Background: High levels of HIV and maternal mortality go hand in hand in many regions of sub-Saharan Africa. Therefore, understanding the interaction between pregnancy and HIV is important, not only for the clinical management of pregnant women, but also for the measurement of maternal mortality, the standard definition of which excludes infectious causes of death not aggravated by pregnancy. Methods: In this thesis the excess mortality attributable to HIV in pregnant and postpartum women is calculated by comparing the risk of mortality in HIV-infected pregnant and postpartum women to their uninfected counterparts using two different data sources: 1) studies identified through a systematic review and; 2) data from six demographic surveillance sites (DSS) in sub-Saharan Africa. Verbal autopsy (VA) data from the DSS are also used to explore the percentage of deaths classified as HIV/AIDS-related. Two additional systematic reviews are conducted to assess whether HIV increases the risk of obstetric complications, or pregnancy accelerates HIV disease progression. Results: HIV-infected women have eight times the risk of pregnancy-related mortality compared with HIV-uninfected women. Based on this estimate, we predict that roughly a quarter of deaths in pregnant or postpartum women are attributable to HIV in sub-Saharan Africa. A lower percentage of pregnancy-related deaths are attributed to HIV/AIDS using VA data. There is little evidence that HIV-infected women are at increased risk of direct obstetric complications, with the exception of sepsis, or that pregnancy increases the risk of HIV disease progression. Conclusion: HIV may cause up to 25% of deaths during pregnancy and in the postpartum period in areas of high HIV prevalence. Most of the evidence suggests that this excess pregnancy-related mortality attributable to HIV is largely coincidental to pregnancy. This implies that there is little reason to discourage healthy, HIV-infected women from becoming pregnant if they desire to do so.

This thesis examines the various interventions proposed for the management of poor responders undergoing IVF treatment. I began by performing a systematic review and meta-analysis to identify the ideal controlled ovarian hyperstimulation (COH) regimen for women with poor ovarian response undergoing IVF. The systematic review found the evidence to be inconsistent and inconclusive. The poor responders intervention trial (PRINT) was thus conceived. PRINT is an RCT comparing the gonadotrophin releasing hormone (GnRH) agonist long versus the GnRH agonist short versus the GnRH antagonist regimens for poor responders undergoing IVF. Results of PRINT showed the GnRH agonist long regimen to be efficacious. The relationship between egg numbers and live birth following IVF is poorly understood. I set out to investigate this by examining a large cohort of IVF cycles. I was able to demonstrate a strong association between egg numbers and live birth following IVF and justify the use of egg numbers as a primary outcome for PRINT. A frequent scenario faced in the management of women who have a poor response is whether to continue with their current IVF cycle or to cancel and start again on the assumption that there could be intercycle variability. I examined this hypothesis by comparing two consecutive IVF cycles with identical COH regimens. There was no significant intercycle variability in poor responders suggesting that the more cost effective option would be to continue with the IVF cycle Over the last decade a number of studies have been published on the use of androgen supplementation in poor responders. I conducted a systematic review and meta-analysis which demonstrated potential benefit from androgen supplementation but highlighted the shortcomings in the existing evidence. Finally, I conclude my thesis by examining the evidence behind some common clinical practices in the management of poor responders with suggestions for future research.

Around 20% women of reproductive age are found to have polycystic ovaries (PCO) during ultrasound examinations and approximately 10% have symptoms of polycystic ovary syndrome (PCOS), which is associated with multiple risk factors for cardiovascular disease. The aim of this thesis was to investigate arterial mechanical properties and responsiveness to vasoactive stimuli in young women with PCOS, PCO and controls, using non-invasive ultrasound techniques. The influence of PCOS-related endocrine and metabolic perturbations on aortic function was investigated in a mifepristone-treated rat model of PCOS. The carotid artery pulsatility index was decreased in PCO and PCOS women and there was a paradoxical vasoconstrictor response to a dilator stimulus in these women relative to controls. Vascular compliance was decreased in the internal carotid artery in PCO and PCOS women PCOS women also exhibited increased intima-media thickness (IMT) of the common carotid and common femoral arteries compared with controls. In the cutaneous microcirculation, the response to the vasodilator acetylcholine (ACh) was depressed in PCOS women, whilst the response to sodium nitroprusside (SNP nitric oxide donor - NO) was unaffected. Mifepristone-treated rats exhibited increased serum luteinising hormone, testosterone, and polycystic ovaries. Ultrasound analysis indicated that aortic diameter and blood flow in vivo were unaffected in treated rats, but aortic compliance was reduced. In-vitro assessment of endothelial and vascular smooth muscle function of rat aorta demonstrated decreased relaxation with ACh, which was not abolished by L-NAME, however, the effect of SNP was greater, a finding which raises the possibility of an alternative dilator mechanism that may be independent of NO system. Since increased IMT, endothelial dysfunction and abnormal reactivity are independent risk factors for cardiovascular disease, these results also provide evidence of preclinical atherosclerotic surrogate markers in women with PCOS and PCO. These findings increase the likelihood of an association between PCOS (and probably PCO) and cardiovascular morbidity and mortality.

