This thesis examines the underlying mechanisms of how in utero growth restriction (IUGR), followed by postnatal catch-up growth, predisposes the offspring to accelerated renal ageing. Advanced renal ageing following in utero nutritional deprivation has been indicated in large population cohort studies, such as the Dutch Hunger Winter or the Leningrad Siege. To address potential mechanisms contributing to accelerated renal ageing, an established rodent model was used in which IUGR is achieved by dietary protein restriction in pregnant Wistar rats. An enhanced nutritional plane after IUGR has been shown to be particularly detrimental to offspring metabolism. To enhance post-natal overfeeding, the offspring were suckled by control dams and also reduced to 4 (males) per litter known as recuperated animals). To investigate the potential role of hypertension and vascular dysfunction, blood pressure was measured in vivo in 3 month old offspring, using radio telemetry, and vascular function was assessed in renal and peripheral resistance arteries in vitro on a wire myograph. No differences between control and recuperated groups were found although control blood pressure was higher and endothelium dependent relaxation impaired compared to historic controls. There was no evidence of enhanced sympathetic activation in the recuperated group. As mitochondrial dysfunction has previously been implicated, renal mitochondrial function in 3 month old animals we determined whether dietary supplementation coenzyme Q10 (CoQ) could restore renal mitochondrial function, however CoQ had a detrimental effect and did not restore activity. Renal function was assessed by measuring proteinuria, creatinine clearance and plasma renin. Renal morphology and inflammation were assessed by electron microscopy, ED-1, CD-3 and a periodic acid schiff (PAS) stain. There were no signs of early programmed differences in renal function. Enhanced renin gene and protein expression in recuperated animals at 3 months did suggest alterations in renin-angiotensin system (RAS) activity. Accelerated renal ageing in offspring of IUGR rats followed by catch up growth is not due to raised blood pressure or vascular dysfunction and is not reversible with an antioxidant strategy at 3 months of age.

Human parturition is a tightly controlled process, but for some women, aberrations in this timing give rise to dysfunctional labour, including preterm birth and dystocia; such complications are associated with increased risk of neonatal mortality and morbidity. Current management strategies are limited in their effectiveness, requiring further understanding of the pathways governing uterine activity. The KV7 subfamily of voltage-gated potassium channels, composed of KCNQ- and KCNE-encoded subunits, are key regulators of smooth muscle cell membrane excitability in a range of tissues, but their role in uterine contractions has yet to be fully explored. The working hypothesis was that KV7 channels are expressed and functionally active in myometrial tissue at the end of gestation and during labour (term and preterm), and that KV7 channel activators can inhibit myometrial contractility in vivo sufficiently to delay preterm labour. Expression of KCNQ1-5 and KCNE1-5 mRNA and protein was analysed in myometrium from pregnant women before and after the onset of labour. The functional contribution of KV7 channels at term was also investigated. A murine model of RU486-induced preterm labour was used to characterise KV7 subunit expression and investigate the in vivo effectiveness of KV7 activators as tocolytics for the treatment of preterm labour. Protein and mRNA for KCNQ4, KCNE3 were downregulated, while KCNQ3 was increased, after the onset of labour (p<0.05 for all). Application of Kv7 activator and blockers decreased and increased ex vivo myometrial contractility respectively (p<0.05 for all). In preterm murine myometrium, KCNQ4, KCNQ5, KCNE1 and KCNE2 were downregulated during preterm labour (p<0.05 for all). KV7 activators, retigabine and ML213, decreased myometrial activity in vitro and significantly delayed the onset of preterm labour in vivo (p<0.05 for both). These novel data provide proof of concept that KV7 channels can be targeted for tocolysis. Together with a better understanding of the KV7 channel composition in human myometrium, this study is the first step in translation to the human condition of preterm labour.

No description available.

No description available.

Pre-eclampsia is a serious condition that occurs during pregnancy, which can lead to significant maternal and neonatal morbidity and mortality. Women with type 1 diabetes are at high risk of developing pre-eclampsia. The aim of this thesis was to explicate the acceptability of a screening test for pre-eclampsia and to identify potential biomarkers for predicting pre-eclampsia in women with type 1 diabetes. A number of approaches were used. Firstly, a qualitative study, consisting of interviews and questionnaires, was conducted to gain insight into women’s views on the potential introduction of a pre-eclampsia screening test. Secondly, statistical analysis was conducted on the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) cohort to assess the impact that pregnancy intention has on a number of pregnancy outcomes, including pre-eclampsia. Thirdly, a systematic review was conducted to identify biomarkers that may be of benefit to measure in the DAPIT cohort to predict pre-eclampsia. Finally, two biomarkers were measured in the cohort to assess their potential. Qualitative findings indicated that women wanted to know their risk of developing pre-eclampsia and were generally accepting of the introduction of screening test for the disease. There was no significant association between pregnancy intention and risk of pre-eclampsia. However, women with unplanned pregnancies were more likely to have a baby who needed to be admitted to the neonatal intensive care unit, a baby with a birth weight <5th centile, and to have a longer stay in hospital. The systematic review identified no potentially useful biomarkers suitable for measurement in DAPIT. After consulting existing literature, Fatty Acid Binding Protein 4 (FABP4) and vitamin D (25OHD) were identified to be measured. FABP4 was significantly associated with the development of pre-eclampsia when measured in the first and second trimester. FABP4 also demonstrated some promise as a predictor of pre-eclampsia. Vitamin D was not associated with pre-eclampsia, but was associated with a number of other adverse pregnancy outcomes, including neonatal respiratory problems and small for gestational age (SGA). In conclusion, women should be encouraged to plan their pregnancies to minimise the risk of adverse outcomes. While a screening test for pre-eclampsia would be acceptable to women, further research is needed to identify the optimal screening tool for the prediction in women with type 1 diabetes.

