Objectives: The aim of this thesis was to evaluate the value of modern high-resolution transvaginal ultrasound for differential diagnosis of adnexal tumours. This was done by performing a series of studies: (1) comparison of risk of malignancy index (RMI) and ovarian crescent sign (OCS) for the diagnosis of ovarian malignancy; (2) assessment of the value of pattern recognition for the diagnosis of borderline ovarian tumours (BOT); (3) comparison of diagnostic accuracy using real-time and static images (4) assessment of the reproducibility of ultrasound pattern recognition for the diagnosis of BOT; (5) assessment of the effect of degree of operator's confidence on diagnostic accuracy; (6) examination of the effect of the quality of gynaecological ultrasound diagnosis on the management of patients with suspected ovarian cancer; and (7) determining the value of preoperative ultrasound examination for selection of women for laparoscopic surgery. Interpretation of findings: (1) The OCS proved to be a simpler and better method in diagnosing ovarian cancer when compared to the RMI. (2) Ultrasound diagnosis of BOT is highly specific but typical features are absent in one third of cases. (3) The diagnosis of an adnexal mass is more accurate when made on the basis of real-time ultrasound examination than on static ultrasound images. (4) Accuracy of ultrasound diagnosis of BOT is less in comparison to benign and invasive malignant lesions. (5) Accuracy of ultrasound pattern recognition in differentiating ovarian tumours depends on the degree of certainty with which the diagnosis is made. (6) Improved quality of ultrasound examination has a measurable positive effect on the management of women with suspected ovarian malignancy. (7) Detailed preoperative ultrasound examination of benign adnexal lesions is helpful for assessing feasibility of their removal by laparoscopic surgery.

Toxoplasma gonedii is a parasite discovered in 1908 by Nicolle and Manceaux; they found a protozoan in tissue of a hamster-like rodent in laboratory of the Charles Nicolle at the Pasteur Institute in Tunisia. It is an obligate intracellular protozoan parasite, capable of infecting most species of warm-blooded vertebrates including mammals and birds. This infection is world-wide and one third of the human population is infected chronically. Toxoplasmosis is an important disease and a causative agent that is responsible for abortion in human and farm animals. T. gondii can be transmitted in three ways: via cat faeces, eating raw meat and congenital transmission (mother to child). To investigate transmission routes and prevalence of T. gondii in human in Libya a set of human tissues samples (umbilical cord) were collected at birth using suitable ethical procedures. One hundred fifty three umbilical cord samples were collected from volunteer subjects in Misurata Central Hospital and Alsaed Hospital in Libya for subsequent DNA extraction and testing for T.gondii infection. The clinical records from these subjects were analysed for factors such as mother age, number of previous children, number of previous miscarriages, pregnancy success and number of current miscarriages. The aim of this thesis was to determine the frequency of congenital transmission of T. gondii in humans and to use clinical records to investigate pregnancy success in Libya. One hundred and fifty mothers were recruited to the study producing 153 children, of these a ratio of male to female of 1.22:1, giving a slightly higher bias than the Libyan average (1.05:1). Mother's ages ranged from 18-45 with an average age of 28 years. The sample contained mothers having their first child to those who had 11 children. The pregnancy success of this cohort was 8 deaths per 145 live births (55.1/1000 live births) which is higher than the Libyan national average (21.9/1000) and the UK national average of 4.93/1000. Overall, the samples set did not appear biased when compared with Libyan national statistics. Miscarriage was analysed with respect to various parameters. As has previously been reported, success of pregnancy declined with increasing with age although this was more marked in mothers older than 38. There was no significant association between miscarriage in the current pregnancy with miscarriage in previous pregnancies (P = 0.96). Interestingly, there was a higher frequency of miscarriage in male than in female children although this was not quite significant (P = 0.062). Of the umbilical cord samples tested for T. gondii 2.01% were infected, giving an overall rate of congenital transmission rate of 2.01%. This is much higher than reported studies using serology, where values of less than 1 per 1000 live births are commonly reported. However, it is lower than a previous study from Libya based on PCR detection (20.1%). Toxoplasma strain typing was carried out on the positive samples and types I and III were found. Toxoplasma infection was not apparent in any of the current miscarried children and there was no association of current infection with miscarriages during previous pregnancies.

