Includes abstract. Includes bibliographical references.

Thesis (MMed (Obstetrics and Gynaecology))--University of Stellenbosch, 2010. / Please refer to full text for abstract.

Epidural analgesia has increased in usage dramatically in the United States as a means of comfort for labor pain. Prior studies have connected epidural analgesia to an increase in cesarean birth rate, an increase in use of instrumentation, an increase in length of labor, episiotomy rate, and maternal fever. Epidural analgesia has produced additional costs to the patient and society. The purpose of this study is to examine the relationship between epidural analgesia during childbirth and childbirth outcomes. The data for this study were obtained from a retrospective patient record review of 200 systematically selected labor patients who delivered in 2002 at a midwestern hospital. The epidural analgesia rate was 72% at this facility in 2002, a significant increase from the previous 5 years. Using the Chi-square test of independence, 3 relationship was established between epidural analgesia and four of the variables examined. A statistically significant relationship was found to exist between epidural analgesia and cesarean birth rate, pitocin augmentation, and the first and second stages of labor with the total sample. The results of the study are important for healthcare providers who are relaying influential wellness information to childbearing women and their partners. The results indicate a need for further education for healthcare providers on alternative methods of pain relief for their patients during childbirth.

This study explores the nature of competence required to fulfil the role of the midwife, learning to become competent, and professional learning beyond registration. The research was undertaken through a qualitative, case study approach, exploring competence as a phenomenon, as experienced by thirty-nine student midwives as they went through the final stages of pre-registration midwifery education programmes, were assessed to be competent, and took on the role of the midwife. The views of the thirty-nine participants of competence and of their own capability, development and learning, were compared with the views of teachers, assessors, other midwives, and supervisors of midwives, working with participants. Also explored are the characteristics of the expert and the characteristics of good and bad midwives. The case is made early on in the thesis that a definition of competence is required for midwifery to develop as a profession, to protect the public, and to facilitate midwife development pre and post registration. Towards achieving this, the research begins to construct a model of midwifery competence as an integrated, holistic concept. The research explores the relationship between the various components and dimensions in the integrated model and the factors involved in being competent across contexts and from situation to situation. Factors involved in the maintenance of competence over time and in learning beyond registration are identified by exploring the nature of learning beyond registration and the characteristics of good and bad midwives.

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Until the sixteenth century, childbirth in England was the exclusive domain of women and was orchestrated by the female midwife. By the end of the seventeenth century, university-educated and church-approved male physicians were systematically beginning to usurp the midwife's role in the lying-in room and to gradually assume authority and power over the process of childbirth. Ultimately doctordominated childbirth threatened, and in some places accomplished, the displacement of the midwife. No one factor was responsible for the shift in delivery room personnel nor was the transition from female midwives to male obstetricians a "natural" one. This thesis looks at three factors which contributed to the success of the transition: first, midwifery practices and the criticism of them by male medical practitioners; second, the association of midwifery and witchcraft; and third, the failure of attempts, particularly in the seventeenth century, to educate and regulate midwives at a time when the male medical profession was doing just that.

The effect of metabolic and inflammatory parameters on pregnancy success in terms of implantation, metabolic adaptation to pregnancy and fetal programming is yet to be fully understood. This thesis explores the activity of metabolic and inflammatory pathways in pregnancy, highlighting their importance throughout gestation. In a cell culture study, a model of in vivo blastocyst-uterine adhesion to study the effect of insulin during uterine implantation was explored. JAR spheroid-RL95-2 monolayer adhesion reached 98% by 24 hours in the absence of insulin. A low dose (0.03nM) of added insulin concentrations resulted in 26% adhesion, or 74% inhibition; a high level (0.24nM) inhibited the JAR spheroid-RL95-2 monolayer adhesion by 9%. Therefore insulin did not have a dose-dependent on JAR spheroid-RL95-2 monolayer adhesion in the cell culture model of implantation. Polymerase chain reaction (PCR) studies revealed laminin α1 RNA detection on JAR cells only, CD44 on RL95-2 cells only, no trophinin on both cell types, FBLN-1 and -2 on JAR and FBLN-1 on RL95-2 cells only and an insulin receptor in both cell types. Western blot and immunohistochemistry (IHC) studies showed laminin α1 detection and stains on the JAR cell extracellular matrix. In a prospective human study, the metabolites of lipid and carbohydrate metabolism and inflammatory mediators very early (between day 0 and day 45) in gestation and their link to successful pregnancy in women undergoing natural cycle frozen embryo transfer (FET) in assisted conception, was investigated. Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), glucose, c-reactive protein (CRP) and non-esterified fatty acid (NEFA) were measured on routine biochemistry; insulin, interleukin (IL)-6, plasminogen activated inhibitor (PAI)-1 and PAI-2 on ELISA; IL-8 (CXCL8), CCL2, CCL3, CCL4 and CCL11 on BioPlex; and human chronic gonadotrophin (hCG) on an Immulite system. For all 196 FET cycles, participants' demographics and plasma parameters of pregnant (n=36) and non-pregnant (n=106) women were explored. Neither obesity, the plasma parameters nor insulin resistance were predictive of successful pregnancy, but ICSI (predominately associated with male factor infertility) was. Overall, the hCG, insulin, rebound TG and HDL-C (except TC), homeostasis model assessment (HOMA), CRP and PAI-2 levels were higher, whereas CXCL8, CCL2, CCL11 and PAI-1 were significantly lower by day 45. Baseline obesity related to positive changes in plasma insulin, HDL-C and HOMA and negative changes in CXCL8, CCL3 and CCL4. In a cross-sectional study in late pregnancy, offspring's reflection of parameters in women with preeclampsia (PE) (n=29) and intrauterine growth restriction (IUGR) (n=14), compared to BMI-matched healthy groups (n=87) and (n=42), respectively, was explored. Fetal cord was found to be hyperlipidaemic, normoglycaemic and had reduced inflammatory response, while mothers who suffered PE had altered plasma TG, TC, NEFA, glucose, leptin and IL-10 compared to controls. IUGR babies were dyslipidaemic. The role of cholesterol transporters was assessed in PE (n=20) and IUGR (n=9) BMI-matched controls (n=20 and n=9) respectively. Among fifteen steroidogenic acute regulatory protein (STAR)-related lipid transfer domains, only STARD6 and STARD15 were not detected in the placenta via PCR. IHC studies were also explored on the placentae. The real-time PCR (RT-PCR) of messenger RNA of low-density lipoprotein receptor (LDLR), STARD3 and ATP-binding cassette A1 (ABCA1) without protein were higher in PE compared to controls. LDLR, STARD3 and ABCA1 localisation and detection were consistent to placental lipid (cholesterol) transport systems. In summary, all this led to the conclusion of the importance of metabolic and inflammatory pathways in all stages of pregnancy in leading to pregnancy success; these pathways may influence implantation, adaptation to pregnancy and, potentially, fetal programming of offspring.

