Background: Prematurity is a major risk factor for intraventricular haemorrhage (IVH). Premature infants often require respiratory support. There is little information on neonates with IVH who require respiratory support in low and middle income countries. Objective: To describe the characteristics and short-term outcomes of very low birth weight (VLBW) infants with IVH who required respiratory support in a tertiary neonatal unit with resource limitations. Methods: This was a matched retrospective observational study. The population included VLBW infants with IVH, who received positive pressure respiratory support between January 2014 and December 2016. Outcomes of infants with severe IVH was compared to those with mild IVH. Outcomes were further analysed according to mode of ventilation. Results: 150 infants were included in the study, 56 (37%) received continuous positive airway pressure (CPAP) only and 94 (63%) mechanical ventilation. Severe IVH was associated with surfactant therapy across both ventilation groups (p=0.03). Oxygen requirement at 28 days was more frequent in infants with severe IVH compared to mild IVH (79% vs 38%, p=0.01) (OR 6.11 (95% CI 1.19-31.34), p=0.03). Severe IVH and the presence of coagulopathy were the strongest predictors of death in both ventilation groups (p <0.0001). Pulmonary haemorrhage was the commonest cause of death in those with severe IVH and blood culture confirmed sepsis in those with mild IVH. Periventricular leukomalacia (PVL) was associated with severe IVH in those receiving invasive ventilation (OR 6.67 (95% CI 1.11-40.17)). Conclusion: Mechanical ventilation, coagulopathy and pulmonary haemorrhage were strongly associated with death in VLBW infants with severe IVH in a resource-limited setting. These prognostic factors may have a role in end of life decisions.

Thesis (MCurr)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Intraventricular haemorrhage is associated with neurological morbidity and mortality in low birth weight infants. In spite of improvements in treatment to reduce the incidence of the haemorrhage, the condition continues to remain a major cause of long term morbidity in low birth weight infants. The evidence from the literature has shown that low birth weight infants might benefit from delayed cord clamping particularly in reducing the risk of intraventricular haemorrhage and its neurological consequences. The primary objective of this review was to assess the effects of delayed versus early cord clamping on intraventricular haemorrhage amongst low birth weight infants. The secondary objectives were to evaluate the effects of delayed versus early cord clamping on the Apgar scores, hyperbilirubinaemia and polycythaemia in infants. The following electronic databases were searched: CINAHL, MEDLINE (searched via PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL). Other information was gathered from the reference lists of retrieved articles and relevant experts. The selection criteria entailed all randomised controlled trials comparing delayed versus early cord clamping following birth in infants with low birth weight. Two reviewers independently extracted the data and assessed the quality of the trials. Disagreements on studies for inclusion were resolved by discussion with the third reviewer. The review included five randomised controlled trials with 215 participants. The risk of intraventricular haemorrhage was significantly reduced in the delayed compared with early cord clamping (RR0.52, 95% CI 0.33 to 0.82, P=0.005). No statistically significant difference was shown between delayed versus early cord clamping for the risk of hyperbilirubinaemia (RR O.48, 95% CI -0.43 to 1.39, P=0.30). There was no data available for other comparisons: Polycythaemia and Apgar scores. There is growing evidence that delayed cord clamping might benefit low birth weight infants. In the included studies, delayed cord clamping for at least 30 seconds appear to have a potential in reducing the risk of intraventricular haemorrhage. The results of this review should however be interpreted with caution due to a limited number of studies with the absence of clinically important secondary outcomes in the included trials. Further research is required on large scale randomised controlled trials. / AFRIKAANSE OPSOMMING: Intraventrikulêre bloeding word geassosieer met neurologiese morbiditeit en mortaliteit in suigelinge met ’n lae geboortegewig. Ten spyte van die verbetering in die behandeling om