Sudden infant death syndrome (SIDS) is the devastating condition in which an infant suddenly and unexplainably passes away over the course of sleeping. This is an unfortunate situation that many new parents dread every night as they lay their newborns to rest. SIDS is the leading cause of death in infants aged from one month to one year, and the medical world still does not fully understand what causes it. However, the triple-risk theory is a new model that sets out to explain the pathology of this syndrome through the combination of genetic vulnerabilities, a critical time period, and external stressors. This thesis summarizes the current research in the realm of the central nervous system (specifically the cerebellum and brainstem) as a means of evaluating the validity of this new model. The analyzed literature concentrated on a few important topics, such as proven risk factors, evidence of homeostatic abnormalities, and significant associations with the occurrence of SIDS. It was found that there was central nervous system dysfunction on most levels, including: damaged Purkinje cells in the cerebellum, malformations of the human choroid plexus, decreased neuropeptide signaling (both orexin and brain-derived neurotrophic factors), malformations of the amino acid neurotransmitters (both excitatory glutamate and inhibitory GABA), and finally significant reductions in the receptor density and activity of the serotonin system. These irregularities were associated, in most studies, with either the prone sleeping position or known maternal nicotine use during pregnancy. In conclusion, the triple-risk model is currently the most accurate description of SIDS, given its reasonable three criteria and present-day research. This is because the studies, and real-life victims, were all concentrated within the critical time period of transition from intra-uterine to extra-uterine life, satisfying the first element of timing. The list of central nervous system dysfunctions found in SIDS cases was compelling enough to fulfill the second factor of inherent vulnerability. Finally, the associations between low oxygen rebreathing and the prone sleep position, or over-heating and tight swaddling displayed a strong relationship with the occurrence of SIDS and satisfied the third and final event, which was the induction of an exogenous stressor. These three factors of the triple-risk model allow for the variations in victim pathology, but still offers a compelling and coherent understanding of the sudden infant death syndrome.

Background: The death of a child has been found to have long term consequences for both individual and family functioning. This is particularly true for bereaved siblings who have been found to be at increased risk of developing mental health difficulties in later life. Literature on parental bereavement proposes that the parenting phenomenon, such as replacement child syndrome, subsequent child syndrome and the parenting paradox, which can emerge after the death of a child, may account for this. However, there is very little research on these labels of observed parenting phenomenon and, as a result, any hypothesis offered remains under elaborated. In addition, limited evidence suggests that, due to the sudden, unexpected and unexplained nature of the loss, SIDS parents are more likely to experience a greater degree of distress and adjustment difficulties than other perinatally bereaved populations. Given this, it could be hypothesised that SIDS parents may be likely to experience these parenting phenomena. Despite this, however, SIDS remains a neglected area of research. Aims: As a consequence of this research gap, the study aims to explore mothers’ experiences of parenting in their transition from being a parent unaffected by Sudden Infant Death Syndrome to a parent affected by Sudden Infant Death Syndrome. Methodology: Semi-structured interviews were conducted with seven mothers who had experienced an incident of Sudden Infant Death Syndrome. The interviews were then transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Results: Five master themes emerged from the analysis: ‘Channelling the Parent Within’, a naturally developing and responsive parenting style that is facilitated by internal mechanisms, such as flexibility and confidence; ‘Parenting Outside of Yourself’, a parenting style that develops in the aftermath of a SIDS event, which is characterised by self doubt and a reliance on external mechanisms such as reassurance and restriction; ‘Restoration Through You’, the restorative effect of the subsequent and surviving children, which allows vindication and re-establishes happiness; ‘The Bitter Restoration’, a restoration that encompasses internal knowledge and external evidence of loss, including a disrupted family composition and a continued awareness of existential threat; ‘A Disruptive Appreciation’, the development of a greater appreciation for the subsequent and surviving children that impacts discipline and incorporates indulgence. These, along with the subthemes contributing to them, are presented as a narrative account. Conclusion: The results imply that mothers who have experienced a SIDS event shift into a permissive and anxious style of parenting which is characterised by safety behaviours. A model of parenting in the aftermath of SIDS has been proposed in order to explain the underlying cognitions and processes which drive this behaviour and the factors which serve to maintain it. By doing this it is hoped that, when working with bereaved parents and siblings, clinicians will be better positioned to frame parenting practices and intervene at a cognitive level.

