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No description available.

No description available.

Recurrent miscarriage is the loss of three or more consecutive pregnancies before 24 weeks gestation and affects up to 1% of women. Until recently there has been a paucity of research into the psychological impact of this experience, and the available research has tended to almost exclusively focus on the incidence and nature of maternal distress and wellbeing. Yet the research on the psychological impact of a single miscarriage suggests that the experience of recurrent miscarriage is likely to affect both partners as individuals and as a couple. The aim of the current study was to address the gap in the literature by carrying out a quantitative cross-sectional examination of the psychological, dyadic and sexual functioning in a sample of 80 couples attending the Recurrent Miscarriage Clinic (RMC) for their first appointment. Measures administered included an assessment of distress using the HADS, an assessment of coping strategies using the COPE, an assessment of couple adjustment using the DAS, and an assessment of sexual functioning using the GRISS. In addition, social support was assessed using the SOS, and the couple's investment in the roles and goals in their life, including becoming a parent, was assessed utilising the RAG. Following the social cognitive and family life cycle models, it was proposed that partners who had relatively over-invested in becoming parents, in comparison with other roles and goals, would be most vulnerable to emotional distress and dyadic/sexual dysfunction, and would be most likely to use inadequate coping. These hypotheses were not supported by the data. However as predicted, dyadic adjustment and avoidance coping were found to be significantly related to emotional distress in both men and women. Furthermore, female emotion- focused coping was significantly related to female anxiety. After controlling for dyadic adjustment, the only type of coping independently associated with emotional distress was female emotion-focused coping in relation to female anxiety. After controlling for coping, dyadic adjustment continued to be a predictor of male anxiety and depression and female anxiety, but not depression. Contrary to predictions sexual functioning was not associated with emotional distress and although social support was found to have a significant independent relationship with female depression, this relationship was no longer significant once other variables were controlled for. The results are discussed in light of clinical implications and with consideration of qualitative feedback also collected from participants.

Late gestation and labour is associated with inflammatory changes in the myometrium that include an increase in neutrophil and monocyte numbers. The mechanisms regulating altered leukocyte dynamics in pregnancy are not well understood, but may be critical in identifying novel targets for the prevention of preterm labour (PTL). PTL is defined as the onset of labour prior to 37 weeks gestation and often results in preterm birth (PTB). Here we investigated local and systemic leukocyte trafficking during late gestation and labour, focussing on the pro-inflammatory Ly-6Chigh monocyte subpopulation in mouse models of normal, preterm and delayed labour. Using flow cytometry and in vivo cell labelling methods, we demonstrated for the first time that blood-derived Ly-6Chigh monocyte densities increase in the myometrium prior to labour onset. Increases were also observed in the pools of intravascular, lung-marginated Ly-6Chigh monocytes and neutrophils during late gestation, which although not mirrored in the circulation is indicative of a systemic inflammatory response. Using exogenous progesterone supplementation and a progesterone receptor antagonist, we demonstrated that progesterone controls Ly-6Chigh monocyte cell densities within the myometrium, with rapid increases following its functional withdrawal. In a mouse model of infection-induced PTL by laparotomy and intrauterine LPS injection, we unexpectedly found that inflammatory leukocyte migration to the myometrium was low pre- labour. Levels of cytokines and chemokines, including the monocyte chemoattractant CCL2, were high in the myometrium, but also systemically in plasma and organ tissue, indicating a significant systemic inflammatory response. In the surgical controls, in which labour was delayed, there were substantial increases in Ly-6Chigh monocytes in the myometrium, which were shown using knockout mice to be CCR2-dependent. Taken together, our data indicate that both local and systemic inflammation play important roles in labour. Despite consistent observations of Ly-6Chigh monocyte infiltration into the myometrium, there was a lack of clear evidence supporting their role in labour, suggesting their late-gestation myometrium infiltration is more relevant to post-partum uterine repair and remodelling.

