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Doctoral Degrees (Obstetrics and Gynaecology)

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    The role of adiponectin, leptin, TNF-α and resistin in HIV associated pre-eclampsia.
    (2015) Govender, Vineshree.; Naicker, Thajasvarie.
    Introduction and aims Hypertensive disorders of pregnancy, in particular, pre-eclampsia, remains an enigmatic problem with global disease burden shared amongst industrialised and non-industrialised countries. It has been estimated that hypertensive disorders complicate 5 – 10% of pregnancies. The leading cause of maternal deaths in sub-saharan Africa is AIDS (43.7%). The Saving Mothers Guidelines for the tri-ennium 2005 – 2007 in South Africa found that hypertensive disorders were directly linked to maternal deaths in 15.7% of cases, of which 83% represents pre-eclampsia. Additionally South Africa now faces the challenge of obesity. These three conditions (HIV, pre-eclampsia and obesity) impact on each other causing adipokine dysregulation. The aim of the study was to examine the levels of adiponectin/leptin/TNF-α and resistin amongst non-pregnant, normotensive and pre-eclamptic pregnant cohorts in respect of their BMI and HIV status. Methods Following institutional ethical approval and informed consent, serum was obtained from a total of 328 women attending the RK Khan Hospital, a regional and district hospital in eThekwini, KwaZulu-Natal. Women were recruited into two groups ie., non-pregnant (n = 120; 36.58%) and pregnant group (n = 208; 63.41%). Pregnant women were further, categorised into the normotensive pregnant (n = 118; 35.97%) and the pre-eclamptic (n = 90; 27.43%) groups. The pregnant cohort was also sub-stratified in accordance with their HIV status. Clinical demographics, height, weight, body mass index (BMI), mid upper arm circumference (MUAC), triceps skin fold thickness were recorded. Indications and mode of delivery as well as associated complications, fetal ultrasound abnormalities, neonatal outcomes (APGARS), weight, placental shape weight and appearance were noted. Serum was assessed by a double antibody sandwich ELISA technique using the DuoSet ELISA Development System for human adiponectin and TNF-α. Additionally, serum leptin and resistin was detected by the Bioplex immunoassay (Biorad). Absorbance was read spectrophotometrically at 450 nm (Systems). SPSS version 21 was used to analyse the demographic and experimental data. A p value < 0.05 was considered as statistically significant. Results Irrespective of the HIV status, body mass index and maternal weight (p = 0.325 vs 0.138) were not statistically significantly different between the normotensive and pre-eclamptic groups respectively. Likewise, the distribution of BMI was the same across the study groups with respect to HIV status (p = 0.124). Mean adiponectin levels varied between 897.93±126.18, 17.19±11.56, 23.16±21.39 and 24.61±12.869 in the non-pregnant, normotensive pregnant, EOPE and LOPE groups respectively. Leptin levels varied from 4887.25±705.29, 2732.27±580.18, 955.75±527.64 and 310.23±177.43 in the non-pregnant, normotensive pregnant, EOPE and LOPE groups respectively. TNF-α was undetected in the non-pregnant group as compared to 608.52±84.89, 661.03±202.60 and 616.43±117.53 in the normotensive pregnant, EOPE and LOPE groups respectively. Resistin varied from 7497.13±1921.95 in the non-pregnant group compared to 3536.50±730.04, 1017.63±69.58 and 286.92±160.30 in normotensive pregnant, EOPE and LOPE groups accordingly. The levels of TNF-α, leptin and resistin were significantly different within the normotensive pregnant versus pre-eclamptic groups. Except for adiponectin (p < 0.292); TNF-α (p < 0.044), leptin (p < 0.004) and resistin (p < 0.006) were statistically significantly different within the pregnant cohorts. The study demonstrated statistically significant differences in adiponectin/ leptin/ TNF-α and resistin between non-pregnant, normotensive and pre-eclamptic cohorts with respect to HIV status and BMI. There were significant differences in the levels of adiponectin/leptin/resistin and TNF-α with respect to HIV status (p=0.00). Additionally, a statistically significant difference in the level of adiponectin in the non-pregnant as compared to the normotensive cohorts (p<0.00) was noted. Furthermore,, there were statistically significant differences in the levels of TNF-α, leptin and resistin in the normotensive as compared to pre-eclamptic cohorts (p<0.000). This study was able to depict baseline adiponectin / leptin / resistin and TNF-α levels according