply. Unlike other vascular tissue the placenta lacks nervous control so any response to such stimuli will be autoregulated by ion channels. Members of the two pore domain potassium channel family (K2P) the Tandem of P domains in a weak inward rectifying (TWIK) related potassium channel (TREK-1) and the TWIK Related acid sensitive K+ channel (TASK-1/3) have been shown to respond to both intracellular and extracellular pH. The hypothesis that there is differential expression and modulation of these candidate ion channels in normal pregnancy was tested. Placentae (N) were collected with written informed consent from healthy patients undergoing elective Caesarean section at term (≥37 weeks). The functional responses of resistance sized arteries (≤500µm) (n) taken from the SVA and the CPA were characterised using wire myography. Vessels were pre-contracted with U46619 and the effect of extracellular pH was studied using 1M lactic acid to produce falls of 0.2 pH units over a range of pH 7.4-6.4. The effects of a variety of ion channel modulators along with tissue oxygenation (20%, 5% and 2% O2) were also investigated on the vascular response of CPA and SVA. Western blot analysis was performed on crude CPA and SVA tissue homogenates with separation by 12% SDS-PAGE to quantify expression of TASK-1/3 and TREK-1. The subcellular localisation of each ion channel was also examined with smooth muscle cells (SMC) cultured from the CPA and SVA by confocal immunofluorescence. CPA and SVA were equally positive for TASK 1/3 (N=31) and TREK 1 (N=40) at the protein level. SMC from CPA and SVA showed expression for TASK 1/3 (N=8) with an increased fluorescence stain around the peri nuclear region. TREK-1 (N=12) expression showed a linear organisation that closely overlapped with α actin IF stain. The acidic pH stimulation triggered a biphasic relaxation that was repeated with each subsequent pH insult. A change from pH 7.4-7.2 produced a 29 ± 3% (n=9) relaxation of CPA which increased to 61 ± 4% at the lowest pH of 6.4 in 20% pO2. Similarly, altering the pH of pre-constricted SVA caused a 21 ± 2% (n=6) fall at pH 7.2 with a maximum relaxation of 69 ± 2% at pH 6.4 (p<0.01). Lowering pO2 from 20% to 5% inhibited the relaxation response seen with CPA (45 ± 3%, n=8) and SVA (34 ± 3%, n=6) at pH 6.4. CPA were also treated with the TREK-1 blocker L-methionine (1mM) which increased the relaxation to 67 ± 7% (n=6 p<0.001) at pH 6.4. Similarly the TASK 1/3 blocker ZnCl2 (1mM) gave a maximum relaxation of 72 ± 5% (n=8 p<0.01) in 20% pO2. The TREK-1 opener riluzole demonstrated a potent relaxation with both CPA (75 ± 5%, n=6) and SVA (78 ± 5%, n=6) in 20% pO2. Our data has shown that tissue oxygenation and extracellular pH within the physiological range has an important role in controlling vasodilatation in the placenta. Protons are readily transported across the cell membrane and can activate a range of targets including the K2P channels. The relaxation by riluzole has not been previously reported and implicates a direct role for TREK-1 in controlling placental vessel function. However, when TREK-1 and TASK-3 channels were blocked, the response by CPA to lower pH was exaggerated, and reflects the complex pharmacology of pH on vascular function. This also suggests that K2P channel activity can be compensated for by other pH sensitive channels and work is currently underway to identify the role of other potential ion channels that may be involved in this pathway.

The ovarian follicle is an individual functional unit that provides the optimal environment for the oocyte within to develop. This thesis outlines the research in the field of ovarian follicular dynamics that has already been established, and further develops these findings to explore in greater detail the relationship between the oocyte and its environment, both in an in vitro and in vivo setting, using a variety of species. The first major research area involved studying the role of oocyte-secreted factors, which was examined using a series of dose response experiments. These were performed using an ovine granulosa cell culture model, and elucidated a possible role for a collaborative action of BMP15 and GDF9 in the promotion of oestradiol synthesis, while inhibiting production of progesterone in this species. This finding was then further investigated using an ovine in vivo immune-neutralisation study, the endocrine and histological results of which confirmed these findings in a proportion of these animals, although this study was limited by the animals appearing to have been in seasonal anoestrus. The second major topic that was investigated was based around the ovarian microenvironment, in terms of angiogenesis and hypoxia. Again, ovine granulosa cell cultures were used, in this instance to examine the effect of hypoxic conditions on steroid hormone production. These experiments indicated that somatic cell steroid hormone production is likely to be compromised by a hypoxic environment, and therefore that the provision of oxygen through a local blood supply may be a vital requirement for these cells. To investigate the relevance of studying ovarian blood supply and physiology in a clinical setting, perfusion studies were carried out based on a series of bovine phantom experiments, which were used to study the effect of varying flow rate on the parameters routinely measured using this technology. The routine clinical ultrasonographic methods of ovarian assessment such as 4D ViewTM, SonoAVCTM and VOCAL were also examined, based on bovine phantom experiments, revealing possible weaknesses in the data provided by ultrasound that are increasingly relied upon in the clinical setting. Finally, a clinical trial was carried out to try and encompass all of the findings of the in vitro and in vivo work, in order to place these theories into context in a human IVF setting. This work was unfortunately limited severely by a lack of patient numbers, but some interesting results were observed with regard to oocyte developmental potential relationships with follicular fluid and somatic cell factors, as well as ultrasound measures of peri-follicular blood supply.