Prokineticin-1 (PK-1) and prokineticin-2 (PK-2) are two closely related cysteine-rich peptides which both bind to the prokineticin-1 and prokineticin-2 receptors (PKR-1 and PKR-2). The prokineticins were originally named due to their ability to stimulate gastrointestinal motility. Since that time, these peptides have been found to play a role in other biological processes including reproduction and nociception. Prokineticin-2 is known to be expressed in regions of the central nervous system involved in food intake. Consistent with this, work from our own department has shown that administration of prokineticin-2 to rodents reduces food intake both in lean and obese rodents. Prokineticin-2 is predominantly expressed within the central nervous system, whereas prokineticin-1 is heavily expressed in the gut. My pilot data showed that prokineticin 1 reduces food intake in rodents. I therefore hypothesised that prokineticin 1 may be a novel gut hormone. In this thesis, I investigate the role of prokineticin-1 on appetite in rodents and also compare the effects of prokineticin-1 with prokineticin-2. I also measured the changes in plasma levels of prokineticin in humans during feeding to establish the potential physiological relevance of prokineticin-1 as an anorectic gut hormone. Prokineticin-1 is also a potent angiogenic mitogen on endocrine vascular epithelium and hence it is also known as 'Endocrine Gland-Vascular Endothelial Factor'. Placental angiogenesis plays an important role in placental function and risk of pregnancy complications such as miscarriage. I therefore hypothesised that prokineticin-1 is a biomarker of pregnancy complications in humans. In this thesis, I have measured circulating levels of prokineticin-1 found in pregnancy and correlated these with the occurrence of pregnancy complications. I have also compared the utility of prokineticin 1 with other potential novel markers of pregnancy complications. Together this body of work investigates the potential physiological roles of prokineticin-1.

Pregnancy is a complex biological condition associated with profound changes in the metabolism of the mother, essential for the growth and development of the fetoplacental unit. We aimed to study molecular pathways that contribute to the gestational alterations in lipid metabolism. The data in this report show that adaptations in lipid homeostasis during mouse pregnancy include raised hepatic cholesterol content, decreased levels of circulating cholesterol and elevated serum triglycerides. Moreover, LXR signalling contributes to the enhanced lipogenesis in early mouse pregnancy by increasing fatty acid biosynthesis in the liver. There is a gradual down-regulation of LXR targets involved in hepatic lipogenesis, cholesterol uptake and clearance following mouse placenta formation. Pharmacological activation of LXR not only blunted the reduction of these genes but also reversed the changes in hepatic and serum lipid profiles observed during normal murine pregnancy. Our results strongly suggest that LXR signalling is altered during mouse pregnancy and this is an essential adaptation to facilitate altered maternal lipid homeostasis. Investigations were performed to establish whether maternal metabolic adaptations in energy homeostasis result from altered diurnal fluctuations in peripheral metabolic pathways. We show that pregnancy alters the activity of core clocks in liver, white adipose tissue and skeletal muscle. Early and advanced pregnancy changes the diurnal fluctuations in the expression of key metabolic genes in the liver in order to enhance or dampen lipogenesis respectively during these gestational periods. We present preliminary data suggesting that the temporal oscillations in bile acid metabolism are shifted during pregnancy independently of feeding patterns. Moreover, fatty acid homeostasis in skeletal muscle is changed during early pregnancy possibly as a consequence of the REV-ERBβ-dependent downregulation of Cpt1β-mediated lipid oxidation. Also, placenta lipid homeostasis exhibits robust temporal oscillations so that pathways mediating fatty acid and cholesterol transport as well as triglyceride hydrolysis become activated during the dark phase. Subcutaneous and visceral white adipose tissue depots were examined to determine whether metabolic pathways in these tissues are differentially regulated during non-complicated pregnancy and gestational cholestasis. We show evidence that although both of these depots expand in the course of gestation in order accommodate triglyceride accrual, subcutaneous fat develops a pro-inflammatory phenotype whereas visceral fat remains quiescent. Feeding of pregnant mice with a cholic acid-supplemented diet raises their serum triglyceride and free fatty acid levels and reduces adipose tissue lipogenesis. Gestational cholestasis also decreases white fat inflammation in a depot-specific manner and interferes with adipose tissue remodelling and expansion. We concluded that failure of fat to grow and store surplus lipids that normally accrue during pregnancy could contribute to the development of cholestatic dyslipidaemia.