to BMI in the local population. Conclusion This study was expedient in the fact that patients were all standardized according to ethnicity, sub-analysed according to BMI and all samples taken from the third trimester of pregnancy – one of the first such studies to be performed within South Africa as well as globally. This study reports significant differences in the BMI of the non-pregnant and pregnant groups, but no significant differences within the pregnant cohorts. In conclusion this study establishes an adipokine baseline for future reference with regards to South African Black pregnant and non-pregnant women. Albeit at term, the study shows a statistically significant difference in the levels of adiponectin/leptin/resistin and TNF-α in HIV positive patients within the non-pregnant versus pregnant population. Within the pre-eclamptic cohort there was no statistically significant difference in EOPE versus LOPE.
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    An audit of perinatal mortality at King Edward VIII Hospital, Durban.
    (2016) Frank, Nadiya.; Ibrahim, T.; Sebitloane, Hannah Motshedisi.
    Abstract not available.
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    Fetal cardiac haemodynamics in normal and complicated pregnancies.
    (2015) Bhorat, Ismail Essop.; Bagratee, Jayanthilall Sarjoo.
    Abstract available in PDF file.
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    Maternal complications in HIV infected women receiving combination antiretroviral treatment in a resource constraint setting.
    (2017) Sebitloane, Hannah Motshedisi.; Moodley, Jagidesa.
    Abstract in PDF file.
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    Women and AIDS: epidemiology and gender barriers to prevention in KwaZulu-Natal, South Africa.
    (2000) Abdool Karim, Quarraisha.; Coovadia, Hoosen Mahomed.; Moodley, Jagidesa.
    No abstract available.
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    Critically ill obstetric and gynaecology patients : the development and validation of an outcome prediction model.
    (2006) Paruk, Fathima.; Moodley, Jagidesa.
    Introduction: Outcome prediction tools have the potential to provide significant adjunctive information for intensivists. Critically ill obstetric and gynaecology patients constitute a unique subset of the general ICU (intensive care unit) population yet, there exists no outcome prediction model developed specifically for these patients. Objectives: To evaluate the APACHE II score, prospectively develop and validate an outcome prediction model, evaluate organ failure (Organ Failure score and SOFA score) and review the SIRS (Systemic Inflammatory Response Syndrome) response in a cohort of critically ill obstetric and gynaecology patients. Design: A prospective study conducted over a 2 year period in the Surgical ICU at King Edward VIII Hospital, Durban. Institutional ethics approval was obtained. Patients were allocated to one of the following categories: Obstetric hypertensive group (Group I), Obstetric non-hypertensive group (Group II) and Gynaecology group (Group III). Group III was further subdivided into a pregnant (Group IIIa) and a non-pregnant group (Group IIIb). Data captured included demographic details, clinical assessment, investigations, treatment, variables required for calculating the APACHE II score, organ failure (OF) assessment, SIRS criteria and patient outcome. The APACHE II system, organ failure assessment and SIRS was evaluated in the entire patient subset. For the purpose of the outcome prediction model, the subset was divided into 2 groups: a development group and a validation group. STATA 7 software was utilised for data analysis. Results: The dataset comprised 260 inpatients. Obstetrics and gynaecology cases represented 18.5 % of the total ICU population (n=1408). The majority of the patients were young (mean age 27 ± 10.5 years). The mean ICU stay was 5.5 ± 7.9 days. The observed mortality for Groups I, II, III, IIIa and IIIb was 23.4%, 43.2%, 42.9%, 33.3% and 55.5% respectively. The mean APACHE II score was significantly higher in nonsurvivors compared to survivors for all patient subgroups (p< 0.0001). However the APACHE II system performed variably in each of the 3 groups. The area under the curve for the ROC curves in each of the 3 main subgroups varied from 0.81 to 0.94 for APACHE II. Groups IIIa and IIIb were too small to permit ROC curve analysis. Age, mean arterial pressure, respiratory rate, temperature, the Glasgow Coma Scale score and pH were identified as significant outcome predictors. Using these parameters