The central theme of the thesis is the phenomenon of cervical ripening which usually takes place during the last few weeks of pregnancy. Cervical ripening is recognised clinically by the changes which occur in the cervix, and these include softening of the tissues, progressive effacement and finally dilatation of the cervix. As these changes take place, the cervix becomes more anteriorly situated in the pelvis and the presenting part may descend. Based on these clinical criteria, a scoring system was developed which enabled an objective assessment of three central questions: 1. What mechanisms control cervical ripening? 2. What are the clinical implications of failure of cervical ripening? and 3. How may the clinical outcome for such patients be improved? The significance of an unripe cervix lies in its association with prolongation of pregnancy beyond term and vri.th increased maternal and fetal morbidity especially if labour is induced induced/by conventional methods. These problems are commoner and acre serious among primigravidae and so the research was concentrated on such patients. A major objective of the work described in this thesis was to examine how prostaglandins influenced cervical ripening and how they could be used therapeutically to improve the clinical outcome. The thesis begins with a historical review which is presented in two parts: a critical review of induction of labour, and an account of the discoverer, development and experience with prostaglandins up to the time the research was commenced. The historical review is followed by a discussion of the current understanding of the physiological control of cervical ripening. The clinical studies are then presented. By means of two studies, one retrospective and one prospective, amniotomy amniotomy/and intravenous oxytocin infusion is shown to be a satisfactory method of labour induction for primiparae who have ripe cervices before the onset of labour; in sharp contrast the two studies show that a poor response to this method of induction may be expected if the cervix is unripe at the time of amniotomy. Laboratory studies carried on in parallel with the clinical studies investigated the role of endogenous prostaglandins in parturition and cervical ripening. Prostaglandins of the E and F series were shown to increase sharply in the amniotic fluid between mid-pregnancy and term. Higher levels were found in early spontaneous labour than in than in/oxytocin induced labour at a time of greater uterine activity, and in both types of case the levels rose steeply during the active or acceleratory phase of labour. The levels of both E and F prostaglandins in amniotic fluid obtained at the time of amniotomy and oxytocin induction were found to be closely related to the degree of cervical ripeness, the uterine sensitivity to oxytocin and the length of Induced labour. The conclusions of the thesis are as follows:-1) The phenomenon of cervical ripening in late pregnancy is an essential part of the normal transition from pregnancy to spontaneous labour. 2) Failure of such ripening is an indication of an abnormality in the endocrine millieu of the pregnancy associated with impaired endogenous prostaglandin production. 3) Induction of labour by conventional means without regard to the condition of the cervix is likely to result in greater morbidity for those in whom it remains unripe. 4) The use of extra-amniotic prostaglandin therapy in such patients, either for induction of labour or for pre-induction cervical ripening, will go some way towards restoring their prospects of a satisfactory labour and delivery. Future research should be directed to further understanding of the mechanisms responsible for the spontaneous onset of labour. labour./In this way, it is hoped that new techniques will be developed which will enable more precise control of uterine activity and cervical changes so as to ensure greater safety for both mother and child.

Childbirth and obstetric factors have been linked to the subsequent development of urinary incontinence. It has been suggested that the practice of pelvic floor exercises during pregnancy may reduce the prevalence of postpartum incontinence. However little is known about current information provision about pelvic floor exercises to pregnant women and rates of practice of the exercises. Motivation of pregnant women to practise the exercises has not been examined. This study was designed to address these deficiencies and to find out if the Revised Theory of Planned Behaviour (RTPB) was applicable to the practice of pelvic floor exercises during pregnancy. A cohort of women (n = 289) attending antenatal clinics in Dundee were interviewed in the third trimester of pregnancy regarding information and practice, as well as beliefs and attitudes about pelvic floor exercises using the RTPB as a framework. A follow-up postal questionnaire was sent between 6 – 12 months after delivery (63.4% response rate). 77.9% of women reported receiving information in the current pregnancy: younger women, first-time mothers and those from more deprived backgrounds were less likely to report receiving information. Just over half the women (54.0%) reported the practice of pelvic floor exercises during pregnancy, and 83.2% of responders to the follow-up reported practising the exercises in the first month after delivery. Non-practice of the exercises in pregnancy was associated with younger age, more deprived area of residence and lower educational level, but not parity. The RTPB variables (‘attitude to the new behaviour’, ‘subjective norm’ and ‘self-efficacy’) explained 53.1% of variance in intention to practise pelvic floor exercises during pregnancy. Perceived vulnerability to incontinence (‘attitude to current behaviour’) had no relationship with intention, but this relationship may have been moderated by current behaviour. Generally women did not think postnatal incontinence was likely. Measures of past behaviour significantly improved the percentage of explained variance in intention. Confidence in ability to correctly perform the exercises (‘self-efficacy’) was significant in predicting subsequent practice. These findings will help to inform future interventions in order to encourage more women to practise pelvic floor exercises.