The presented thesis is an investigation of the incidence and pathophysiology of first trimester threatened miscarriage and its outcomes. First trimester threatened miscarriage is the commonest complication of pregnancy, affecting 10-20% of women with clinically recognised pregnancies, and the incidence and mechanisms for long term adverse outcomes are poorly understood. Early placental development requires a delicate balance between the entry of oxygenated maternal blood and the capacity of the villous trophoblast to metabolise oxygen and eliminate its metabolites (free radicals). There is a rapid increase in placental markers of oxidative stress as the maternal circulation is established, which may serve a physiological role in stimulating placental differentiation, but which equally may result in free radical damage if antioxidant defences are depleted. In normal early pregnancy, the rapid increase in oxygen tension is paralleled by a rise in the expression of placental antioxidant enzymes. Bleeding in early pregnancy could change the delicate equilibrium of placental production of reactive oxygen species and its natural antioxidant defences, leading to disruption of normal development of the early placenta and placental membranes. This disruption results in a range of adverse pregnancy outcomes, from miscarriage in the first trimester, to pre-term pre-labour rupture of the membranes, pre-term labour, fetal growth restriction and pre eclampsia in the third. This study examines in detail the incidence and possible mechanisms of adverse outcome in women with threatened miscarriage and the role of placental function, in terms of placental hormone production and markers of oxidative stress, in both the causation of threatened miscarriage and the subsequent outcome of the pregnancy. It confirms an association between threatened miscarriage and adverse outcome, and provides potential markers of placental damage or stress to add to a growing body of research elucidating the role of oxidative stress in the developing placenta and later pregnancy complications.

This thesis investigated the role of stress in RM using both psychometric and biochemical measures. The majority of previous studies on the impact of stress on RM only addressed the psychological aspect without concurrent biochemical stress measurements. In this thesis the stress status in women with RM was evaluated by using a validated questionnaire package and biochemical measurements of stress markers including cortisol, natural killer cells and prolactin. The first part of this thesis compared the psychological stress status in a cohort of women with unexplained RM with that of fertile health women. The results showed that women with RM had higher levels of psychological stress than fertile women. RM women with higher perceived stress and being less optimistic appeared to have an increased likelihood of live birth. Based on the findings in the present study we speculate that stress coping strategies adopted by individuals may have a prognostic value on subsequent pregnancy outcomes more than stress levels in women with RM. The next part of this thesis investigated the biochemical stress markers including natural killer cells, cortisol and prolactin in the same cohort of women with unexplained RM. The increases in pNK CDdim cells were found to be associated with a higher risk of a subsequent miscarriage in women with RM, suggesting a prognostic value of measuring pNK subset of CDdim cells in RM. In addition, no correlation between the measurements of pNK cells and those of uNK cells was found in women with RM, suggesting that pNK measurements do not reflect uNK measurements in RM. Next, we conducted a study to investigate the relationship between prolactin and RM. We found that within normal physiological range low plasma prolactin concentrations were associated with an increased risk of a subsequent miscarriage in women with RM. No significant difference in the measurements of endometrial prolactin receptor was found between women with RM and fertile women. There was also no association between the expression of endometrial prolactin receptor and subsequent pregnancy outcomes in women with RM. The following part of this thesis examined the activation of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in women with RM with cortisol measurements. No non-suppression of cortisol following Dexamethasone Suppression Test (DST) was found in women with RM. There was also no association between cortisol measurements and pregnancy outcomes in women with RM. Based on the findings in this study we speculate that chronic stress of RM has no effect on feedback dysregulation of the HPA axis. The final part of this thesis correlated the results of various stress measurements. High levels of fertility stress were associated with a decrease in the numbers of pNK CDbright cells. High basal salivary cortisol concentrations were associated with an increase in uNK cell measurements. The results of serum cortisol suppression following DST had an inverse correlation with the values of pNK CDdim cells whereas the results of salivary cortisol suppression following DST had a positive association with uNK cell measurements. The exact physiological mechanism of this observation is not known. In summary, the studies presented in this thesis showed that stress was associated with RM. There was some evidence that stress affected subsequent pregnancy outcomes in women with RM.

