Background Each neonatal death counts, as recognised by the Every Newborn Action Plan (ENAP). This is an important aspect in attaining the third Sustainable Development Goal by 2030. Accurate neonatal mortality data as well as an understanding of the causality and context is essential to plan interventions to reduce neonatal deaths and attain the third Sustainable Development Goals (SDG) of a neonatal mortality rate of less than 12 per 1000 livebirths by 2035. Objectives The objectives of this study were: (i) to determine neonatal mortality occurring in and out of health facilities in the Metro West GSA using the three audit programmes; Perinatal Problem Identification Programme (PPIP), Child Healthcare Problem Identification Programme (Child PIP) and Forensic Pathology Services (ii) to ascertain the cause of death specific neonatal mortality (iii) to describe the avoidable factors in each death as coded by the three audit programmes (iv) to make recommendations for the alignment of existing audit databases to obtain accurate neonatal statistics for the Metro West GSA. Methods This was a retrospective descriptive study of neonatal deaths undertaken in the public healthcare setting in the Cape Town Metro West GSA from January 2014 till December 2017. Existing data from PPIP, Child PIP and the CDR/FPS was used. Neonatal deaths were defined as in the first 28 days of life where there had been signs of life at delivery and a birthweight greater than 500g. Neonatal deaths were excluded where birth had occurred outside of the GSA or in the private health care setting. The audit data with regards to cause of death and avoidable or modifiable factors was obtained for each death. Results From a total of 134843 live deliveries, 1243 neonatal deaths were identified: 976(78%) from PPIP, 58(5%) from Child PIP and 209 (17%) from CDR/FPS. Sixteen per cent of the deaths occurred outside of healthcare facilities. The neonatal mortality rate (NMR) for PPIP was 7.2, Child PIP 0.43 and CDR 1,6 per 1000 livebirths. When the audit systems were combined, the annual NMR over the study period varied from 8.05 to 10.1 with a mean of 9.2 per 1000 livebirths over the entire period. Seventy-eight per cent of the deaths occurred in the early neonatal period with a mean early neonatal mortality rate of 7.2 per 1000 livebirths. The mean late NMR was 2 per 1000 livebirths. Where all neonatal deaths were considered for those more than 500g, the main cause of death was immaturity related, then infection related followed by congenital disorders and then hypoxia related. Seventy-four per cent of deaths occurred in those less than 2500g at birth and 41% were less than 1000g and defined as extremely low birthweight. In the group of neonates greater than 1000g, the main cause of death was infection related deaths, closely followed by congenital disorders and then hypoxia, followed by immaturity. Most of infection related deaths were collected by the CDR and Child PIP. A third of Child PIP and PPIP deaths and half of the CDR deaths were coded as avoidable. The prevalence of deaths due to abandonment either by passive or active neonaticide contributed towards the higher proportion of preventable deaths in the CDR group. Conclusions The burden of deaths due to immaturity is high and may be attributed to the finding that 41% of neonatal deaths were in the ELBW group. Current viability criteria that aim at optimum use of resources may improve survival amongst this group. Infection related deaths were shown by this study to have a greater burden than recorded from PPIP data; most of these deaths were derived from Child PIP and CDR data. Also, where 10% of neonatal deaths were sudden unexpected deaths (SUDIs), a better understanding and definition of this group is urgently required as many of these deaths were subsequently found to be secondary to lower respiratory infections. It is further relevant that where 20% of CDR deaths or 3% of all the study deaths were due to active and passive neonaticide, this entity should be monitored and investigated. The study showed that the GSA has achieved the SDG for NMR of less than 12 per 1000 livebirth. However, a mean NMR of 9.2 per 1000 livebirths is not comparable to other upper middle-income countries. As 38% of the deaths were coded as avoidable, appropriate programmes to address these factors could reduce the NMR to 5.7 per 1000 livebirths. A strong recommendation from this study would be to use all three audit systems to calculate the NMR, understand the causes of neonatal deaths and plan programmes to improve neonatal survival in this GSA.

