Background: Antibiotics are the most commonly used medications in the neonatal intensive care unit, and when used appropriately, can be lifesaving in the NICU. However, their inappropriate use has been found to be associated with certain adverse effects like Late Onset Sepsis, Necrotizing Enterocolitis, Chronic lung disease, Candidiasis, antibiotic resistance and death. Objective: This study seeks to describe the current antibiotic practices and management of neonatal sepsis including antibiotic use in a level III Neonatal unit in South Africa Method: The study was conducted at the Groote Schuur Hospital Neonatal Unit in South Africa which provides both emergency and continuous care for neonates in the Western Cape Province. All positive cultures as well as the duration of antibiotics within the period of 1st January 2016 to 31st December 2016 at the GSH Neonatal Unit were entered into a database. Data on infection and antibiotic use in Very Low Birth weight infants was extracted from the Vermont Oxford Network (VON) database. The GSH Neonatal Unit is one of the contributing units to the VON database. This was in addition to 2 Quality audits on antibiotic use in the unit done on 2 separate days in the months of February and November in 2016. The 10 month interval between the 2 audits was to allow for any policy changes to be implemented based on a series of educational webinars for staff that were organized during that period. Another audit was done in a randomly selected month collecting data of all infants on antibiotics for the entire month. Results: The overall incidence rates of Early and Late onset sepsis among the VLBW infants were 1.0% and 5.2% respectively with the 24 – 26 week Gestational age category having the highest rates. GBS and Klebsiella pneumonia were the leading pathogens for EOS and LOS respectively. The incidence of sepsis among babies bigger than 1500g was 0.52%.The commonly used antibiotics were Ampicillin, Gentamycin and Meropenem, which were consistent with the Unit‟s protocols. The major reasons for continued use of antibiotics beyond 48 hours were clinical signs concerning for risk of sepsis, pending culture results and laboratory results concerning for risk of sepsis. Regarding infants who received antibiotics for more than 48 hours, vii a comparison of both audits showed GSH plotting below the lower quartile at 30% in the 1st audit, and at 67% between the median and the lower quartile in the 2nd audit. Discussion: Gestational age has always been a universal risk factor for neonatal sepsis, and this was confirmed in this study. Inappropriate use of antibiotics in neonates arises on account of the difficulty clinicians face because of the nonspecific and vague nature of the signs of neonatal sepsis, especially in the VLBW category. Additional biomarkers for sepsis are increasingly being used to aid in the decision of whether or not to discontinue antibiotics after 36 - 48 hours. Conclusion: There is the need for stricter antibiotic stewardship to reduce the inappropriate use of antibiotics among neonates. Antibiotics being used at GSH are appropriate for the prevailing organisms although there are some resistant organisms.

Background: The maternal struggle to provide adequate breast milk for the infants' nutritional needs disadvantage preterm infants as the outcomes of those exclusively breast milk fed are superior to those fed infant formula. Objectives: To determine the proportion of Mothers' Own breast Milk (MOM) consumed by very low birth weight (VLBW) infants at Groote Schuur Hospital and explore potential maternal difficulties to provide MOM. Methods: In a prospective cross sectional study of 104 VLBW infant-mother dyads admitted between January and May 2015, an interviewer administered a structured questionnaire to the participating mothers before day 3 and on day 14. Infant folders were reviewed for gestational age, weight, and mode of delivery and the proportion of MOM received on days 1, 7 and 14 of life. Results: Ninety-one (88%) infants received <25% of enteral feeds as MOM on day 1. MOM made up >75% of enteral feeds in 60 infants (62%) on day 14 of life and 56(57.7%) received 100% as MOM. Infants with 2 or less siblings (22.2% vs 33.7% p=0.010) received a greater proportion MOM on day 14 as compared to those with larger families. 85.7% of the interviewed mothers would have preferred to stay in the hospital with their infants post discharge. Infant's weight, mode of delivery, maternal age, HIV status, hypertension, breastfeeding counselling, income, transport mode or distance from the hospital had no impact on MOM provision. Conclusion: Domestic responsibilities may affect mothers' breast milk provision to the newborn preterm. Breast-feeding counselling did not improve breast milk provision in this study. The effectiveness of current counselling methods may need to be examined and improved. Facilitating accommodation and rooming in of mother infant pairs from delivery to discharge may be useful in improving MOM provision to VLBW infants.

Objective: To evaluate the impact of small for gestational age on outcomes of very low birth weight infants at Groote Schuur Hospital, Cape Town, South Africa. Study design: Data was obtained from Vermont Oxford Network Groote Schuur Hospital database from 2012 to 2018. Fenton growth charts were used to define small for gestational age as birth weight < 10th centile for gestational age. Results: Mortality (28.9% vs 18.5%, adjusted risk ratio (aRR) 2.1, 95% confidence interval (CI) 1.6-2.7), bronchopulmonary dysplasia (14% vs 4.5%, aRR 3.7, 95% CI 2.3-6.1) and late onset sepsis (16.7% vs 9.6%, aRR 2.3, 95% CI 1.6-3.3) were higher in the small for gestational age than in the non-small for gestational age group. Conclusion: Small for gestational age infants have a higher risk of mortality and morbidity among very low birth weight infants at Groote Schuur Hospital. This may be useful for counseling and perinatal management.