die gevalle van bloeding te verminder, duur die toestand voort as ’n belangrike oorsaak van langtermyn morbiditeit in lae gewig geboortes. Bewyse uit die literatuur toon dat suigelinge met ’n lae geboortegewig voordeel mag trek uit vertraagde afklemming, veral deur die vermindering van die risiko van intraventrikulêre bloeding en die neurologiese gevolge daarvan. Die primêre doelwit van hierdie navorsing was om die effek van vertraagde, versus vroeë afklemming op intraventrikulêre bloeding onder suigelinge met ’n lae geboortegewig te bepaal. Die sekondêre doelwit is om die effekte van vertraagde, versus vroeë afklemming op die Apgar uitslae, hiperbilirubinaemia en polisitaemia by suigelinge te evalueer. Die volgende elektroniese databasisse is nagegaan: CINAHL, MEDLINE (soektog via PubMed); Cochrane Central Register of Controlled Trials (CENTRAL). Ander inligting is verkry uit die bronnelyste van nagevorsde artikels en van relevante deskundiges. Die seleksie kriteria behels alle ewekansige beheerde toetsing, insluitende toekomstige studies wat vertraagde, versus vroeë afklemming vergelyk by suigelinge met ’n lae geboortegewig. Twee resensente het onafhanklik data geneem en die kwalititeit van die toetse bepaal. Verskille oor insluiting van navorsing, is met ’n derde resensent deur middel van bespreking opgelos. Die navorsing het vyf ewekansige beheerde steekproewe met 215 deelnemers ingesluit. Die risiko van intraventrikulêre bloeding is beduidend verminder in die vertraagde gevalle, in teenstelling met vroeë afklemming (RR0.52, 95% CI 0.33 tot 0.82, P=0.005). Geen statistiese beduidende verskil is bewys tussen vertraagde teenoor vroeë afklemming ten opsigte van hiperbilirubinaemia nie (RR 0.48, 95% CI – 0.43 tot 1.39, P=0.30). Daar was geen data beskikbaar vir ander vergelykings nie: Polisytaemia en Apgar uitslae. Daar is groeiende bewyse dat vertraagde afklemming lae geboortegewig suigelinge mag beïnvloed. Dit wil in die ingeslote studies voor kom dat vertraagde afklemming van ten minste 30 sekondes die potensiaal het om die risiko van intraventrikulêre bloeding te verminder. Die uitslae van hierdie beskouing sal nietemin met omsigtigheid geïnterpreteer moet word, weens die beperkte aantal studies met die afwesigheid van klinies belangrike sekondêre uitkomste in die ingeslote proewe. Verdere navorsing word benodig op grootskaalse ewekansige beheerde proewe.

Haemorrhage within the germinal matrix with extension into the ventricle is commonly seen in very low birth weight babies. Outcome following severe haemorrhage, in particular when associated with post haemorrhagic hydrocephalus and congestive venous infarction is poor, whilst outcome following moderate degrees of haemorrhage remains variable. The Neural Stem Progenitor Cells (NSPC) within the GM have been shown to be exquisitely sensitive to micro-environmental cues, as such, haemorrhage within the GM is postulated to impact on neurological outcome through aberration of normal NSPC behaviour. Here we have developed a stereotactic model of autologous blood injection which recapitulates key features of Papile grade II/III Germinal Matrix Haemorrhage / Intraventricular Haemorrhage (GMH/IVH). This model demonstrates that GMH/IVH causes an activation of the NSPC within the wall of the lateral ventricle and increases the number of transient amplifying cells within the transcallosal pathway. Further to this RNA extraction from the NSPC (selected using a CD133 MACS protocol) revealed that GMH/IVH causes a significant down regulation of the transmembrane receptor Notch, a finding that was validated using Hes5 in situ hybridisation (ISH). Using a battery of behavioural tests including assessment of developmental landmarks, neuromotor and reflex development we found that GMH/IVH causes subtle but significant impacts on early neonatal development. GMH/IVH in transgenic mice overexpressing the polycomb group gene Bmi1 in NSC (Nestin+ve) revealed increased self-renewal and resistance to oxidative stress (properties of Bmi1 overexpression) reduced the impact of GMH on the oligodendrocyte population, it also revealed a unique behavioural phenotype. We propose that GMH/IVH down regulates Notch in the NSPC causing a burst of precocious proliferation and depleting the NSPC pool, which impacts on neurological outcome due to altered cortical architecture. Further we suggest that modulation of NSPC properties may play role in determining outcome and should be further explored for its therapeutic potential.