This thesis explores the hypothesis that stress, which is commonly experienced by patients undergoing assisted reproductive treatments, has a negative effect on. the process of conception and pregnancy. In attempting to explore possible mechanisms underpinning any such effects, several studies were conducted. A systematic review of literature exploring which psychosocial factors are associated with distress in IVF patients revealed two groups of variables, one protective against distress (which included optimism, social support, acceptance, secure attachment style, caring spouse) and the other conferring a higher risk of emotional problems (which included neuroticism, self-criticism, escapist coping strategies, controlling spouse, and insecure attachment styles). This is followed by a study exploring whether natural variance in positive and negative affect either before commencing IVF treatment or on the day of embryo transfer could predict pregnancy odds. This revealed that both male and female depression scores were associated with reduced pregnancy odds. The effects of positive emotion however were dependent on gender. Active positive emotions (in females but not males) predicted increased pregnancy odds. Relaxed positive emotion (in males but not females) predicted reduced pregnancy rates. A randomised controlled trial was also undertaken to compare the effects of two different psychological techniques for managing stress and emoti~n. Unfortunately recruitment rates were lower than expected, resulting in too small a sample size to test these intervention effects. However, the baseline data from this study were explored for relationships between implicit and explicit stress measures. This revealed two groups of interrelated variables, one that was associated with higher distress levels, and another that was associated with better emotional outcomes. These two groups of variable fit well with the findings of the systematic review. Collectively the results presented in this thesis suggest a major role of attachment style in orchestrating multiple other coping related processes, including autonomic, attentional and behavioural strategies. Several complimentary theoretical frameworks are discussed in relation to these data. Finally an intervention approach focused on reducing distress via activation of affiliative affect systems is suggested as a possible approach for IVF patients to improve psychological health.

Introduction: This Portfolio contains a journal paper for submission to the British Journal of Obstetrics and Gynecology (BJOG), an Extended Paper describing background literature, further details concerning the methodology and an analysis of themes that could not be covered in the Journal paper, followed by appendices. The author reflects on how her experiences of treatment shaped this research. Objective: To explore women's experiences of vaginismus treatment with vaginal trainers and propose draft guidelines for improving treatment. Design: Qualitative study using semi-structured interviews Setting: Recruitment through a specialist clinic, 2 gynecologists, university campus adverts and two online forums. Sample: 13 women who had used vaginal trainers for vaginismus. Methods: Individual interviews (face-to-face/ telephone/ Skype) were audiorecorded, transcribed verbatim and analysed using Thematic Analysis. Main Outcome measures: Themes concerning treatment experience and possible avenues for improvement of future treatment and Draft Guidelines. Results: Four superordinate themes: (1) Lack of Knowledge, (2) Invalidation of suffering, (3) Difficult Journey, and (4) Making the Journey Easier. The BJOG Journal paper describes (3) and (4). Difficult Journey described the sometimes long and ardous 'Journey Into Treatment', including difficulties asking for help, undergoing physical investigations and negotiating 'the system' of medical referrals. It also described the sometimes demoralising process of 'Being in Treatment', which included emotional and practical demands of treatment. Making the Journey Easier described the importance of and limits to 'Partner Support'. 'Professional Support' comprised personal qualities of professionals/ therapeutic relationship, the value of specialist skills and knowledge and the need for facilitating couple communication about vaginismus. 'Peer Support! Helping each other' described the importance of supportive vaginimus networks and sharing tips with other women. The Extended Paper describes the remaining two superordinate themes (1) and (2). Lack of Knowledge comprised lack of Public Knowledge, including the women's enthusiasm for 'Breaking the Silence' surrounding vaginismus and a sense that 'Vaginismus is not a priority' for people who have not experienced it; Lack of Personal Knowledge, which included confusion about defining the symptoms as 'normal/abnormal' which impeded help-seeking, 'seeking/finding information', 'Difficulty communicating the problem' and describing symptoms and regrets about continuing with activities that caused a 'vicious cycle' of increasing symptoms; and Lack of Professional Knowledge, which resulted in professionals having difficulty 'recognising the problem' and over-estimations of vaginal trainers as a 'simple and effective treatment'. Invalidation of Suffering comprised of Judgemental and Dismissive Attitudes, which related to 'Pop-psychologising' by professionals and the 'importance of manner' when communicating about sensitive topics and women's experience of the Impact of Vaginismus on 'self', 'relationship' and 'fertility'. Conclusions: Women seek and access treatment within a context of general ignorance about vaginismus and its treatment and can experience unhelpful and abusive reactions from professionals. When the problem is recognised, treatment quality varies. Guidelines concern earlier detection and treatment, practical and emotional support during treatment, building therapeutic relationships, dissemination of specialist knowledge and further research.