The aims of this thesis are firstly, to establish reference ranges of serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and free thryroxin (FT4) at 11-13 weeks’ gestation in singleton and twin pregnancies and to examine the effect of maternal characteristics and serum antithyroid antibodies and free ß-hCG on the levels of TSH, FT3 and FT4, and secondly to investigate the possible association between maternal thyroid dysfunction in pregnancies complicated by fetal death, preeclampsia (PE), delivery of small for gestational age (SGA) neonates, preterm delivery and fetal aneuploidies. The study population was derived from a prospective screening study for adverse obstetric outcomes in 4,852 women attending for their routine first hospital visit in pregnancy at 11+0-13+6 weeks’ gestation. In some of the pregnancy complication groups, we identified additional cases that were examined after screening period. Serum concentrations of FT3, FT4, TSH, anti-TPO and anti-Tg were measured by immunoassay using direct, chemiluminometric technology. In normal pregnancy (n=4318), TSH increased whereas FT3 and FT4 decreased with gestation and all three were lower in Afro-Caribbean than in Caucasian women. Serum FT3 and FT4 decreased, but TSH did not change significantly with maternal age, TSH and FT3 increased whereas FT4 decreased with body mass index, TSH decreased whereas FT3 and FT4 increased with serum free ß-hCG. In the antibody positive group, compared to the negative group, median TSH was higher and median FT3 and FT4 were lower. In 45% of women with known hypothyroidism (n=164) diagnosed before pregnancy and receiving levothyroxine at least one of the three biochemical tests was suggestive of persistent hypothyroidism. In pregnancies resulting in miscarriage or fetal death (n=202), the median serum TSH was increased and FT4 was decreased. In pregnancies that developed PE (n=102), there was evidence of hypothyroidism and increased serum TSH was observed in 5 times as many cases with PE compared with those who did not develop PE. In pregnancies delivering SGA neonates (n=212) and in those ending in spontaneous early preterm delivery (n=102) maternal thyroid function was not significantly different from pregnancies with normal outcome. In pregnancies with fetal trisomy 21 (n=30) free ß-hCG was increased and TSH was decreased and in cases with trisomy 18 (n=25) free ß-hCG was decreased and TSH was increased. In normal twin pregnancies (n=235), compared to singletons, serum FT4 was not significantly different but TSH was about 40% lower. The levels of serum TSH and FT4 were similar in dichorionic and monochorionic twins, with or without twin-to-twin transfusion syndrome (n=19) and there were no significant differences between the three groups in serum free ß-hCG. The thesis established reference ranges of maternal thyroid function in early pregnancy and demonstrated altered function in association with certain pregnancy complications.

Background: The current approach to prenatal care, which was established more than 80 years ago, is characterised by a high concentration of visits in the third-trimester of pregnancy which implies that firstly, most complications occur at this late stage of pregnancy and secondly, most adverse outcomes are unpredictable during the first or even the second trimester. Objectives: The objective of this thesis is to provide evidence that most pregnancy complications are predictable as early as 12 weeks’ gestation. The pregnancy complications examined include fetal aneuploidies, fetal structural defects, preeclampsia, preterm birth, gestational diabetes mellitus and fetal macrosomia. Methods: I have critically examined fourteen articles reporting on screening for pregnancy complications at 11-13 weeks’ gestation, where more than 90,000 singleton pregnancies were prospectively assessed at 11-13 weeks’ gestation as part of a routine prenatal visit for screening for trisomy 21. We recorded a series of maternal characteristics and history, measured maternal weight and height, performed a detailed ultrasound examination of the fetus, measured maternal uterine artery Doppler pulsatility index and maternal mean arterial pressure and collected blood for analysis of biomarkers for prospective or retrospective analysis. All data were prospectively entered into our data base as well as the pregnancy outcomes as soon as they became available. Ethical approval was obtained for these studies. Multivariate regression analysis was used to define the contribution of each maternal characteristic and history in predicting each adverse outcome and those with a significant contribution formed an algorithm to estimate the background risk (a priori risk) for each one of these complications. The potential value of biophysical and biochemical markers in improving the performance of the a priori risk in predicting adverse pregnancy outcomes, was evaluated. Results: First trimester effective screening for adverse pregnancy outcomes was provided by a combination of maternal factors and biophysical or biochemical markers. The developed predictive models could correctly identify the vast majority of aneuploidies, early preeclampsia and more than half of the cases of spontaneous preterm birth and gestational diabetes. First trimester prediction of fetal macrosomia was less effective compared with other complications. First trimester examination of fetal anatomy was feasible resulting in a high detection of fetal non-chromosomal defects, including more than half of fetal cardiac defects. Conclusions: Assessment of the mother and fetus at 11-13 weeks’ gestation can provide effective early identification of the high risk group of pregnancies with fetal and maternal adverse outcomes.

