Hypertensive disorders of pregnancy are an increasingly common disorder in modern society. The increasing prevalence of women with pre-eclampsia superimposed on a background of chronic hypertension is a significant burden in modern society and is profoundly detrimental to both mother and child; during pregnancy and beyond. Little is understood about the development of these multifactorial hypertensive disorders, however there is increasing evidence that the manifestation of hypertensive disorders during pregnancy is not solely due to placental-derived dysfunctions and has important maternally-driven components. The stroke-prone spontaneously hypertensive (SHRSP) rat is a well-established model of human essential hypertension. SHRSP dams remain hypertensive throughout pregnancy and demonstrate an abnormal uterine artery structure and function at term. This project aimed to more fully characterise pregnancy in the SHRSP rat. The objectives were to assess maternal responses and determine how maternal hypertension impacts maternal and fetal well-being as well as placental development; to investigate the underlying genetic mechanisms behind the eventual abnormal pregnancy-dependent uterine artery remodelling; and, finally, to increase the maternal cardiovascular load in SHRSP pregnancy to establish a model of superimposed pre-eclampsia. In vivo and ex vivo techniques were used to characterise cardiovascular function in the hypertensive SHRSP and normotensive WKY rats during gestation, as well as assess pregnancy outcomes. The SHRSP dams were found to have similar cardiac function compared to WKY, yet there was evidence of impaired systemic vascular structure and function in late gestation and placental abnormalities. Nevertheless, the SHRSP maintained similar litter sizes to WKY and did not demonstrate any major impact on fetal growth. Further similarities between SHRSP and WKY pregnancy were revealed with the assessment of uterine artery function in early gestation. However, using RNA sequencing to elucidate the transcriptomic profiles of the uterine arteries, SHRSP were found to have strikingly different responses to pregnancy at the transcript expression level, compared to WKY. Finally, a model of superimposed pre-eclampsia was established by increasing the cardiovascular stress in the dam using angiotensin II infusion during pregnancy in SHRSP. This model had a significantly higher systolic and diastolic blood pressure than the already hypertensive SHRSP. The pregnancy-dependent increase in cardiac output, observed in SHRSP, was negated by AngII infusion and was reduced in the highest treatment group. These major cardiovascular impairments were observed alongside increased proteinuria and reduced fetal growth; all phenotypes found in severely pre-eclamptic women. This work has provided information on systemic and uterine specific vascular responses to pregnancy in SHRSP and WKY rats alongside detail of underlying transcriptional differences. This study was the first to examine uterine artery gene expression changes during pregnancy. The different transcriptomic profiles of early pregnancy changes in the two strains make this an intriguing model to study maternal-driven vascular remodelling in hypertensive pregnancy. Furthermore, this work demonstrated that increasing the cardiovascular load during pregnancy in SHRSP successfully mimics superimposed pre-eclamptic phenotypes and could be used in the assessment of novel therapeutic strategies. To conclude, the SHRSP has the potential to aid our understanding of human pre-eclamptic conditions, especially when endeavouring to determine the impact of maternally-driven components of hypertensive disorders of pregnancy.

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Objective To undertake Health Technology Assessment (HTA) in maternal and perinatal medicine for tests and treatment in the areas of pre eclampsia, preterm labour, epilepsy and congenital heart disease (CHD) in newborn. Methods The work undertaken in the thesis is divided into 4 sections: Delphi survey of practice; Systematic review of reviews; Systematic reviews of therapeutic effectiveness; Systematic reviews of test accuracy Results The Delphi survey identified blood pressure to be the best predictor of complications. A significant benefit of progestational agents was observed in reducing preterm delivery before 37 weeks (OR 0.42, 95% CI 0.31 to 0.57). The combined rate of seizure deterioration was 0.40 (95% CI 0.26 to 0.55) in pregnant women with epilepsy on lamotrigine dosage based on serum levels compared to 0.73 (95% CI 0.56 to 0.86) in those managed by clinical features only. The abstracts of 19,500 citations were reviewed to identify the studies of accuracy of tests in pre eclampsia including proteinuria, uric acid, liver function tests, symptoms and blood pressure. The sensitivity and specificity were 0.63 (95% CI 0.39, 83) and 0.998% (95% CI, 0.99, 100) respectively for detecting CHD in the newborn by pulse oximetry. Conclusion Through the HTA of tests and treatment in priority areas of maternal and perinatal medicine, the thesis has led to the generation of clinical recommendation where there was clear evidence of benefit and for further research where there were gaps in evidence.