X-ray mammography is the imaging modality of choice in screening to detect breast cancer in its early stages. In recent years, film-screen systems have been replaced by various digital mammography technologies as these can deliver better performance than conventional film-screen technology. However, it remains unclear how the physical performance of such systems and the choice of their operating parameters is correlated with the ,ability to detect early breast cancer. While clinical trials are used to address this issue, they have many associated limitations such as unethical extra exposure, time consuming data collection and completion of trials. Alternatively, a simulation framework whereby suitably realistic synthetic breast cancer pathology is inserted into normal clinical mammograms to form a large database can enable a more efficient comparison of multiple systems and study of technical parameters which influence the detection task. This thesis presents a novel computational model of breast mass appearance using fractal growth which can exhibit a range of lesion appearances. Masses generated using Random Walk (RW) and Diffusion Limited Aggregation (DLA) models were inserted into raw digital 2D mammograms using a physical model of the imaging process, thus avoiding ad hoc post-processing of the final image. The simulation framework accounted for local glandularity, polychromatic X-ray spectra, image degradation caused by the imaging system acquisition process, scatter and finally processing with manufacturer's image processing software to produce realistic lesion attenuation and contrast. An ROe study of realism gave an average AUC and corresponding 95% CIs of 0.55 (0.51, 0.59) for DLA masses. This suggests that the DLA approach appears to produce a more realistic range of mass appearances compared to the RW approach, which achieved an AUC of 0.60 (0.56, 0.63). Both results demonstrate improvement compared to previously published ROe studies of realism of the simulated masses. The mass simulation models may be used subsequently as part of a tool to evaluate different breast imaging technologies (2D and 3D) and their performance in the detection task. Digital breast tomosynthesis (DBT) may have superior performance compared to 2D mammography in terms of cancer visibility, especially in dense breasts. Lesions grown using the DLA method, previously validated in 2D mammograms, were used to simulate breast masses into clinical DBT projection images. A pilot study was performed where radiologists feedback suggests that DLA masses can be successfully embedded in DBT projections and can produce visually authentic DBT images containing synthetic pathology. However, mass appearance whilst entirely satisfactory in 2D, does not always reliably infer satisfactory appearance in DBT.

This thesis investigated the role of three – dimensional transvaginal ultrasound in the identification, classification and management of uterine pathology. We performed serial measurements of fibroids over a period of time to examine their natural history. We found that fibroids tend to grow at a relatively fast average rate in pre-menopausal women, which is influenced by the initial fibroid volume and patients’ demographic characteristics. Our findings could help to rationalise the follow up and plan better the treatment of women with fibroids. Our results also provided novel insights into the possible pathogenesis of fibroids. 3D – SIS has been previously demonstrated to be equivalent to hysteroscopy to measure the degree of submucous fibroids protrusion into the endometrial cavity. However compared to hysteroscopy, 3D – SIS provides additional information including objective measurement of fibroid size and position. We evaluated these additional ultrasonic variables and identified diameter and size of the intramural portion as predictive of complete resection at a single TCRF. GnRH analogues have been given to women with submucous fibroids before transcervical resection to improve the chance of complete resection. However evidence for this practice is limited and the treatment is associated with significant side effects. We carried out a double - blind , placebo – controlled, randomized trial which did not demonstrate a benefit in the preoperative administration of GnRH analogues in women scheduled for TCRF. This thesis also investigated the role of 3D ultrasound in the diagnosis and treatment of endometrial cancer. Currently women with postmenopausal bleeding are investigated by transvaginal ultrasound to measure endometrial thickness. This results in a substantial 22 number of women needing endometrial biopsy to confirm benignity. We evaluated the ability of three 3D - PDA with objective quantification of vascularity indices to differentiate between benign and malignant lesions in women at high risk of endometrial cancer. We found that this shows promise but does not eliminate the need for biopsy. Currently women diagnosed with cancer undergo surgical staging that increases surgical morbidity. We investigated the usefulness of endometrial volume measurement in such patients to predict cancer stage which may be used in preoperative planning.

