3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Glucose metabolism and pregnancy in South African women(2018) Macaulay, ShelleyBackground Gestational diabetes mellitus (GDM) refers to diabetes with first onset during pregnancy. A diagnosis of GDM has serious implications for the affected woman and her unborn child. Women with GDM are at risk of developing Type 2 diabetes mellitus (T2DM) and children are at risk of being born large for gestational age, becoming overweight or obese, and developing T2DM later in life. The prevalence of T2DM and GDM is increasing worldwide and particularly within low-to-middle income countries (LMICs). However, there is a lack of data on GDM prevalence and the effects of GDM-exposure amongst African populations. Like other LMICs, South Africa’s public healthcare system is heavily burdened and underresourced. In terms of antenatal care, South Africa utilises a selective screening approach for GDM whereby only women with certain risk factors are investigated further, and prenatal ultrasound services are not readily available to all. These two factors make the identification of women with GDM, the monitoring of fetal growth, and clinical decisions around gestational age at delivery, difficult. Evidence-based data is required in order to propose changes to current policies governing maternal health. Aims The overarching aim of this study was to investigate GDM amongst black South African women. The study set out to discern what GDM prevalence figures exist for the African continent, determine the prevalence of GDM amongst women living in urban Soweto, Johannesburg, assess the effects of GDM exposure on fetal growth and neonatal birth measures, and evaluate the reliability and validity of using last menstrual period (LMP) dates to estimate gestational age. Methods Firstly, a systematic review was performed to determine what GDM prevalence figures exist for Africa. Secondly, a cross-sectional screening study was performed to ascertain the GDM prevalence amongst black South African women living in Soweto. Pregnant women were recruited from the Chris Hani Baragwanath Academic Hospital in Johannesburg. Inclusion criteria were; black South African females, ≥18 years of age, residing in Soweto, ≤20 weeks pregnant with singleton pregnancies. A total of 3 656 women who fulfilled the inclusion criteria were briefed on the study and invited to access free GDM screening when they were 24-28 weeks pregnant. A total of 2 009 women underwent a two-hour 75 g oral glucose tolerance test (OGTT) at 24-28 weeks gestation and a diagnosis of GDM was made using the World Health Organization’s 2013 criteria. Of those 2 009 women, 1 909 had complete and conclusive OGTT readings and formed the study sample for the ‘GDM screening’ component of this study. Thirdly, a subgroup (n=1 017) of the 3 656 women formed the Soweto First 1000 Days study (S1000); a longitudinal pregnancy cohort study. These pregnant women were followed up from early in their pregnancies with repeated fetal ultrasounds and neonatal birth measures were taken at delivery. A total of 741 women from the S1000 study underwent an OGTT and had conclusive glucose results. These women formed the ‘fetal growth and neonatal birth measures’ component of this study whereby GDM-exposed fetuses were compared to unexposed fetuses. Furthermore, amongst these 741 women, gestational age was determined by last menstrual period (LMP) and ultrasonography. Comparisons between the two methods were made. Multiple statistical analyses were performed. Results Only six of the 54 African countries had reported data on GDM prevalence. At the time the systematic review was performed, South Africa had four reported studies of which only two involved black women. Based on the limited number of African studies, the GDM prevalence across Africa was estimated to be around 5%. The GDM screening study revealed a 9.1% (95% confidence interval (CI) 7.9, 10.5) (174/1906) GDM prevalence. Compared to the women without GDM, those with GDM were significantly heavier with higher body mass indexes (BMIs), older, and of higher household socioeconomic status. A family history of diabetes and a diagnosis of anaemia were also more common amongst the women with GDM. Being ≥35 years, having a BMI ≥30 kg/m2 (obese) and a family history of diabetes were found to be significant GDM risk factors. Furthermore, the fasting plasma glucose reading had a high sensitivity (83.3% (95% CI 77.0, 88.5)) in diagnosing GDM. The longitudinal cohort study involving the 741 women who underwent repeated fetal ultrasounds showed that GDM exposure was associated with an increase in fetal growth measures, especially abdominal circumference which was already seen at 16-18 weeks gestation. When stratified by sex, male fetuses showed a significant association between GDM exposure and increased abdominal circumference (p=0.009) but this was not observed amongst female fetuses (p=0.286). There was no difference in birth measures between the GDM-exposed and unexposed neonates. Gestational age dating by LMP overestimated estational age by 0.2 days. Women with discrepancies between their LMP-based and ultrasound-based estimates were of significantly lower weight and household socioeconomic status that those without discrepancies. Whilst there was substantial agreement between the two methods, LMP had poor sensitivity in identifying late-term (41 weeks 0 days - 41 weeks 6 days gestation) and post-term (≥42 weeks gestation) pregnancies (29.0% (95% CI 14.2, 48.0) and 33.3% (95% CI: 4.33, 77.7) respectively). Conclusion Only 11% of the African continent reported GDM prevalence figures. The GDM screening component of this study represents the largest GDM prevalence study in South Africa to date. A GDM prevalence of 9.1% amongst black South African women living in urban Soweto is concerning and warrants further discussion around current GDM screening policies. Whilst universal screening for GDM may be unrealistic in South Africa’s heavily burdened public healthcare system, the use of a fasting plasma glucose screen was shown to be highly sensitive in identifying women with GDM and should be considered as a possible screening tool. Additionally, repeated ultrasound measures identified the effects