Introduction: Abnormal fetal growth remains a major problem in pregnancies complicated by diabetes and is associated with increased maternal and offspring mortality and morbidity. Insulin-like growth factors (IGFs) stimulate fetal growth while their effects are inhibited by binding proteins (IGFBPs). IGFBP-1 is a significant IGFBP in maternal and fetal circulation and the only binding protein acutely affected by glucoregulatory hormones; as such, IGFBP-1 is particularly important in pregnancy with diabetes. In plasma of healthy human adults, the fully phosphorylated (pIGFBP-1) isoform is predominant. During pregnancy the phosphorylation status of IGFBP-1 changes; in addition to pIGFBP-1, non-phosphorylated (np) IGFBP-1 and 3 lesser phosphorylated (lp) IGFBP-1 variants with lower affinity for IGF-I are detected in the maternal circulation. The change in the phosphorylation status of IGFBP-1 in pregnancy may provide a physiological mechanism for the increased IGF-I bioavailability at the maternal/fetal interface required for placental and fetal growth.Hypothesis: IGFBP-1 de-phosphorylation occurs at the maternal/fetal interface and this process is catalyzed by placental alkaline phosphatase (PLAP). Fetal overgrowth (macrosomia) in pregnancy with diabetes may be a consequence of elevated IGF-I action at the placenta secondary to increased PLAP activity.Methods and Results: In vitro: Explants of human term placentas from normal pregnancies (n=5), or their conditioned media (CM), were incubated with pIGFBP-1 in the presence or absence of an anti-PLAP function blocking antibody. Addition of pIGFBP-1 to explants resulted in its binding to the tissue and de-phosphorylation, with npIGFBP-1 isoforms appearing in the medium. pIGFBP-1 was not de-phosphorylated when cultures were carried out in the presence of anti-PLAP antibody. In solution phase assays, PLAP failed to de-phosphorylate pIGFBP-1. Thus, placenta de-phosphorylates IGFBP-1 as a result of PLAP activity, and this requires its binding to the tissue.To investigate factors which may affect the activity of PLAP, placental explants (n=3 for each series of experiments) were incubated with pIGFBP-1 in the presence of insulin, IGF-I/-II or under hyperglycemic or hypoxic conditions. Following incubation, the phosphorylation status of IGFBP-1 present in placental-CM was assessed by native electrophoresis and western blot. PLAP-mediated IGFBP-1 de-phosphorylation was not affected in vitro by hyperglycemia, hypoxia, insulin or IGF-I/-II. In vivo: 30 patients with any type of diabetes in pregnancy and 20 controls were recruited. Maternal/cord blood was collected at term and analysed for IGF-I/-II, total IGFBP-1 and the phosphorylation status of IGFBP-1. Placentas were analysed for PLAP expression and activity. The maternal blood levels of both IGFs and total IGFBP-1 were similar in the diabetes and control groups, while cord IGF-II was elevated in diabetes. Unexpectedly, the p/npIGFBP-1 ratio in maternal serum was elevated in patients with diabetes, which may be a result of decreased IGFBP-1 de-phosphorylation. In controls, maternal p/npIGFBP-1 ratio correlated with infant weight, whilst this correlation was not demonstrated in women with diabetes. Placental PLAP expression/ex-vivo activity and total IGFBP-1 levels in maternal serum were unaltered in diabetes and did not relate to fetal growth in either diabetes or control groups. Conclusions: The hypothesis that activated PLAP and therefore enhanced IGFBP-1 de-phosphorylation may increase the effect of IGF-I on placental cell turnover and accelerate fetal growth in diabetes was not supported by the results of this study. Further work is required to reveal mechanisms by which the maternal/placental/fetal IGF-IGFBP-PLAP pathways modulate fetal growth in normal and compromised pregnancy.