Background The timeous achievement of full enteral nutrition in a preterm infant is a critical prerequisite for optimal growth, neurodevelopment and long-term wellbeing. However, the optimal enteral feeding regimen for preterm infants has not been established, and wide variations occur in practice. The debate on the most appropriate feeding strategy is nuanced by studies suggesting that early introduction of enteral feeds and the rapid advancement of enteral feeds may increase the risk of feeding intolerance and may be involved in the pathogenesis of necrotising enterocolitis (NEC). Objective 1. To review randomised controlled trials (RCT); examining the effect that the rate of advancement of enteral feeds has on the incidence of; NEC, mortality, growth, health care utilisation and other morbidities in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. 2. To establish the safety and efficacy of commencing enteral breast milk feeds at 24 ml/kg/day on the day of birth and advancing enteral breast milk feeds at 36 ml/kg/day, in infants weighing ≤ 1000 g.

Includes abstract. Includes bibliographical references.

To describe the growth velocity of extremely low birth weight babies seen at Groote Schuur Hospital nursery and to compare this to growth velocities of similar babies in published literature.

Background: International consensus guidelines recommend that term or near-term newborns with moderate or severe hypoxic ischaemic encephalopathy (HIE) should be treated with induced hypothermia within 6 hours of birth, but many of the affected babies are born outside treatment centers. There are conflicting data describing the influence of birth site on outcome after HIE - and no published data from South Africa. Objective: To compare the frequency of abnormal outcome (mortality or abnormal aEEG) before discharge between inborn and outborn infants treated with hypothermia Methods: This was a retrospective analysis of data extracted from a prospectively collated registry of babies with moderate or severe HIE, treated with hypothermia in a tertiary hospital in South Africa, between 1 January 2011 and 31 December 2012. Results: A total of 57 babies were treated with hypothermia of which 23 (40%) were inborn and 34 (60%) outborn. Cooling was initiated earlier among the inborn babies (age 2.3 hours vs. 4.3 hours, p=0.002). Pregnancy complications and abnormal intrapartum fetal heart rates occurred more frequently in inborn infants (65.2 % vs. 24.2 %, p=0.0001 and 47.8% vs. 20.6%, p =0.03 respectively). More outborn babies died or had an abnormal aEEG at 48 hours (32 % vs. 22 %, p=0.556) and fewer outborn babies achieved normal feeding at discharge (22% vs. 38%, p = 0.189), but these differences were not statistically significant. Conclusion: The majority of infants treated with induced hypothermia in an urban/peri-urban setting in South Africa were not born in a cooling centre. There were significant delays in initiating cooling among the outborn babies. Short-term morbidity and mortality were not significantly different in outborn babies but interpretation is limited by the small sample size.

Background and rationale: Inhaled nitric oxide (iNO) is recommended for the treatment of severe persistent pulmonary hypertension of the newborn (PPHN) because it reduces the need for extracorporeal membrane oxygenation (ECMO). There is insufficient evidence that iNO reduces mortality in the absence of ECMO. Although neonates in some South African public hospitals have access to iNO, ECMO is not available. Oral sildenafil can be effective in settings where iNO is not available, but its effect on outcome and cost of treatment in this setting have not been described. The literature review in the first part of this thesis describes five studies reporting short-term outcomes of PPHN in the absence of ECMO. No studies from South Africa were identified. Only two studies described outcomes after iNO – the coadministration of Sildenafil with iNO was only reported in one small study. There were insufficient published data to guide management in settings where ECMO is not available. Aim: To describe a cohort of term and near term neonates with PPHN who were treated with iNO, with or without sildenafil, in a tertiary neonatal unit in South Africa Objectives: (i) to describe the characteristics at birth, the clinical course, and shortterm outcomes; (ii) to determine if any variables were associated with mortality; (iii) to describe the relationship between the use of sildenafil and cost of care, represented by the duration of intubation and iNO use; and (iv) to describe the frequency of sildenafil prescription. Methods. A retrospective review was carried out on folders of neonates with PPHN who were treated with iNO in Groote Schuur Hospital, Cape Town, South Africa, between January 2010 and December 2014. Results. Forty neonates were included – most were full term (85%). Meconium aspiration syndrome (MAS) was the commonest cause of PPHN (50%), followed by intrapartum hypoxia (20%), sepsis (17.5%), pulmonary hypoplasia (7.5%) and idiopathic (5%). Fourteen neonates (35%) died. Pulmonary hypoplasia and pneumothorax were associated with mortality (p=0.037 and p=0.004 respectively). An FiO2 of 1.0 and an iNO dose of ≥ 20 ppm at 24 and 48 hours respectively, both predicted death (specificity 89% vs. 100%, sensitivity 67% vs. 43% and p=0.003 vs. p=0.007 respectively). Sildenafil was prescribed more often after 2011 (83% vs. 65%) and was associated with increased survival (p=0.018) – early administration was associated with a shorter time to extubation (p=0.012) and a shorter course of iNO (p=0.044). Conclusion. The treatment of PPHN with iNO in the absence of ECMO was associated with high mortality, particularly in neonates with congenital lung abnormalities. The FiO2 and iNO requirements at 24 and 48 hours respectively could be used to identify neonates who are unlikely to benefit from continued treatment. Sildenafil was prescribed with increasing frequency during the study. The combination of iNO with sildenafil was associated with more cost-effective care and improved short term outcomes. These findings provide a potential basis for costsaving measures and resource allocation.