an obstetric and gynaecology outcome prediction (OGOP) model was developed for Groups I, II and III. The area under the curve for the ROC curves in each of the subgroups was >0.9 for the OGOP Model. A predictive equation could not be developed for Groups IIIa and IIIb (due to a small number of admissions in these two groups.) Duration and the number of organ failures, correlated with outcome. The duration and number of organ failures associated with mortality differed for each group. Three OF exceeding 72 hours, 3 OF exceeding 48 hours and 3 OF equal to 48 hours were invariably fatal in Groups I, II and III/IIIa/IIIb respectively. SOFA scores were significantly higher in nonsurvivors compared to survivors (p<0.0001). A day one SOFA score equal to 18 (Group I), 15 (Group ll) and 13 (Group III, IIIa, IIIb) was also invariably fatal. A SIRS response was noted in 94.2% of the patient cohort (245/260). The SIRS response varied in the subgroups. Sterile shock and septic shock were associated with a high mortality rate. Groups IIIa and IIIb differed with respect to the mean age, duration of hospital and ICU stay and mortality rate. Although these subsets were numerically restricted (24 and 18 admissions respectively), the results suggest that the two subsets are distinctly different in nature. Comment: The OGOP model is easier to calculate and it is superior to the APACHE II System. It needs to be validated in other local and international units. Organ failure assessment as well as the SIRS response provides useful supplementary outcome information. Although current outcome prediction tools are not designed for individual application, continued research and refinement of the available tools, as well as the exploration of novel methods, may one day result in "near-perfect" prediction estimates and further broaden the scope of their utility.
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    The effect of childbirth on the anal sphincters demonstrated by anal endosonography and neurophysiological tests.
    (1994) Sultan, Abdul Hameed.; Nicholls, R. John.; Green-Thompson, Randolph Robert.
    Obstetric trauma is a major cause of faecal incontinence in women resulting in considerable social disability. Until recently the development of faecal incontinence has been attributed largely to damage to the pelvic nerves. However the advent of anal endosonography has added a new dimension to our understanding of the pathophysiology of faecal incontinence. In this thesis, gross dissection and histological studies of 19 anorectal specimens was performed to demonstrate the normal anatomy. Simultaneous dissection and sonography of the anorectum (14 in vivo and 12 in vitro studies) has clarified the normal sonographic anatomy of the anal sphincters. Anal endosonography was performed in 114 healthy volunteers to demonstrate gender differences in anal sphincter anatomy. A prospective study of 12 patients undergoing secondary sphincter repair and 15 patients undergoing lateral internal anal sphincterotomy has validated the appearance of sonographic sphincter defects. A new technique of demonstrating the anal sphincters at rest using vaginal endosonography has been demonstrated in 20 women. A prospective study of 202 pregnant women using anal endosonography and neurophysiological tests has demonstrated that 35% of primigravidae (13% symptomatic) and 44% of multigravidae (23% symptomatic) develop occult anal sphincter defects during vaginal delivery. Although pudendal nerve damage can be identified in 16% of women 6 weeks after delivery, in the majority this recovers with time. Forceps delivery was identified as the single independent variable associated with sphincter damage although damage was also sustained in the absence of instrumental delivery. In a separate study of 50 women who sustained a recognized third degree tear 47% were found to be symptomatic despite a primary sphincter repair. In 85% of these women persistent anal sphincter defects were identified sonographically. In a further study of 43 women who had an instrumental delivery (17 vacuum and 26 forceps) anal sphincter defects were identified in 81% (38% symptomatic) of women who were delivered by forceps compared to 12% (21% symptomatic) delivered by the vacuum extractor. One hundred and fifty doctors and midwives were interviewed to assess their knowledge and training in perineal anatomy and repair. There was a clear deficiency in knowledge and inconsistencies in classification of third degree tears were apparent highlighting the need for more focused training in perineal anatomy and repair.