Background: Congenital heart disease (CHD) is the leading non-infectious cause of paediatric morbidity and mortality worldwide and a significant social and healthcare burden. The aetiology of CHD is poorly understood, though heritable genetic factors including copy number variants (CNVs) have been shown to contribute to the risk of CHD in individuals of European ancestry. However, the role of rare CNVs in the development of CHD in African populations including South Africa is unknown. This study aims to identify pathogenic and likely pathogenic CNVs in South African cases of CHD. To our knowledge, this is the first study to investigate the genetic basis of CHD in a South African cohort. Methods: The study cohort included 105 patients presenting to the cardiac clinics at Red Cross War Memorial Children's Hospital and Groote Schuur Hospital with non-syndromic isolated CHD (n = 76), nonsyndromic CHD with additional extra-cardiac anomalies (n = 17), and positive controls with syndromic CHD (n = 12). Genotyping was performed using the Affymetrix CytoScan HD platform. Rare CNVs were filtered using stringent criteria for their size and algorithm-specific quality score and were compared against a gene panel of known CHD-associated genes. Candidate genes were considered based on pLI scores and reported CHD phenotypes in mouse models. The identified CNVs were validated by quantifying the read-coverage of available whole-exome sequencing data of a similar overlapping cohort. Results: Chromosomal microarray analysis was successful for 101 participants (including 89 non-syndromic CHD cases and 12 control cases) and led to the identification of eight CNVs overlapping genes known to be causal for CHD (GATA4, TBX1, FLT4, CRKL, NSD1, and B3GAT3), and four CNVs encompassing candidate genes likely to play a role in the development of CHD (DGCR8, JARID2, KDM2A, and FSTL1). The CNVs were identified in nine unrelated individuals: five of the CNVs were classified as pathogenic or likely pathogenic (5.6% of the cohort) and four were classified as variants of unknown significance (4.6%). CNVs of interest were validated using the available whole-exome sequencing data. Conclusions: In this study, we show that chromosomal microarray analysis is an effective technique for identifying CNVs in patients diagnosed with CHD and that this approach can be performed locally in South Africa, producing results similar to those seen in international CHD studies. The findings of this thesis highlight the wide genetic heterogeneity of CHD and the growing importance of CHD genetic studies for both research and clinical purposes. Advancing our understanding of CHD aetiology will help define disease risk in South Africa and improve the way we care for and assess our cardiac patients.

Background Effective phototherapy reduces neonatal jaundice and its complications. Irradiance increases as the distance of the light source decreases from a single phototherapy light. There are limited studies of the effect of distance and positional changes on different LED light designs on achieving effective phototherapy. Objectives To describe and compare the effect of distance, angle and plastic barriers on three different LED lights of different design. Methods Comparisons were made using a Servolite LED light, a General Electric (GE) Lullaby and a Ningbo David LED phototherapy light. Measurements were done according to methods described by the International Electrotechnical Communission (IEC). The effective irradiated area was measured on a grid measuring 60 x 30 cm subdivided into 5 x 5 cm squares. Measurements were done for the following scenarios: light placed at the manufacturers' recommended distance, 20 cm closer, 20 cm further, at an angle, through clear plastic and through scuffed perspex. Results When the lights were placed closer to the irradiated surface than the manufacturers' recommendations, the maximum irradiance increased, but the median irradiance and uniformity ratio decreased. When the lights were angled at 45 the median irradiance was decreased. A decrease in the median irradiance was also seen when phototherapy lights passed through scuffed plastic and food grade plastic. Conclusion Our study demonstrated that placing LED lights closer than the manufacturers recommendations, the use of transparent barriers and the use of lights at an angle, compromised phototherapy irradiance and distribution. Only the GE light met IEC standards.