Background: Syphilis is a disease that was first described in the 1300s and now 700 years later, despite preventive measures and effective treatment, continues to impact on a global scale, with the burden falling largely on the developing world. We could find no recent published literature looking at predictors of outcomes in neonates born with symptomatic congenital syphilis, especially in the context of a tertiary neonatal setting. Methodology: The study design was a retrospective descriptive folder review of neonates born with symptomatic congenital syphilis at Groote Schuur Hospital (GSH) from January 2011 to December 2013. One of the primary objectives was to address outcome as well as look at modifiable preventable factors. All neonates treated at GSH (inborn and outborn) who tested serologically positive for syphilis together with clinical signs of syphilis were included. Data was obtained from the National Health Laboratory System (NHLS) database, as well as the notification and death registers at GSH nursery. All data was collected in a Microsoft excel spread sheet and analysed using Microsoft StatPlus. Results: Fifty of eighty neonates (62.5%) with positive syphilis serology as well as clinical signs of congenital syphilis were included together with their fifty mothers. The majority (98%) of mothers were inadequately untreated. Nineteen neonates demised. There were no statistically significant differences between the deaths and survivors in terms of gestational age (p = 0.15), birth weight (p = 0.08) or maternal age (p = 0.51). Two significant predictors of mortality were one minute and five minute Apgar scores of less than five ([RR], 3.5; 95% CI 1.6-7.7 and [RR], 2.9; 95% CI 1.5-5.3 respectively). Hydropic neonates, tended to be sicker at birth, requiring intubation and inotropes, which was associated with a poorer outcome (increased risk of mortality). Conclusion: Despite the introduction of a National Syphilis Screening programme more than twenty years ago together with a large proportion of pregnant women having access to antenatal care, congenital syphilis is still prevalent in South Africa. Failure to access antenatal care, poor partner tracing and a number of modifiable health worker related failures contribute to poor maternal diagnosis and treatment. Many neonates with congenital syphilis require aggressive interventions and there is a high mortality rate. This dissertation adds to the existing body of research particularly with regard to predictors of outcome in tertiary neonatal settings. Certain categories of neonates have a lower survival rate and guidelines about limitation of care may need to be considered in order to optimise resource allocation particularly in resource-constrained settings. Further research is required to elaborate how best to develop protocols in these neonates.

Introduction: HIV exposed but uninfected infants have been shown to have a higher morbidity and mortality than unexposed infants. There is almost no literature comparing the short-term outcomes of HIV exposed versus unexposed VLBW neonates who are born prematurely. Methods: A retrospective review of all VLBW neonates who were admitted at Groote Schuur Hospital nursery from 2012-2014. Data were obtained from the Vermont Oxford Database and the Prevention of Mother to Child register. Results: A total of 1593 VLBW neonates were admitted during the 3 years of which it was possible to obtain maternal HIV status in 1579 babies. Of these 1579 babies, 316 (20%)were HIV exposed. Eleven of the 230 (4.8%)infant HIV tests were positive. There was no difference in mortality, birth weight, gestational age, length of stay, sepsis and delivery room outcomes for the HIV-exposed (HIVE), maternal ARV-exposed (mARVE) and HIV-positive neonates. Differences between HIV exposed and HIV unexposed neonates were noted in an increased risk of NEC [OR 1.83 (1.2-2.8)] and an increased need for ventilation [OR 1.35 (1.01-1.8)]. Maternal antiretroviral exposed neonates developed less NEC compared with maternal antiretroviral under-exposed neonates with a birth weight under 1000grams appearing to contribute in the development and outcome of NEC. Differences in HIV-positive neonates included more chronic lung disease [OR 5.49 (1.31-23)] and more necrotising enterocolitis [OR 4.12 (1.02-17.18)]. Conclusion: This study is the first to compare the short-term outcomes of HIV exposed and HIV unexposed very low birth weight infants and consider maternal ARV exposure. It demonstrated no difference in birth weight, gestational age, mortality or sepsis. Necrotising enterocolitis is increased in the HIV exposed neonates especially if they are under-exposed to maternal antiretrovirals. Adequate maternal antiretrovirals may have a protective effect on incidence of necrotising enterocolitis and respiratory outcomes.