La mort subite du nourrisson (MSN) est un phénomène imprévisible et mal compris. Elle est définie par « le décès d’un nourrisson âgé de moins d’un an dont les causes restent inexpliquées malgré des investigations approfondies, incluant une autopsie et un examen de la scène du décès ». Si l’incidence est en décroissance depuis 1994 et le début des campagnes de prévention, la MSN reste la première cause de décès post-néonatale. La MSN est un phénomène multifactoriel qui survient préférentiellement chez des enfants vulnérables exposés à des facteurs de risques environnementaux. Ainsi, le fait d’identifier ces enfants à risque est un enjeu majeur dans la prévention de cette pathologie. La réponse vagale exacerbée, exprimée biologiquement par une surexpression des récepteurs muscariniques de sous-types M2 (RM2), pourrait être un facteur de risque de MSN. Nous avons déjà constaté cette anomalie biologique dans notre modèle animal d’hyperréactivité vagale et dans des cœurs de nourrissons décédés de MSN. Le but de ces travaux est d’analyser l’expression sanguine des RM2 en tant que paramètre biologique reflétant une hyperactivité vagale chez l’Homme, dans des cas de malaises vagaux et de malaises sévères inexpliqués du nourrisson. L’implication de la génétique a également été étudiée dans une famille présentant plusieurs cas de MSN. Une surexpression des RM2 a été observée chez des patients présentant des malaises vagaux. Pour la première fois, des anomalies biologiques ont été identifiées dans cette pathologie. Si l’on parvenait à valider ce paramètre biologique en tant que marqueur de risque, cela pourrait permettre d’aider au diagnostic différentiel et à la prise en charge thérapeutique de ces syncopes vagales. Les mêmes anomalies ont été observées chez des enfants de moins d’un an présentant des malaises sévères idiopathiques. Après une première analyse des données du séquençage haut débit d’exomes issus d’une famille présentant plusieurs cas de MSN, nous avons pu identifier 3 gènes pouvant être impliqués dans la MSN. Néanmoins, le scénario et le mode de transmission sont difficiles à définir. Les premières hypothèses s’orientent vers un digénisme ou même un trigénisme. La surexpression des RM2 chez les 2 parents et chez certains enfants est un premier élément suggérant la transmission du caractère « hyperactivité vagale » chez l’Homme.Nos travaux ont permis de mettre en évidence une anomalie biologique commune entre les malaises vagaux, les malaises inexpliqués du jeune enfant et la MSN, à savoir la surexpression des RM2. Ce paramètre, facilement dosable dans le sang, pourrait être un élément complémentaire dans le diagnostic différentiel et la prise en charge de ces pathologies, notamment chez les jeunes enfants pour lesquels ces malaises peuvent être très délétères. L’avancée dans le séquençage du génome permettra peut-être l’identification de facteurs de risque génétiques impliqués dans les malaises inexpliqués ou les MSN. / Sudden Infant Death Syndrome (SIDS) is an unpredictable and poorly understood phenomenon. It is defined as the "sudden unexpected death of a child younger than one year during sleep that cannot be explained after a postmortem evaluation including autopsy, a thorough history, and scene evaluation". Although the incidence has been decreasing since 1994 and the start of prevention campaigns, SIDS remains the leading cause of post-neonatal death. SIDS is a multifactorial phenomenon that occurs preferentially in vulnerable infants exposed to environmental risk factors. Thus, identifying these children at risk is a major challenge in the prevention of this pathology. The exacerbated vagal response, biologically expressed by overexpression of muscarinic M2 receptors (M2R), may be a risk factor for SIDS. We have already observed this biological abnormality in our animal model of vagal hyperreactivity and in hearts of SIDS. The aim of this work is to analyze the blood expression of M2R as a biological parameter reflecting vagal hyperreactivity in humans, in cases of reflex syncope and idiopathic apparent life-threatening events (iALTE) of infants. The involvement of genetics has also been studied in a family with several cases of SIDS (SIDS family). Overexpression of M2R has been observed in patients with reflex syncope. For the first time, biological