The mechanisms by which immune tolerance is maintained during human pregnancy are unclear but include a range of modifications to the local and systemic maternal immune system. There is considerable T cell infiltration of the maternal decidua during pregnancy, however, the functional properties of this T cell response remains poorly defined. We investigated the specificity and regulation of CD4+ and CDS+ T cells in human third trimester decidua and show that the ratio of highly differentiated effector to naive CD4+ and CDS+ T cells is increased markedly in comparison to peripheral blood. Decidual T cells were also found to display a unique functional profile with simultaneous production of interferon-y (IFN -y) and interleukin 4 (IL-4 ). Decidual T cells proliferated in response to fetal tissue, a function that was regulated by T regulatory cells, and HY -specific T cells with high levels ofProgrammed Death Protein 1 (PD-1) were detectable in the decidua of women with male pregnancies. Transcriptional analysis of CD4+ and CDS+ decidual T cells revealed a unique gene profile characterized by elevated expression of proteins associated with the response to interferon signaling. These data have considerable importance for the investigation of fetal-specific alloreactive immune responses within disorders of pregnancy.

The purpose of this project was to highlight an intervention to increase breastfeeding initiation and exclusive breastfeeding during the birth hospitalization in a coastal mid-Atlantic inner city hospital. Although researchers and national standards promote early initiation and exclusive breastfeeding, there continues to be a significant number of women who do not breastfeed and/or supplement with formula. The advantages of breastfeeding for mother and infant are substantial and include protecting babies from allergens to reducing maternal breast and ovarian cancer. Breastfeeding rates of initiation and exclusivity at the project hospital were below benchmarks set by international, national, and state agencies. The project intervention utilized bedside RNs who were educated and trained by the Perinatal Unit Clinical Nurse Specialist and the unit lactation counselors on bedside lactation support. The educational intervention capitalized on Dennis's theory of breast-feeding self-efficacy, which emphasizes maternal confidence in breastfeeding success. A convenience sample of breastfeeding rates of initiation and exclusivity from one month's delivered mothers pre-intervention (n = 203) compared to one month's breastfeeding rates of delivered mothers post-intervention (n = 220) was derived from electronic medical record nursing documentation and formed the data points for analysis. Outcome measures demonstrated an institutional increase in rates of breastfeeding initiation and in breastfeeding exclusivity. Chi-square analysis of both outcomes was not statistically significant; however progression towards the benchmarks was made, demonstrating clinical significance. Future social change from the project's success will be evident in reduction of sequelae from the above named maternal and infant acute and chronic illnesses.

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T2DM is a growing health problem worldwide. It is now increasingly being diagnosed earlier in life. The factors involved in such an epidemic are complex. The intrauterine environment has long been known as an important contributor to many diseases including metabolic disorders such as T2DM. Recently, there is emerging evidence for maternal micronutrients affecting vital developmental processes in utero which can adversely “programme” the offspring to develop metabolic disorders in later life. Thus, “gene-diet” interaction during foetal development is likely to be a significant contributor to the epidemic of T2DM. In particular, the intrauterine imbalance between the two related vitamins, vitamin B12 and folate, affect DNA methylation and in turn programme the foetus for the whole life. Evidence from mandatory folic acid fortification studies suggests that in the presence of adequate folate, neural tube defects due to vitamin B12 insufficiency have tripled. In India, children born to mothers with “high folate and low vitamin B12” had higher adiposity and insulin resistance. Therefore, micronutrient status during pregnancy is likely to have a significant impact on the metabolic risk of the offspring. This thesis examines whether vitamin B12 insufficiency is prevalent in pregnancy, especially in a non-vegetarian population across the world as well as the Saudi pregnant population. As estimated intake is an accepted measure for micronutrient levels, we also examined the relationship between estimated vitamin B12 and folate intake with actual levels in the blood. We have found that vitamin B12 insufficiency was not uncommon during pregnancy across the world even in the non-vegetarian population and is also common in the Saudi population. Surprisingly, vitamin B12 insufficiency was observed in 50% of the tested population even in the presence of adequate vitamin B12 intake. In addition, we have also shown for the first time in the Saudi population that maternal BMI is inversely related to vitamin B12 levels, particularly in pregnancy. Even though we have shown a similar (or worse) picture in mothers with gestational diabetes, this study needs to be replicated, as our numbers are too small. Prospective studies linking the role of vitamin B12 insufficiency especially in the presence of high folate on birth outcomes in the Saudi population as well as intervention studies investigating the role of vitamin B12 supplementation in women of childbearing age and in pregnancy are urgently needed.