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    The antenatal management of the twin fetus from 30 weeks gestation.
    (1979) Houlton, M. C. C.; Philpott, R. Hugh.
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    Pharmaco-immunological-virological dynamics in intrapartum HIV-1 transmission (PIVD study)
    (2009) Singh, Michelle.; Moodley, Dhayendre.; Moodley, Jagidesa.
    Background: Multiple factors contribute to mother-to-child transmission (MTCT) of HIV-1, including virological, obstetric and biological factors. Other possible contributory determinants for high MTCT rates include immunological factors such as host genetics and viral genetic variations. Despite several therapeutic, prophylactic and obstetric interventions to reduce the proportion of infants infected during labour and delivery, mechanisms for intrapartum HIV-1 transmission remain elusive and current interventions, could, therefore remain sub-optimal. Much controversy has surrounded the correlation of HIV-1 RNA (viral load) in the systemic and genital compartments of women. The influence of short-term antiretroviral (ARV) drugs on genital tract HIV-1 is also unclear. At the time the present study was initiated, a regimen of maternal intrapartum and neonatal postpartum single-dose Nevirapine (sdNVP) was the standard of care for the prevention of mother-to-child transmission (PMTCT). In most low and middle-income countries, including South Africa, sdNVP has been documented as effective intrapartum HIV-1 prevention based on plasma pharmacokinetic levels, decreased viral loads (HIV-1 RNA) and reduced rates of intrapartum transmission, yet operational studies continue to report high intrapartum transmission rates despite the administration of sdNVP. As a result perinatal HIV-1 transmission remains a significant public health concern in several African countries. Aim: The primary aim of this study was to describe the pharmacological dynamics of Nevirapine in association with virological and immunological risk factors for intrapartum HIV-1 transmission in a South African PMTCT programme where sdNVP was the standard of care. Methods: Following regulatory approval from the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (UKZN), one hundred and twenty pregnant HIV-infected women who received the sdNVP regimen for prevention of mother-to-child HIV-1 transmission were enrolled between April-December 2006 at King Edward VIII Hospital (KEH) in Durban. Blood and cervicovaginal lavage (CVL) samples were collected from women at pre-NVP (during pregnancy) and post-NVP dosing (during labour/delivery). In addition to infant blood sampling at birth (post-NVP), postnatal infants were assessed at four and six weeks postnatally. Pharmacological laboratory investigations involved measurement of NVP drug concentration by Tandem Mass spectrophotometry. Virological investigations comprised HIV-1 RNA (viral load) quantitation, HIV-1 drug resistance testing (HIV-1 transmitting women only) and HIV-1 DNA PCR testing (infants only). Immunological investigations were only undertaken in a selected case-control subset of HIV-1 transmitting women and their infants. In this component, laboratory investigations included the determination of CCL3 and CCL3-L1 gene copy numbers, identification of single nucleotide polymorphisms (SNP’s) and haplotype characterisation of the CCL3 gene. All women were also screened for the presence of sexually transmitted infections (STI’s) during pregnancy. Results: One hundred and twenty women were enrolled onto this study. Of these, 110 women delivered 117 live infants (103 singletons and 7 twin pairs). Twelve (10.9%) women transmitted HIV-1 to their infants, while 95 (86.0%) were classified as non-transmitters. As a result of seven twin deliveries, the infant cohort comprised of 117 infants in total. Following two separate DNA PCR tests, HIV-1 infection was identified in 14 (11.9%) of study infants while the remaining 90 (76.9%) were exposed-uninfected. HIV infection status remained unknown for 13 infants due to infant demise (1.7%), lost