Maternal obesity has been at the forefront of pregnancy-related research in recent times. The impact of this chronic health condition has been highlighted in reports on maternal mortality (CEMACH, 2007, CEMACH, 2011), where 30% of mothers who died from pregnancy related causes were obese (CEMACH, 2011). The importance of maternal obesity and how it affects maternal adaptation to pregnancy is well documented with obese women exhibiting low grade inflammation, greater coagulability and poorer improvement in vascular function during pregnancy compared to lean women (Stewart et al., 2007a). These findings suggest that obese women display similar characteristics to the non-pregnant adult metabolic syndrome and these attributes may be important in explaining why obese pregnancies have higher rates of obstetric complications including gestational diabetes (GDM) and pre-eclampsia (PET). In non-pregnant adult obesity it has been found that central or truncal adiposity is associated with increased NEFA (non-esterified fatty acids) turnover and ectopic fat (especially liver) deposition. It has been suggested that obese pregnant women may also preferentially gain fat in central depots and this may be the mechanism by which poor vascular improvement and inflammation are initiated. The aims of this thesis were to assess subcutaneous fat accumulation and distribution throughout pregnancy in both lean and OW/OB women. Furthermore this thesis aimed to acquire a better understanding of the impact of anatomical fat deposition on metabolic and vascular function during pregnancy. A final aim was to assess vascular function and evidence of lipotoxicity during pregnancy and test whether the site of fat accumulation and distribution was associated with gestational improvement of vascular function. A longitudinal study was performed and anthropometric data was collected from 26 lean and 16 OW/OB women at three antenatal time points (15, 25 and 35 weeks’ gestation) during pregnancy. Direct measurements of energy metabolism (basal metabolic rate, substrate utilisation, physical activity and diet) were also collected to assess the impact of energy metabolism on fat accumulation and distribution. A comprehensive panel of plasma markers of carbohydrate and lipid metabolism (fasting glucose, fasting insulin, total cholesterol [TC], total triglyceride [TG], high density lipoprotein [HDL] and NEFA) and inflammatory (C-reactive protein [CRP], interleukin-6 [IL6] and tumour necrosis factor alpha [TNF]) were quantitated at each study appointment. Endothelial function was measured using laser Doppler imaging (LDI). Measurement of plasma and urinary biomarkers of endothelial function and lipotoxicity including soluble intracellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), oxidised low density lipoprotein (oxLDL), plasma superoxide and urinary isoprostanes were undertaken. Lean and OW/OB women gained similar amounts of total body weight and fat mass during pregnancy. Only in lean women was there an anatomical preference for site of fat storage and this was in the upper peripheral subcutaneous depots. In healthy OW/OB pregnancy no such anatomical preference of fat deposition was found. The study of energy metabolism found that OW/OB women had higher basal metabolic rate and higher fat oxidation than lean women, whilst lean women had higher rates of carbohydrate oxidation and physical activity than OW/OB women. In the lean and OW/OB groups dietary macronutrient intakes were similar. Overall the parameters of energy metabolism were not associated with overall fat mass accumulation or distribution. During pregnancy, OW/OB women were more insulin resistant and pro-inflammatory (CRP and TNFα) than lean women and lean women had higher concentrations of plasma HDL. Interestingly the lean group had higher plasma concentrations of IL6 which may be a result of higher rates of vascular remodelling and may reflect a physiological rather than pathological process. In both lean and OW/OB pregnancies the gestational increase in subcutaneous adipose depots was not associated with the gestational changes in markers of carbohydrate, lipid or inflammatory profiles. Both lean and OW/OB women exhibited similar gestational improvement in endothelial microvascular function. During pregnancy both groups showed an increase in markers of lipotoxicity but levels were not associated with vascular function. Changes in anatomical subcutaneous fat distribution were also not associated with the changes in vascular function during pregnancy. In conclusion, in pregnancy, only lean women exhibit an anatomical site-specific fat accumulation. Although the OW/OB group displayed some aspects of the metabolic syndrome in general the OW/OB women studied here adapted to pregnancy in a similar way to lean women in terms of vascular function and levels of lipotoxicity. However, visceral adiposity was not assessed and OW/OB women with larger visceral adipose stores may exhibit a more lipotoxic phenotype and more pathological adaptation to pregnancy that may make them susceptible to metabolic complications of pregnancy. This study highlights the heterogeneity of maternal obesity and suggests that further studies into ‘metabolically healthy’ and ‘metabolically unhealthy’ lean and OW/OB women is warranted.