Uterine leiomyomas (fibroids) are common benign neoplasms arising from the smooth muscle layer of the uterus, the myometrium. Despite their prevalence in reproductive age women, little is understood of their pathobiology. The work in this thesis examined genetic and functional factors involved in the aetiology of sporadic leiomyomas, those in the hereditary leiomyomatosis and renal cell cancer syndrome, and leiomyomas from patients of African/Afro-Caribbean ethnicity, who develop more severe tumours at an earlier age. Work was carried out studying: the role of apoptosis in the tumours mutations in the FH gene and mtDNA and copy number change by microarray CGH. The findings of this work demonstrated further differences between the pathobiology of HLRCC leiomyomas, compared to sporadic lesions, particularly with regard to the mechanisms of resistance to apoptosis of each tumour type. Furthermore, germline FH mutations, which cause HLRCC, were excluded as a major cause of overall uterine leiomyoma prevalence in both sporadic cases, and in African/Afro-Caribbean women. A 1Mb resolution microarray CGH screen demonstrated a number of novel regions of copy number change, not previously reported, that may harbour novel genes involved in leiomyoma development. Furthermore, this study identified a minimal region of 7q deletion of 3.82Mb. Progressing from this, a tiling-path resolution CGH microarray specific for chromosome 7q was constructed and a number of tumours from different ethnicities were tested. This array narrowed the minimal region of deletion to 273kb on 7q22.2, a region containing 2 genes, SRPK2 and MLL5, either of which could potentially be involved in uterine leiomyoma aetiology. The results from this array also demonstrated a common overlap in the pathobiology of uterine leiomyomas from Caucasian and African/Afro-Caribbean women, who demonstrated equal frequencies of 7q deletion.