Technological advances in prenatal screening and diagnosis mean that it is now possible to test for a wide range of congenital conditions (Hewison et al., 2007). Traditionally testing has been carried out during pregnancy (prenatal diagnosis, PND). However, advances in technology have made it possible for diagnosis of an embryo created through in vitro fertilisation, prior to implantation into the womb (pre-implantation genetic diagnosis, PGD). This means that women can avoid the birth of a child with a genetic condition without the stress of terminating a pregnancy. This raises questions about what women want from reproductive technologies, as it means they are making decisions based not only on the condition diagnosed but also on the technology used to test. Two studies were carried out to examine this further. In the first study, 216 participants completed a questionnaire either based on PND or PGD. Participants were asked whether they would terminate a pregnancy (PND condition) or avoid implantation (PGD condition) following diagnosis of five different genetic conditions, ranging in severity. The results suggest an interaction between the technology (PND or PGD) and the severity of the genetic condition diagnosed, such that for the most and least severe conditions, the number of people choosing to terminate/avoid implantation was similar for the PND and PGD groups. However for conditions in the middle range of severity significantly more people said they would avoid implantation. A within subjects interview study was carried out to explore this further and thematic analysis identified a number of themes that influenced participants’ responses. Overall, the results suggest that PGD may be more acceptable for women in some cases. Women considering diagnoses are likely to benefit from detailed information about both PND and PGD in order to make a fully informed decision as to which is best for them.

Nuclear receptors, including the pregnane x receptor (PXR) and the farnesoid x receptor (FXR), regulate the expression of genes that maintain bile acid (BA) homeostasis. Intrahepatic cholestasis of pregnancy (ICP) is a common gestational liver disease and BAs are implicated in its pathogenesis. Rodents exhibit maternal liver growth in order to meet the metabolic demands of pregnancy. This process is found to precede changes in body weight, occur in the presence of raised serum BAs and is likely to be driven by a placental lactogen. While the growth is normally achieved by hepatocyte hypertrophy, potentially harmful hyperplasia makes a major contribution in mice lacking Fxr. Consistent with reports of raised serum BAs in normal pregnant women, hepatic BAs are found in association with pro-cholestatic gene expression in normal pregnant mice. Gestation could be a state of reduced Fxr function because BA-fed and Fxr-/- mice do not develop raised hepatic BAs during pregnancy. Sequencing and functional assessment of PXR variants revealed that polymorphisms in this gene are unlikely to contribute to the aetiology of ICP. Surprisingly, Pxr-/- mice have enhanced hepatic metabolism and are resistant to toxicity caused by lithocholic acid (LCA). Furthermore, while hepatic Pxr is activated by intraperitoneal injection of LCA, it is not activated by physiologically relevant LCA-feeding. Summary: Pregnancy causes liver growth, raised hepatic BA and pro-cholestatic gene expression in normal mice. In humans, these adaptations may expose predisposed individuals to gestational liver disease. Genetic variation in PXR does not contribute to ICP and Pxr may play only a limited role in mediating hepatic responses to toxic BAs.

Mounting evidence suggests prenatal stress can affect child development. Clinical studies of this concept, termed fetal programming, focus predominantly on early childhood. Also, little is known about the mechanisms underlying how maternal stress is transmitted to the fetus. This thesis will test if maternal anxiety during pregnancy is associated with (1) behavioural outcomes from childhood to early adolescence, (2) cortisol output in adolescence and (3) an altered placental phenotype. For Studies 1 and 2 participants were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC). Psychometric data from 9,871 mother child pairs (5,098 males, 4,773 females) were analysed using latent growth curve analysis. A subsample of the ALSPAC children aged 15 years (n = 899) provided saliva samples on three days at waking, +35mins, after school and before bed, for later cortisol analysis. For Study 3 a new cohort of women (n= 73) was recruited. Maternal psychometric data was collected one day prior to elective caesarean section, and the placenta collected after delivery. Study 1 showed that maternal prenatal anxiety was associated with conduct and emotional problems, and symptoms of ADHD at age 13 years, after allowing for a range of confounders, including postnatal anxiety. There were marked sex differences in the developing patterns. Saliva cortisol demonstrated a marked diurnal profile with a clear sex difference at age 15. Higher maternal prenatal anxiety was associated with a reduced cortisol awakening response. High levels of maternal prenatal anxiety were associated with reduced placental expression and activity of the cortisol metabolising enzyme 11β-Hydroxy steroid dehydrogenase 2 (11β-HSD2) and also with reduced placental weight. This thesis provides evidence that maternal prenatal anxiety can affect behavioural and neuroendocrine outcomes in adolescence. It also provides preliminary evidence that maternal anxiety is associated with alterations in the function of the placenta, which may underlie some aspects of fetal programming. These findings have public health implications. Increasing awareness about the lasting effects of prenatal anxiety may ultimately benefit mothers, the care they receive and their families.