abnormalities have been identified in this pathology. If this biological parameter could be validated as a risk marker, it could help for differentially diagnosis and treatment of these vagal syncopes. The same abnormalities were observed in children under one year old with iALTE. After a first analysis of the data of the “next generation sequencing” of the exomes of our “SIDS family”, we were able to identify 3 genes that could be involved in SIDS. However, the scenario and the mode of transmission are difficult to define. The first hypotheses are oriented towards a digenism or even a trigenism. The overexpression of M2R in both parents is a first element suggesting the genetic transmission of the character "vagal hyperactivity" in humans. Our work highlights a biological abnormality which is common to reflex syncope, iALTE and SIDS, namely the overexpression of M2R. These results confirm the hypothesis of the involvement of the vagal system overactivity in these pathologies. This parameter, easily measurable in the blood, could be a complementary assessment useful in the differential diagnosis and the management of these pathologies, in particular in infants for whom syncope can be very harmful. The development of the sequencing of human genome will probably allow the identification of genetic risk factors involved in iALTE or SIDS.

Thesis (MScMedSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Background: Sudden infant death syndrome (SIDS) is considered the second most frequent cause of infant mortality worldwide. Research specifically pertaining to SIDS is limited in the South African setting. Identifiable causes for sudden infant death remain challenging despite full medico-legal investigations inclusive of autopsy, scene visit and ancillary studies. Viral infections could contribute to some sudden unexpected death in infancy (SUDI) cases, especially since a multitude of respiratory viruses have been detected from autopsy specimens. The specific contribution of viruses in the events preceding death, including the subsequent involvement of the immature immune response in infants, still warrants deciphering. Infancy is characterised by marked vulnerability to infections due to immaturities of their immune systems that may only resolve as infants grow older when these sudden deaths rarely still occur. In South Africa there is a lack of a standard protocol for investigations into the causes of SIDS, including the lack of standard guidelines as to which specimens should be taken, which viruses should be investigated and which laboratory assays should be utilised. Objectives: In this prospective descriptive study we aimed to investigate the prevalence of viruses in SUDI and SIDS cases at Tygerberg Forensic Pathology Service (FPS) Mortuary over a one year period. The primary aim was to explore possible respiratory viral infections in SUDI and SIDS cases and to determine the usefulness of molecular techniques to detect viruses from SUDI cases. To determine the significance of viruses, we assessed signs of infection from lung histology. The secondary objectives included collecting demographic data to investigate possible risk factors for SUDI and to look for possible similarities between viruses confirmed in living hospitalised infants at Tygerberg, during the study period compared to viruses detected from SUDI cases. Methods: Between May 2012 and May 2013 samples were collected from 148 SUDI cases presenting at Tygerberg FPS Mortuary. As part of the mandatory routine investigations into SUDI, shell vial culture (SVC) results were collected from lung and liver tissue specimens and bacterial culture results were collected from left and right lung and heart swabs at autopsy. To investigate the possibility of viruses implicated in some of the infant deaths we used the Seeplex® RV15 Ace detection multiplex polymerase chain reaction (PCR) assay to establish the frequency of 13 ribonucleic acid (RNA) respiratory viruses (influenza A and B, human parainfluenza 1-4, human coronavirus [OC43, 229E/NL63], human rhinovirus A, B and C, respiratory syncytial virus A and B, human enterovirus and human metapneumovirus) from RNA extracted from tracheal and lower left and right lung lobe swabs. Tissue from the lower left and right lung lobes were also assessed for histology signs of