The UK has the highest incidence of teenage pregnancy in Western Europe, accounting for -7% of all births in England and Wales. Teenagers are more susceptible than adults to delivering small for gestational age (SGA) and growth restricted infants. These infants are at an increased risk of perinatal morbidity and mortality, and chronic health problems in later life. The reasons for teenagers' susceptibility to reduced fetal growth are unknown. Previous studies implicate continued maternal growth as a potential risk factor. In support of this, growing adolescent sheep deliver growth restricted fetuses due to impaired placental growth and nutrient transfer to the fetus. However, a recent prospective observational study (the About Teenage Eating Study; ATE) of 500 pregnant teenagers in the UK demonstrated that maternal growth was not detrimental to fetal growth. One third of teenagers continued to grow during pregnancy and these teenagers delivered fewer SGA (13.1 % vs. 19.5%) and more large for gestational age (10.7% vs. 4.1 %) infants than nongrowing teenagers. The birthweight profile of infants delivered to growing teenagers resembles that in a normal adult population suggesting they can overcome the inherent susceptibility for SGA birth related to young maternal age. My PhD investigated potential placental mechanisms linking maternal and fetal growth, and tested the hypothesis that differences in pregnancy outcome between growing and non-growing teenagers were associated with alterations in placental growth, development and/or function. Placentas were collected from a subset of teenagers recruited to the ATE study. The impact of maternal growth was examined on placental villous morphometry and cell turnover; expression and activity of the amino acid transporter, system A; and maternal- and placental-derived growth factors. The aim was to explore the link between maternal growth factors and placental system A activity. Maternal growth had no major effects on placental weight, morphometry or cell turnover, and thus could not explain the difference in infant birthweight between growing and non-growing teenagers. However, growing teenagers, had higher birthweightplacental weight ratios than non-growing teenagers, suggesting that they have placentas which are more efficient. To determine whether this was due to increased nutrient transport, placental system A activity was assessed. Placental system A activity was lower in teenagers than adults, when comparing those who delivered infants that were appropriately grown for gestational age (AGA). This was consistent with reduced placental mRNA expression of system A transporters, slc38a 1, 2 and 4, in AGA infants delivered to teenagers compared with adults and indicated that placental system A transport, was inherently reduced in teenagers. In contrast, placental system A activity was higher in growing compared to non-growing teenagers, and was equivalent to the levels measured in adults. This could not be explained by changes in mRNA expression of the slc38a genes, indicating up-regulation of system A in growing teenagers at the level of activity. This suggests that growing teenagers were able to overcome inherently reduced placental system A activity. To explore the potential mechanisms, maternal plasma concentrations of insulin-like growth factor (IGF)-I, previously shown to stimulate of system A activity, were compared between growing and non-growing teenagers. Higher concentrations of IGF-I were detected in growing teenagers. However, short term application of IGF-I did not stimulate system A activity in placental villous fragments in vitro. Recent studies suggest that maternal growth is beneficial, rather than detrimental, to fetal growth, and that non-growing teenagers are more susceptible to SGA births. The current study provides evidence of inherently reduced placental nutrient transfer in teenagers, which may contribute to teenagers' susceptibility to SGA births. However, growing teenagers appear able to overcome this susceptibility with increased placental nutrient transport, which may be the result of a maternal hormonal milieu that is conducive to fetal growth. These studies indicate maternal growth primarily impacts placental nutrient transport rather than development. Further studies are required to delineate the underlying mechanisms and identify potential therapeutic strategies to improve pregnancy outcome in the teenage population.

The first study investigates the effect of daily low-dose mifepristone on proliferation markers [phospho-histone H3 (pH3) mitosis marker] and steroid receptors [oestrogen receptor, progesterone receptor, androgen receptor (AR)] in the endometrium. There was a significant down-regulation in pH3 and PR expression following mifepristone treatment whereas AR expression was up-regulated. Since androgens antagonize oestrogen-effects on the endometrium, mifepristone-induced AR up-regulation could play a role in its anti-proliferative effects. The second study investigates the effects of daily low-dose mifepristone on endometrial parameters [microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR)]. The majority (15/16) of subjects were amenorrhoeic, mean oestradiol concentrations remained in the mid-proliferative range and most (9/16 subjects) endometrial samples showed proliferative histology. GR expression was induced in the nuclei of glands and surface (luminal) epithelium and there was a significant increase in micro-vessel density and decrease in stromal VEGF following treatment. Glucocorticoids can modulate angiogenesis and the high incidence of mifepristone-induced amenorrhoea may be related to change in the regulation of vascular function. The third study investigates the effects of daily low-dose mifepristone on vaginal morphology, histology, steroid receptor and Serine Leukocyte Protease Inhibitor (SLPI) content. There was no change in vaginal thickness, steroid receptor and SLPI content and distribution following mifepristone treatment. The absence of changes, in contrast to other oestrogen-free hormonal contraception, is reassuring. The fourth study investigates the effect of three single doses of mifepristone on menstrual cycle and the feasibility of timing administration as a once-month-contraceptive pill based on the length of previous menstrual cycles (calendar). It is not possible to use the calendar approach to identify the correct time of administration of mifepristone and mifepristone disrupts menstruation in a dose-dependent manner.

No description available.