Background: Long term survival of children living with HIV due to improved early access to antiretroviral therapy (ART) is contributing to a growing population of adolescents living with perinatally acquired HIV (PHIV+) at risk of developing chronic multisystem comorbidity. There is limited knowledge on the overall burden, progression and causes of morbidity in PHIV+ adolescents, especially in resource limited settings. Much of what is known about morbidity in PHIV+ adolescents relates to single organ system pathology and there is a lack of a holistic approach to PHIV+ adolescents and their overall health. The aim of this PhD project was therefore to investigate the spectrum and determinants of chronic morbidity, the progression of disease and intercurrent illness in PHIV+ adolescents on ART over a 4- year period. Methods: This was a prospective study of participants enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC), a longitudinal cohort study, that recruited 515 PHIV+ adolescents and 110 HIV negative (HIV-) adolescents matched by age from 7 health care sites in Cape Town, South Africa. Eligibility criteria included PHIV+ adolescents who were aged 9-14 years, who had been on ART for at least 6 months and were aware of their HIV status. All adolescents and caregivers gave informed consent/assent. Participants were followed 6-monthly with questionnaires, clinical examination with detailed pulmonary (lung function), neurocognitive (magnetic resonance imaging and a battery of neurocognitive tests), cardiovascular (echocardiogram and ECG) and laboratory investigations. Analyses for each specific objective of the PhD were developed. Three analyses used data from the enrolment visit and were primarily descriptive and two were longitudinal and examined the incidence of hospitalizations, QuantiFERON conversion (an interferon gamma release assay used to measure Mycobacterium tuberculosis infection) and Tuberculosis (TB) disease. Results: Five hundred fifteen PHIV+ and 109 HIV- participants had a median follow-up of 4.1 years (IQR: 3.7–4.6). At enrollment, PHIV+ adolescents had a median duration of ART of 7.6 years (IQR: 4.6–9.2), median CD4 count of 713 cells/mm3 (IQR: 561.0–957.5) and 387 (75%) had a viral load of <50 copies/mL. Neurocognitive impairment was present in more than half of the PHIV+ cohort (56.3% vs. 45.3% in HIV-, p=0.05) but renal impairment was rare (2.3% in PHIV+ vs. 2.1% in HIV-, p=0.89). Microalbuminuria was also rare (8.0 in PHIV+ vs. 9.0% in HIV-, p=0.80). Respiratory or cardiac impairment were more common in PHIV+ adolescents than in HIV- participants (27.1% vs. 14.7%, p=0.01 and 46.1% vs. 33.7%, p=0.03, respectively). Multisystem impairment (defined as impairment of ≥ 3 systems) was uncommon, with only 10% of PHIV+ adolescents having 4-system impairment. Metabolic abnormalities, such as insulin resistance (IR), were relatively common but IR rates did not differ compared to HIV- adolescents (18 vs. 20%, p= 0.17). Incidence rates for hospitalization were 6.6 per 100-person-years (PY) in PHIV+ adolescents, three times that of HIV- adolescents. Sixty percent of hospitalization episodes were due to non-infectious causes and 24% due to infectious causes, of which pneumonia and TB were the predominant causes. PHIV+ adolescents had a substantially higher incidence of TB disease than HIV- adolescents (2.2/100 PY, 95% CI 1.6-3.1 vs. 0.3/100 PY, 95% CI 0.04-2.2), despite a similar rate of TB infection, as measured by QuantiFERON positivity. TB disease was associated with low CD4 counts and high viral loads in PHIV+ adolescents. Conclusion: Chronic single system morbidity experienced by PHIV+ adolescents on ART was common and merits further study, as this population begins to engage in adult lifestyle factors, such as smoking and alcohol use, that may compound these abnormalities. However, multisystem morbidity was relatively rare. In addition, in a relatively small percentage of adolescents there were subclinical metabolic abnormalities (IR and microalbuminuria) that may result in increased morbidity especially with regards to diabetes and cardiovascular disease in later life. The high burden of hospitalization and intercurrent disease, mainly due to TB, could be prevented by proven strategies, such as TB preventive therapy and ensuring adherence to optimal ART regimens.

Includes bibliographical references. / The study objectives were to: determine the prevalence of perinatal mortality (PNM) and causes of early neonatal deaths (ENNDs), describe socio-demographic factors of mothers with PNM and assess some of the associations with PNM at Kamuzu Central Hospital.

Includes bibliographical references / Background: In recent years there has been increasing debate about the impact of scaled-up ART and PMTCT programmes on the uptake and outcomes of reproductive health services, in particular the potential detrimental effects of HIV-care on the overall capacity of fragile health systems. The objective of this study was to evaluate changes in the uptake of reproductive health services as well as the main pregnancy outcomes during the scaling up of ART and PMTCT in Thyolo District, Malawi. Methods : Study design: retrospective descriptive district-wide cohort analysis for the period 2005 to 2009. Setting: Thyolo District, an area with around 600,000 inhabitants, an adult HIV-prevalence of 21% and a Total Fertility Rate of 5.7 in 2004. HIV-care including ART and PMTCT was scaled up since 2004 in Thyolo District to reach district-wide coverage in 2007. HIV-care is provided at district hospital, health centre and community health post levels. Outcomes: uptake of antenatal, intrapartum and postpartum care, family planning and treatment of sexually transmitted infections; infrastructural changes, and changes in maternal and perinatal pregnancy outcome. Data collection and analysis: data were collected from facility antenatal, intrapartum and postpartum records, as well as from MoH and MSF databases maintained for routine programme monitoring. Chisquare tests were performed comparing the baseline year (2005) with the year of study end (2009). Results: Uptake of peripartum care had improved markedly by the end of the five-year study period: the percentages of pregnant women who took up antenatal, intrapartum and postpartum care increased by 30%, 25% and 20% respectively. The number of family planning consultations increased by almost 50% and the number of women treated for sexually transmitted infections more than doubled. Interactions between HIV-care and general reproductive health care had positive effects on key health system components, including governance, health financing, human resources and drug supply. Reliable pregnancy outcome indicators for the entire observation period were difficult to obtain due to likely under-reporting of facility-based maternal and perinatal mortality. However, previously documented results from Thyolo show a reduction of facility-based severe maternal complications, including uterine rupture, between 2007 and 2009. Conclusions: Uptake of reproductive health services and facility-based maternal outcomes increased markedly during the period of HIV scale–up. This implies that the scale up of HIV-care did not inhibit, and likely increased, uptake of reproductive health services, while quality improvements in perinatal care could still be successfully implemented. The finding that ART and PMTCT care may be successfully integrated into broader reproductive health services with satisfying outcomes is a strong argument for continued scale up of ART and PMTCT in similar settings.