Preterm birth is a persistent and expensive global health problem accounting for almost 8% of all live births in the UK. There are some effective interventions available however, due to the heterogeneous nature of the condition; it is still difficult to tailor the correct management for each woman. A major obstacle to the development of effective treatment strategies is a limited understanding of the molecular events preceding preterm labour. Using SCOPE, a prospectively acquired global cohort, this MD investigated the three areas of clinical risk factors, biomarker discovery using proteomic technology and directed candidate cytokine analysis. Clinical risk factor algorithms have been developed with the most clinically relevant group, those delivering less than 34 weeks, exhibiting the best predictive performance. The algorithm has an area under the ROC curve of 0.74, negative predictive value of 99%, with a positive predictive value of 33%. This is likely to be indicative of the best performance achievable using clinical data to predict preterm birth in a healthy nulliparous population. A proteomic discovery study was performed comparing term and preterm birth. The proteins that were discovered appeared to be mainly plasma proteins related to systemic inflammation and therefore were not specific enough as predictors of spontaneous preterm birth. As there is strong evidence to support a role for cytokines in the initiation of inflammation/infection-induced preterm labour, a panel of 27 were assessed as predictive markers for preterm birth. Of these, five cytokines (IL-4, IFN-γ, IL-6, IL-17α and MIP-1α) appeared to be the most sensitive with a predictive accuracy of 71.25%. The data from this thesis have provided further understanding into preterm birth and provides a pathway for future investigation into the prediction and prevention of spontaneous preterm birth.

No description available.

No description available.

Pregnancy is a major physiological stress of the cardiovascular system. Weight gain significantly contributes to physical limitations. This thesis examines the effects on both physical and cardiac performance of weight gain in pregnancy. Utilising cardiac power output at rest and maximal exercise, I measured the effects of (i) inert weight loading (ii) pregnancy and (iii) obesity in the non-pregnant state, to determine the acute, chronic and also reversible changes. Weight loading using a pregnancy simulator suit (“Empathy Belly”) showed reduced physical performance, whilst showing an improvement in cardiac performance, predominantly by increasing the pressure generating capacity of the heart. Additional load carriage with the “Empathy Belly” and a rucksack, showed further reduction in physical performance, but no further improvement in cardiac performance. Pregnancy revealed significant reductions in physical performance and maintenance in cardiac performance compared to the non-pregnant post-partum. Contrary to this, there were significant reductions in both physical and cardiac performance in pregnancy, compared to pre-conception. Changes in cardiac performance throughout pregnancy gradually improved, whilst there was a deterioration in overall physical performance. Obesity in the non-pregnant state, showed significant reduction in physical performance with a marked increase in cardiac performance. This was primarily driven by an increase in the flow generating capacity of the heart; the cardiac output. Inert weight loading, weight carriage in pregnancy and non-physiological weight gain in obesity in the non-pregnant state, all reduce physical performance. In contrast to this, both inert weight carriage and weight carriage in obesity increase cardiac performance. Acute weight loading induces an increase in pressure generating capacity, whilst chronic weight carriage leads to an increase in flow generating capacity. For the first time, I have shown that peak cardiac performance reduces in pregnancy from pre-conception, although this gradually improves throughout pregnancy and is likely to be in part caused by an increase in weight gain.

Iron is an important micronutrient essential in carrying oxygen and maintaining the function of many body enzymes. It is of particular importance during gestation as body demands increase leading to iron deficiency in women with inadequate iron stores at the start of pregnancy. Animal studies have shown that iron deficiency in pregnancy leads to offspring with adverse cardiovascular risk profiles compared to offspring of iron replete mothers. This thesis aimed to examine the association of maternal iron intake and status in pregnancy with short and long term birth outcomes that are considered cardiovascular risk indicators later in life. Analysis of data from three cohorts and one Mendelian randomisation study was included in this thesis. Total maternal iron intake in early, but not late, pregnancy was positively associated with birth size. There was no evidence of association between taking iron-containing supplements in pregnancy and size at birth. However, taking multivitamin-mineral supplements, which contain iron, in late pregnancy was associated with an increased risk of preterm birth. Also taking iron supplements up to 32 weeks gestation was associated with lower offspring systolic blood pressure at 10 years. Maternal iron deficiency and anaemia in early pregnancy were associated with an increased risk of giving birth to a SGA baby. Infant brachio-femoral PWV measured at 2-6 weeks of age was found to be higher in women who were anaemic in early pregnancy, but not in those who were only iron deficient. Finally, using a Mendelian randomisation design, maternal iron status measured by serum ferritin with C282Y mutation as an instrumental variable, was not found to be associated with adult offspring BP and adiposity. In conclusion, maternal iron intake and status in early pregnancy seem to be associated with short term birth outcomes like size at birth, while associations with long term offspring cardiovascular indicators were not detected in this thesis.