Thesis (MMed (Obstetrics and Gynaecology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Introduction: Hypertensive disease is one of the cardinal causes of maternal morbidity and mortality in South Africa. According to the National Confidential Enquiry into Maternal Deaths (NCEMD) report for 2005-2007, the “big five” causes of maternal death have remained the same as in the previous triennium, with hypertensive disease in second place, being the causative factor in 15.7% of cases.1 Women under 20 years of age were at greater risk of dying due to complications of hypertension. In this light, the early identification and treatment of hypertensive disease remains important priorities in improving maternal care. Various serum markers have been studied to identify women at risk of pre-eclampsia, including biological markers and genetic factors.2 It is also well known that chronic hypertension is one of the major predisposing factors to the development pre-eclampsia.2 A continued search for a genetic screening test to assist in early diagnosis could facilitate a reduction of maternal morbidity and mortality. Aims: The aim of this project is to determine the prevalence of the R563Q mutation of the -subunit of the epithelial sodium channel (-ENaC) gene in a cohort of primigravid women with hypertensive disease in pregnancy and to compare pregnancy outcomes in this group of hypertensive patients to those not identified to be carriers of the mutation. Methodology: A retrospectively collected study cohort of patients with early onset pre-eclampsia, obtained from pooled samples and data from the GAP study (Genetic Aspects of Pre-eclampsia, project number C99/025), was used. The planned sample size was 200, with 200 controls who were ethnic-matched, normotensive women. Exclusion criteria were gestation 34 weeks, multiple pregnancy, known underlying collagen vascular disease and type I Diabetes Mellitus. Outcome criteria: The pregnancy outcomes were analysed with respect to the degree of hypertensive disease and related complications (maternal, placental and neonatal). Results: Blood samples form 104 patients and 80 control samples were analysed. Pre-eclamptic patients were significantly younger than controls (p<0.0001). The presence of the mutation was not significantly increased in the pre-eclamptic group (p=0.33). The mutation bearers did not exhibit a significant tendency towards a specific degree of pre-eclampsia (p=0.51). There were no significant differences in the other studied maternal or fetal outcome measures. A composite outcome (the presence of 1 adverse outcome compared to no adverse outcome) was created which did not differ between the mutation positive and negative pre-eclamptic patients. Data of the index study was combined with the data form a prior relevant study9 and combined odds ratios were calculated. The increased mutation frequency amongst pre-eclamptics compared to healthy controls then remains significant, OR 2.57(95%CI 1.23-5.36). Conclusion: In this study the R563Q mutation of the ß-subunit of the epithelial sodium channel gene was not linked to pre-eclampsia. No significant negative correlation could be established between the presence of the R563Q mutation and the outcomes of pre-eclampsia. Further research aimed at chronic hypertensive patients in pregnancy and unstable pre-eclampsia in larger study groups could shed more light on the relation between the mutation and the pre-eclamptic phenotype. / AFRIKAANSE OPSOMMING: Inleiding: Hipertensie-verwante siektes is een van die hoof oorsake van moederlike morbiditeit en mortaliteit in Suid-Afrika. Volgens die Nasionale Vertroulike Ondersoek insake Moederlike Sterftes (NCEMD) verslag vir 2005-2007, is die “groot vyf” oorsake van moedersterftes dieselfe as in die vorige triënnium, met hipertensie-verwante siektes in tweede plek, as die oorsaak van 15.7 % van die sterfgevalle. 1 Vroue jonger as 20 jaar het ‘n groter risiko om te sterf aan die komplikasies van hipertensie-verwante siektes. In die lig hiervan is die vroeë identifikasie en behandeling van hipertensie-verwante siektes ‘n priorteit in die verbetering van moedersorg. Verskeie serum merkers is al bestudeer met die hoop om vroue met verhoogde risiko vir die ontwikkelling van pre-eklampsie te identifiseer, wat biologiese merkers en genetiese faktore insluit. 2 Dit is ook welbekend dat chroniese hipertensie een van die hoof predisponerende faktore is vir die ontwilkkeling van pre-eklampsie.2 ‘n Voortgesette soektog na ‘n genetiese siftingstoets wat kan bydra tot vroeë identifisering, sou moederlike morbiditeit en mortaliteit kon verminder. Doelwittle: Die doelwit van hierdie projek is om die prevalensie van die R563Q mutasie van die -subeenheid van die epiteliële natrium kanaal (-ENaC) geen te bepaal in ‘n kohort primigravida vroue met hipertensie-verwante siekte in swangerskap en om die swangerskapsuitkomste van hierdie groep te vergelyk met pasiente wat nie draers van die mutasie is nie. Metodologie: ‘n Retrospektief versamelde studie kohort met vroeë aankoms pre-eklampsie, verkry van die monsterbank en data van die GAP studie (Genetic Aspects of Pre-eclampsia, projek nommer C99/025) is gebruik. Die beplande steekproef grootte was 200, met 200 kontroles, wat etnies- en ouderdomvergelykbare normotensiewe vroue was. Uitsluitingskriteria was gestasie 34 weke, onderliggende bindweefselsiekte en tipe I Diabetes Mellitus. Uitkomskriteria: Swangerskap uitkomste was geanaliseer met betrekking tot die graad van hipertensiewe siekte en verwante kompliksies (moederlik, plasentaal en neonataal). Resultate: Bloed monsters van 104 pasiënte en 80 kontroles is ontleed. Pre-eklampsie pasiënte was betekenisvol jonger as kontroles (p<0.0001). Die teenwoordigheid van die mutasie was nie betekenisvol verhoog in die pre-eklampsie groep nie (p=0.33). Die mutasie-draers het nie ‘n geneigdheid tot ‘n spesifieke graad van pre-eklampsie getoon nie (p=0.51). Daar was geen betekenisvolle verskille tussen die ander moederlike of fetale uitkomste wat bestudeer is nie. ‘n Gesamentlike uitkoms (teenwoordigheid van 1 swak uitkoms vergeleke met geen swak uitkoms) is geskep; daar was geen verskil tussen die mutasie-positief en negatiewe pasiënte met pre-eklampsie nie. Data van die indeks studie en relevante data uit ‘n vorige studie9 is saamgevoeg en die gesamentlike kansverhouding is bereken. Die verhoogde mutasie frekwensie onder pasiënte met pre-eklampsie vergeleke met gesonde kontroles was betekenisvol, KV 2.57(95%VI 1.23 - 5.36). Gevolgtrekking: In hierdie projek was daar nie ‘n verband tussen die R563Q mutasie van die -subeenheid van die epiteliële natrium kanaal (-ENaC) geen en pre-eklampsie nie. Geen betekenisvolle negatiewe korrelasie tussen die R563Q mutasie en pre-eklampsie uitkomste kon aangetoon word nie. Verdere navorsing gerig op pasiënte met chroniese hipertensie of akute, onstabiele pre-eklampsie in groter studiegroepe kan die verband tussen die mutasie en die pre-eklampsie fenotipe moontlik beter toelig.