to follow-up (7.7%) or study withdrawal (1.7%). During active labour (sampling that was best representative of the intrapartum phase) and within 20 hours of dosing, the median NVP concentration of 1070 ng/ml in the maternal systemic compartment was almost 44 times higher than the NVP levels detected in the genital compartment [24.5 ng/ml] (p < 0.001). NVP drug levels were below the 100 ng/ml therapeutic target in seven (13.7%) of 51 plasma and in all 39 CVL samples. While no significant association was found between NVP concentration in the systemic compartment and HIV-1 transmission (p = 0.4), this association was statistically significant in the genital compartment(p = 0.02). The median plasma NVP level detected among infants at birth was 83 times above the IC50 WT (10 ng/ml) and eight times higher than the 100 ng/ml therapeutic target for NVP. More than 71.0% of the infants achieved NVP drug levels above the therapeutic target. In general, higher levels of HIV-1 RNA (viral load) were observed in maternal plasma when compared to CVL. Following intrapartum sdNVP dosing, reduction in HIV-1 RNA levels did occur, however R80.0% of the women experienced no change to their HIV-1 RNA levels in both systemic and genital compartments during active labour. These findings were further supported by the strong correlation observed when comparing pre and post-NVP HIV-1 RNA levels in both maternal systemic [r = 0.81, p < 0.0001] and genital compartments [r = 0.80, p < 0.0001] during active labour. HIV-1 transmitting women had significantly higher viral loads than their non-transmitting counterparts in systemic and genital compartments, before and after intrapartum sdNVP administration. In terms of perinatal transmission this observation was only statistically significant for plasma (p = 0.02) and not CVL (p = 0.7). Maternal viral load was inversely correlated with maternal CD4 cell counts in both systemic and genital compartments. Almost 40.0% of women in this study had at least one type of STI detected during pregnancy. Maternal STI’s were detected in four (66.6%) intrapartum transmitting women and in 38 (38.8%) of non-transmitting women. No significant association was observed between the presence of maternal STI’s and the risk for intrapartum MTCT (p = 0.2,RR: 2.90, 95% CI: 0.60-15.40). The presence of maternal STI’s was associated with higher median viral loads in both systemic and genital compartments of all women, independent of intrapartum HIV-1 transmission. Despite trial-like conditions and optimal sdNVP dosing, the overall MTCT rate in this exclusively formula-fed cohort was 11.9%, of which 50.0% were in utero and 50.0% were intrapartum HIV-1 transmissions. In utero and intrapartum MTCT rates were 5.9% and 5.9% respectively. Discussion/Conclusion: Detectable CVL HIV-1 RNA that correlated well with plasma HIV-1 RNA, in conjunction with sub-optimal NVP drug concentration in maternal CVL during active labour, suggests that intrapartum HIV-1 infected women continue to act as reservoirs for both vertical and horizontal HIV-1 transmission throughout the duration of pregnancy. These findings confirm that the role of sdNVP in PMTCT was primarily one of infant prophylaxis. This was further supported by relatively unchanged maternal HIV-1 RNA (viral load) during active labour, in both systemic and genital compartments. Early identification of women who need highly active antiretroviral therapy (HAART), and initiation of such therapy as early as possible during pregnancy, not only benefits maternal health but remains the best prophylaxis against mother-to-child HIV-1 transmission. Universal access to HAART and improving strategies to optimize coverage of the current dual ARV regimen sdNVP and Zidovudine for PMTCT remain urgent research priorities in several resource-limited settings. Ongoing STI counseling, intensive screening/testing of women and their partners together promotion of condom usage, safer sex practices and aggressive STI treatment are simple interventions with tremendous impact for PMTCT in resource-limited settings.