Pretenn birth is the most important cause of neonatal death and morbidity, with immense costs to families and health care systems. In spite of advances in obstetric care, approximately thirteen million pretenn birth occur annually world wide. Preterm birth is multifactorial in origin, but in the last 20 years, infection has emerged as an important and frequent cause of pretenn labour and birth. The most common pathway of infection into the uterus is the ascending route from the vagina. Since infection is associated with pretenn birth and there are adverse effects from antibiotic use, it is logical to ask whether antibiotics can prevent prematurity. Do antibiotics given systemically (for example: for urinary infection or dental caries) which have the potential to alter vaginal flora, decrease the incidence of pretenn birth? To assess the effectiveness of antibiotics given for any reason to prevent pretenn labour an umbrella review was carried out to assess systematically clinical trials of antibiotics and other relevant systematic reviews. Forty five clinical trials were included in the meta-analysis. The results indicated that the use of antibiotics during pregnancy for any reason had no effect in preventing pretenn labour before 34 weeks and this is accompanied by an increase in the maternal adverse effects. Another important finding was that metronidazole may increase the risk of pretenn labour. Antibiotics were also shown to be not effective in preventing neonatal morbidity associated with prematurity. A historical review was carried out as piece of methodological work to assess the numbers and quality of randomised clinical trials. The results confirmed our hypothesis that the number and quality of randomised clinical trials of antibiotics during pregnancy improved since the sixties. Probiotics may be a potential preventitive treatment for preterm labour. Normal vaginal flora is dominated by Lactobacilli which is associated with reduced risk of bacterial vaginosis and urinary tract infection. Probiotics consist of live Lactobacilli that are freeze dried with or with out sugar. Probiotic Lactobacilli displace bacteria, block pathogen attachment to vaginal epithelium and produce bacteriocins which inhibit pathogen multiplication. More importantly, lactobacilli produce hydrogen peroxide which maintains vaginal acidity - an unfavourable environment for pathogens. Probiotics have been shown to modulate the immune response by interfering with the inflammatory cascade that leads to preterm labour and birth. The administration of probiotics has been shown to be safe and effective in reducing and treating urogenital infections in non-pregnant populations. It is logical to ask whether probiotic therapy can restore the normal flora and may decrease the incidence of preterm birth? To assess probiotic's effectiveness and safety for preventing preterm labour and birth a Cochrane review was conducted. Four trials were assessed for inclusion in the review. One trial started in February 2005 and is still ongoing. One trial was excluded because there were no data to be extracted from the article. Of the two trials included in the review, one enrolled women after 34 weeks of pregnancy using oral fermented milk as probiotic, while the other study utilised commercially available yogurt to be used vaginally by women diagnosed with bacterial vaginosis in early pregnancy. Reduction in genital infection was the only prespecified clinical outcome for which the data were available. Results of this review showed that although the use of probiotics appears to treat vaginal infections in pregnancy, there are currently insufficient data from trials to assess impact on preterm birth and its complications. Given the lack of evidence highlighted in the Cochrane review, there was a compelling case to conduct a randomised controlled trial to test whether probiotics are effective in preventing preterm labour and birth or not. An exploratory trial was to be an important part of this thesis. A trial protocol was prepared but it was not approved by the MHRA. MHRA authorisation was refused because probiotics are licensed as food supplements and only medicinal products can be used in clinical trials. Given the failure to get MHRA approval, a decision was taken to perform an exploratory study to investigate if cervical immunology and morphology would better refme high risk status for future clinical trials. The hypothesis behind this cervix study is that a defective cervical barrier is a major cause of preterm labour. This hypothesis was assessed immunologically by using flow cytometry to quantity leucocytes subpopulation in the cervix, morphologically by cervical length and volume as assessed by 3D ultrasound, and the cervical blood circulation was assessed by 3D ultrasound with power Doppler in patients at high risk of preterm labour. Immunologically, the most prevalent cervical leukocyte was the macrophage. Macrophages and the rest of leukocyte types in general were fewer in high risk patients than in normal pregnant controls, but this difference did not reach statistical significance. This could be due to the sample size. Or this could be due to the collection of the cervical samples very early in pregnancy. The influx of leukocytes is expected later in pregnancy or at the time of cervical ripening prior to labour. Morphologically, this study showed a significant association between cervical length and preterm labour, but not cervical volume. This could be due to the sample size or due to the difficulty of estimating cervical volume. Also, there is increase in the vascularisation of the cervix in preterm labour patients and this could be due to the small sample size, difficulty of defining the cervix landmarks or premature remodelling of cervical architecture since all these women had previous histories of preterm labour.

No description available.

No description available.

No description available.