Endometriosis is the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflammatory reaction. It is a common and debilitating gynaecological condition, which may cause severe pain, significant impairment of quality of life and infertility. Non-invasive techniques to establish the presence and severity of pelvic endometriosis would be valuable to patients in a number of ways: to guide patient choice regarding treatment; to plan fertility or medical treatment; to enable referral to the most appropriate centre and surgeon if surgery is chosen; to enable pre-operative counselling; and better plan the operation including the involvement of other specialties as indicated. This thesis aims to assess: the ability of ultrasound to pre-operatively predict the presence and severity of pelvic endometriosis; the reproducibility of these findings; the benefit of tenderness mapping, symptomatology and serum CA125 measurement both on their own and in addition to ultrasound. The introduction to this thesis discusses: the pathogenesis and impact of endometriosis; the literature regarding the diagnostic tests available including MRI and ultrasound; and the usefulness of serum markers. Study one assesses the reproducibility of the assessment of severity of pelvic endometriosis by transvaginal ultrasound. Study two assesses the accuracy of the ultrasound diagnosis of the specific features of pelvic endometriosis and assesses the impact on the diagnostic accuracy of lesion location and total number of lesions. Study three assesses the ability of ultrasound to accurately assess the overall severity of pelvic endometriosis and therefore to enable preoperative triaging of patients. Study four assesses if symptoms alone or in combination with the ultrasound findings are diagnostically useful. In addition, tenderness mapping is assessed as an addition to the ultrasound findings. Lastly, in study five CA125 is assessed as a test for endometriosis on its own and as an addition to the ultrasound findings.

No description available.

Background Pelvic floor muscle exercises are a recommended first-line treatment for stress urinary incontinence (SUI) in women (NICE, 2006). Poor adherence to pelvic floor muscle exercises (PFME) is a recognised problem which has the potential to compromise successful treatment (Bø, 1995; Alewijnse et al., 2001). Biofeedback is thought to help motivate PFME practice but so far this has not been evaluated in a randomised study. Aim This study tests the hypothesis that use of clinic-based sEMG biofeedback improves women’s motivation to exercise (PFME adherence) by increasing pelvic floor muscle exercise self-efficacy, an important construct in pelvic floor muscle exercise adherence behaviour. Method After ensuring that they are able to make an informed decision to participate, a sample of sixty women referred for physiotherapy treatment of SUI between December 2008 and February 2010, gave consent to participate in the study. They were randomised into one of two groups. Thirty one women received clinic-based sEMG biofeedback in addition to the usual care, twenty nine received the usual care. Each participant attended clinic twice in a three month treatment period. Women were also asked to adhere to a daily home exercise programme (HEP). The primary outcome was pelvic floor muscle exercise self-efficacy. PFME self-efficacy and HEP adherence, were assessed by means of self-completed questionnaires. Results Ten women dropped out of the study before completion. Both groups improved on all outcomes, but no significant difference was found between the groups in terms of self-efficacy levels or exercise adherence rates. PFME recall was more accurate in the intervention group receiving clinic-based sEMG biofeedback. A positive and significant relationship was confirmed between PFME self-efficacy and PFME adherence. These findings are discussed in respect to the concept of self-efficacy and behavioural change. xi xii Conclusion In the short term, clinic-based sEMG biofeedback does not increase PFME self-efficacy or HEP practice beyond that achieved through instruction using vaginal palpation. These findings refute the belief that monitoring with sEMG biofeedback improves self-efficacy or women’s motivation to adhere to a HEP, but does suggest that biofeedback may be a useful adjunct to teaching PFME.