Genes that are imprinted are subject to a developmentally determined epigenetic marking, which restricts expression to a single allele, dependant on the parent of origin. Selection of imprinted genes for monoallelic expression indicates their function is highly dosage sensitive. Altered dosage of imprinted genes has been linked to a number of neurological conditions, including psychosis. Cdkn1c is an example of an imprinted gene whose expression is sensitive to the in utero environment. Considerable development of the nervous system takes place in utero and suboptimal pregnancies have been linked to the occurrence of psychiatric and other behavioural disorders in adults. One mechanism through which the maternal environment may impact foetal development is by altering the epigenetic regulation of vulnerable genes. A prenatal low protein or high fat diet resulted in alterations in a subset of imprinted gene in the brains of the offspring at E18.5. This was accompanied by sexually dimorphic changes in the dopaminergic system. Previously published findings reporting sensitivity of Cdkn1c to a prenatal low protein diet were replicated with a 1.8 fold increase in neural Cdkn1c expression observed. This was shown to be due to a change in the parental contribution to expression levels of this gene. Modelling the specific alteration of an increase in Cdkn1c genetically (Cdkn1cBACx1 line) revealed anhedonia, but with an increased motivational drive, towards a palatable solution, with corresponding changes in the reward system responsivity and chemistry in the adult brain. Additionally presence of a Cdkn1cBACx1 animal in a group destabilised the social hierarchy, negatively effecting fitness of all group members. An adverse inutero environment increases Cdkn1c levels to those reminiscent of the genetic ‘loss of imprinting’ model. Such alteration in expression of Cdkn1c has significant consequences for adult neurochemistry, reward processing and the social environment and fitness of the group. This work suggests a potentially crucial role, of at least Cdkn1c, and perhaps imprinted genes more generally, in mediating the negative consequences of an adverse in utero environment.

Diabetes is the most frequently encountered endocrine disorder in pregnancy and is associated with adverse outcomes. Despite the urgent need for interventions to improve the outcomes for pregnancies complicated with diabetes, and the consistent recognition of preconception care as an effective intervention, there has been lack of systematically produced evidence to support it. My first publication (Preconception Care for Diabetic Women for Improving Maternal and Fetal Outcomes: a Systematic Review and Meta-analysis) was the first systematically produced high level evidence addressing the effectiveness and the safety of all aspects of preconception care. This publication had high impact on practice and research evident by the incorporation of its findings in clinical guidelines and the number of times it was cited in the literature. My second publication (Pre-pregnancy care for women with pre-gestational diabetes mellitus: a systematic review and meta-analysis) was designed for deeper analysis of the safety of preconception care. The third and the fourth publications addressed the prevalence of pre-gestational and gestational diabetes and the rate of complications associated with diabetes in pregnancy in Saudi Arabia and contributed to the quantification of diabetes in pregnancy as a public health problem in the country. These two publications provided important information, considering that there was paucity of publications about diabetes in pregnancy in Saudi Arabia for more than a decade, and they gave the needed evidence to revise the hospital policy for screening and management of diabetes in pregnancy as well as the implementation of preconception care for women with pre-existing diabetes. My fifth publication investigated an important clinical intervention for pregnant women with diabetes which is induction of labour. Similar to the second and third publication there was paucity of information about the indications and the determinants of successful induction of labour in Saudi Arabia. This publication was the first to address this important intervention in the practice of obstetrics in general and in the specific management of women with diabetes. Thus my work in "diabetes in pregnancy as a clinical and public health problem" provided an important evaluation of interventions at the clinical and public health levels and important information for the management of diabetic pregnant women in Saudi Arabia and across the world.