In this thesis safety, efficacy and acceptability of early medical abortion with mifepristone and the prostaglandin analogue gemeprost are investigated in Chapters 2,3 and 5. In Chapter 4 the mechanism of abortion with these agents is explored. The use of a single dose of 400 mg, 500 mg or 600 mg of mifepristone followed 48 hours later by a half or a whole 1 mg gemeprost pessary was shown to induce complete abortion in 95% of women of £ 56 days amenorrhoea. No significant differences were demonstrated between the three treatment regimes. When 600 mg of mifepristone was given with either a half or a whole gemeprost pessary, women receiving the smaller dose of prostaglandin experienced significantly less severe pain. Abortion rates were not compromised by a reduction in the dose of prostaglandin with 98% of women receiving a half pessary aborting, compared with 100% of women receiving a whole pessary. Pretreatment with mifepristone or gemeprost 48 hours prior to the administration of 1 mg gemeprost was also studied. Measurement of uterine tone with an intrauterine pressure catheter showed that while pretreatment with gemeprost had no effect on uterine tone following a further dose of gemeprost, pretreatment with mifepristone exerted a significant effect. In addition, the pattern of uterine activity following gemeprost or mifepristone pretreatment was shown to differ. Blood loss was measured during and after the induction of abortion with mifepristone and gemeprost in 222 consecutively treated women of <63 days of amenorrhoea. The median loss <56 days amenorrhoea was 72 mls. Blood loss was found to increase with increasing gestation and was significantly greater in women treated between 56 and 63 days of amenorrhoea. Although the introduction of prostaglandins to gynaecological practice has improved midtrimester abortion techniques, it remains a long, unpleasant and relatively high risk procedure.

No description available.

The research described in this thesis endeavours to rationalise certain aspects of the secondary care management of women with heavy menstrual loss, particularly endometrial surgery. The work was undertaken in a gynaecology department with an established record in research evaluating endometrial ablative techniques. The hospital is the regional referral centre for all women with menstrual disorders; hence a centralised and stable study population was available. Chapter 1 outlines the aetiological and known epidemiological factors for dysfunctional uterine bleeding. A review of the medical treatment options for menorrhagia is undertaken. The equipment requirements and techniques of transcervical resection of the endometrium (TCRE) and microwave endometrial ablation (MEA) are described. The randomised controlled trials evaluating TCRE that have been published to date, are discussed and critically reviewed. Chapter 2 presents the patterns of referral, socio-demographic and clinical details, primary care treatment, and effect on health related quality of life of women referred to this centre, over one year with heavy menstrual loss. Chapter 3 describes the subjects, methods and outcomes at four months of a prospective randomised comparison of medical management with TCRE for women with heavy menstrual loss. Chapter 4 outlines the clinical and quality of life outcomes at two years for the randomised trial of medical treatment versus TCRE. Chapter 5 describes the subjects and methods for a prospective randomised controlled trial comparing MEA with TCRE. Operative details and outcomes at four months are presented. MEA was a significantly faster technique than TCRE (11.4 v 15 minutes). Post operative stay was less with microwave, though not significantly so, and analgesia requirements were low and equivalent (<30%) for both techniques. Satisfaction rates were slightly lower following MEA (74% v. 81%), whilst acceptability of treatment rates were equivalent (92% v 94%). MEA lead to more significant improvements in health related quality of life measurements than TCRE. Chapter 6 concludes that: - Primary care management guidelines are required, whilst treatment preferences and expectations should be established prior to deciding on treatment. Quality of life measurements should be used to determine degree of debilitation and to ascertain treatment success. Medical treatment was less effective than TCRE, irrespective of previous treatment or type of medical management received.