Includes abstract. Includes bibliographical references.

Includes bibliographical references. / Syphilis is a common sexually transmitted disease in South Africa and infection acquired during pregnancy is associated with an increased rate of miscarriage, stillbirth, preterm labour, intra uterine growth restriction (IUGR), neonatal death and congenital syphilis in the newborn. This study was undertaken in the Potchefstroom and Wolmaranstad Districts of the North West Province and was aimed at contributing to reducing perinatal mortality and morbidity within these districts. The objectives of this study were: + To determine the prevalence of syphilis amongst women attending antenatal and/or delivery care in the two selected districts. + To evaluate the effectiveness of antenatal screening and management of syphilis + To determine the perception of consumers (antenatal attendees) concerning screening for syphilis at antenatal clinics. + To determine the perception and understanding of health workers concerning the provision of antenatal syphilis screening and treatment. + To analyse any inadequacies revealed in the antenatal screening and management of syphilis in the two districts + To make recommendations for guidelines arising from the results of the research in order to improve syphilis screening in service delivery.

Background Many critically ill children in South Africa are cared for in regional hospitals by general Paediatricians. Critically ill adults and children are usually cared for in the same units. There is limited data on the numbers of children admitted and the outcomes of these children. Objective To describe the patient profile and outcomes of children admitted to a general high care unit (HCU) in a regional hospital in the Western Cape, South Africa. Methods This was a retrospective descriptive study of all children admitted to the HCU of George Regional Hospital during a one year period (2016). Demographic data, HIV, anthropometric data, immunisation status, diagnoses, medical interventions, length of stay, death or survival, and referral data to the tertiary paediatric intensive care unit (PICU) were collected. The PIM3 score and Standardized Mortality Ratio (SMR) was calculated. Results Thirty percent (144/468) of the HCU admissions were children. Most (70%) were admitted after hours. Half were under 9 months (range 3 days to 149 months). Sixty-five percent of the children required respiratory support and 45% needed inotropic support. Twenty percent of the children were transferred to the PICU. Twelve children (8,5%) died with most deaths (75%) occurring at regional level. Half of the deaths were due to sepsis with pneumonia (25%) and diarrhoea with shock (25%) accounting for the rest. The cumulative PIM3 score was 9.049 (95%CI 6.430-11.668) with an SMR of 1.326 (95%CI 1.028-1.866) observed. Conclusion Critically ill children accounted for a third of HCU admissions. Most children needed medical interventions. These require specific training and equipment that are often lacking. After hours admissions also put strain on limited staff. Most children were successfully discharged demonstrating a good outcome. This was achievable with good channels of communication and transport to a tertiary PICU.

Background: Breast milk provides optimal nutrition for infants. Human milk banks allow breast milk feeding for infants who do not have access to their own mother's milk. However, there are variable perceptions and attitudes towards human milk banking. Aim: This study aimed to evaluate community members' and healthcare workers' knowledge, perceptions and attitudes towards breast milk donation and use in Empangeni, KZN. Methodology: The research was conducted at a large regional hospital and an affiliated primary health care centre in the area. There were five focus group discussions held with healthcare workers employed at the two sites which explored the attitudes regarding donating and receiving breast milk. In addition, there were sixteen individual semi-structured interviews held with community members. Content analysis was used to analyse the data. Results and Discussion: Five main themes were found which includes: “Breastfeeding is an optimal feeding choice”, “Infant feeding choice”, “Misperceptions of HIV”, “Knowledge of DHM” and “Acceptance of DHM”. Though most participants were aware of breastfeeding benefits, there are poor breastfeeding rates within the area. Many mothers choose to formula feed their infants due to the fear of HIV transmission. There is also a fear of HIV transmission when using DHM. Acceptance of DHM was largely related to knowledge of DHM and exposure to its use. Conclusion: Healthcare workers need to be given updated, evidence-based information (in accordance with national guidelines and policies) to ensure appropriate counselling of caregivers. Furthermore, community awareness and engagement is required to improve breastfeeding rates and acceptability of DHM.