of GDM as early as 16-18 weeks gestation, with GDM-exposed male fetuses having lager abdominal circumferences than unexposed fetuses. This highlights that sexual dimorphism in relation to in utero exposure to GDM exists with male fetuses being particularly susceptible to the hyperglycaemic environment and abdominal circumference being an indicator of increased fetal growth. A low rate of macrosomia and large-for-gestational age neonates was observed amongst the GMD-exposed group of neonates compared to historical GDM-exposed populations. In the absence of ultrasound, LMP is a reliable alternative for gestational age dating during early pregnancy. However, LMP estimates should not be relied upon to make clinical decisions regarding elective Caesarean sections or induction of labour for supposed prolonged pregnancies. In the case of GDM, fetal ultrasonography appears important for fetal sexing and the monitoring of fetal growth, as well as for informing clinical decisions around delivery. Health systems strengthening through increased availability of ultrasound services and detection of GDM should be considered in order to improve maternal and child health in South Africa.Item Cystic fibrosis genetic counselling: an audit of counsellees and their at-risk relatives(2009-02-11T11:14:54Z) Macaulay, ShelleyABSTRACT Cystic fibrosis (CF) is an autosomal recessive disorder that occurs in all ethnic groups. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene are responsible for pulmonary obstruction, chronic lung infections, pancreatic insufficiency, meconium ileus, failure to thrive and infertility. Genetic testing for CF at the DNA level is available. A diagnosis of CF in an individual has implications for other family members and so genetic counselling should form part of CF management. Genetic counselling has been offered by the Clinical Unit of the Division of Human Genetics, National Health Laboratory Service and the University of the Witwatersrand, Johannesburg, for many years. At the beginning of 2006, genetic services were introduced into the CF Clinics of Johannesburg Hospital by way of specialist Genetic Counselling Clinics. The study aimed to determine who utilises the CF genetic counselling services and why, to estimate the number of at-risk relatives per family, and how many of them had mutation testing and genetic counselling. Finally, the study explored what impact the specialist Genetic Counselling Clinics had on the overall service of genetic counselling. The files of 153 families seen for CF genetic counselling from 1990 to 2006 were analysed. The majority of counsellees (93%) were white. Most counsellees were parents of CF probands (35%). Relatives with carrier risks of 67% (siblings) and 50% formed only 7% and 6% of all counsellees respectively. Most individuals attended genetic counselling in order to gather information. On average, 5.9 ± 3.45 families were seen for CF genetic counselling per year from 1990 to 2005, whereas in 2006, 58 families were seen. Paediatrician, physician and nurse referrals increased notably during 2006 compared to prior years. In 140 unrelated CF-affected families, 1991 at-risk relatives, with carrier risks above 25%, were identified. Only 11% of these relatives had mutation testing and only 8% attended genetic counselling. Uptake of genetic counselling is greater when the service is integrated into CF treatment clinics than when it is offered externally. The low uptake of mutation testing and genetic counselling by at-risk relatives suggests that new methods of educating individuals for cascade screening and testing are required.Item Genetic susceptibility to fetal alcohol syndrome in the Northern Cape coloured population: Potential roles of astrotactin and reelin(2007-02-19T12:39:25Z) Macaulay, ShelleyFetal alcohol spectrum disorder (FASD) encompasses a range of conditions induced by prenatal alcohol exposure. Fetal alcohol syndrome (FAS) is the most severe of these conditions. FAS is characterised by discriminating facial features along with growth deficiencies and central nervous system abnormalities. FASD is a growing concern in South Africa, particularly in the Northern and Western Cape Provinces. In the Northern Cape, astounding prevalence rates of 122 and 73.8 per 1000 school entry children have been established for the towns of De Aar and Upington respectively. Studies involving twin concordance research and animal models have indicated that there is a genetic influence contributing towards FAS susceptibility in individuals. FAS is considered a complex disease whereby both genetic and environmental factors interact in disease pathogenesis. For this reason a case-control study involving the investigation of appropriate candidate genes was conducted. The neuronal migration pathway in the developing brain is targeted by prenatal alcohol exposure. The astrotactin (ASTN) and reelin (RELN) genes were selected for investigation based on their fundamental role in neuronal migration. A FAS case-control study involving 45 cases and 112 controls was conducted on the Northern Cape Coloured population. Four single nucleotide polymorphisms (SNPs) including missense and non-coding variants were selected within ASTN and four missense SNPs were selected within RELN. The study aimed to determine the genotype and allele frequencies of the variants within the case and control groups and to assess whether any association between the gene variants and the predisposition to FAS existed. Statistical analyses indicated a significant genotypic association (P= 0.049) between RELN’s rs607755 marker; the C/T genotype was more likely to be found amongst controls thus inferring a possible protective effect against FAS. A logistic regression model supported the above association by indicating the C/T genotype as being independently significant (P= 0.026). The most limiting factor of this study was the small sample size and consequent lack of power to detect genes with minor effects. It would therefore be suggested that the study be repeated once a larger sample size has been established. A larger sample size would increase the chances of detecting true associations between genes of minor effect and FAS, thus minimising false-positive associations from arising.