infection. Results: During our study we confirmed multiple known demographic risk factors for SIDS, such as the age peak around 1-3 months, the male predominance, bed-sharing, sleeping in the prone position, heavy wrapping in warm blankets, prenatal smoke exposure, and socio-economic factors. With the Seeplex® RV15 Ace detection assay between one and three viruses were detected in 59.5% (88/148) of cases. Of the 88 cases that had viruses detected, 75% (66/88) had one virus and 25% (22/88) had co-detections of two to three viruses. The most common viruses detected were HRV in 77% (68/88) of cases, RSV in 18% (16/88) of cases and HCoV in 14% (12/88) of cases. Many of the viruses we detected from our cases are included in the SVC test that forms part of the medico-legal laboratory investigation for all SUDI cases at Tygerberg FPS Mortuary. SVCs were positive in 9.5% (14/148) of all cases only. We showed that the SVC method is potentially missing most of the 13 respiratory viruses we investigated that could contribute to death in some of the SUDI cases. Conclusion: In some cases that had a Cause of Death Classification - SIDS, the PCR viruses detected cannot be ignored, especially when it is supported by histological evidence of infection. We thus propose that the use of PCR could alter a Cause of Death Classification from SIDS to Infection in some of these cases. Further research is needed to determine the significance of detecting viruses from SUDI cases wherein no significant histological evidence of infection was observed. This questions whether PCR may be too sensitive and is detecting past and latent viral infections that do not play any role in the cause of death. The histological picture also requires further characterisation to determine if it accurately predicts infections or lethal events and can truly support virology findings, especially in young infants whose immune systems are still maturing. Without determining the true prevalence of viruses in SUDI cases and the viral-specific immune response, the contribution of virus-specific infections to this syndrome will remain largely undetermined. / AFRIKAANSE OPSOMMING: Agtergrond: Wiegiedood (“SIDS/SUDI”) word beskou as die tweede mees algemene oorsaak van sterftes in kinders jonger as een jaar wêreldwyd. Toegewyde SIDS-spesifieke navorsing in die Suid-Afrikaanse samelewing is beperk. Dit bly steeds „n uitdaging om oorsake te probeer identifiseer vir hierdie onverwagte sterftes in kinders (SUDI) ten spyte van volledige medies-geregtelike ondersoeke, insluitende die lykskouing, ondersoek van die doodstoneel en aanvullende ondersoeke. Virusinfeksies kan aansienlik bydra tot sommige onverwagte sterftes in kinders, aangesien verskeie respiratoriese virusse alreeds aangetoon is in monsters verkry tydens outopsies. Die spesifieke rol wat virusse speel in die prosesse wat die dood voorafgaan, asook die bydraende rol van „n onder-ontwikkelde immuunrespons in babas, regverdig verdere ondersoek. Die eerste jaar van lewe word gekenmerk deur verhoogde vatbaarheid vir infeksies weens die ontwikkelende immuunstelsels soos wat babas ouer word, en die voorkoms van SUDI neem stelselmatig af met „n toename in ouderdom. In Suid-Afrika bestaan daar tans geen standaard protokol vir die ondersoek van wiegiedood nie en daar is ook nie standaard riglyne oor die tipe monsters wat geneem moet word, watter virusse ondersoek moet word en watter laboratorium toetse uitgevoer moet word nie. Doelstellings: In hierdie prospektiewe beskrywende studie is gepoog om die virusse wat in gevalle van wiegiedood of SUDI voorkom te ondersoek. Die studie is uitgevoer by die Tygerberg Geregtelike Patologie Dienste lykshuis oor 'n tydperk van een jaar. Molekulêre tegnieke om virusse aan te toon in hierdie gevalle is gebruik om spesifieke virusinfeksies te ondersoek. Die resultate is met histologiese tekens van infeksie in longweefsel gekorreleer. Demografiese data is verder versamel om moontlike risikofaktore vir wiegiedood te ondersoek. Dit is verder vergelyk met virusse wat met dieselfde diagnostiese tegnieke in babas geïdentifiseer is wat tydens die studieperiode in Tygerberg Hospitaal opgeneem was met lugweginfeksies. Metodes: Monsters van 148 SUDI gevalle wat by die Tygerberg lykshuis opgeneem is, is versamel tussen Mei 2012 en Mei 2013. As deel van die roetine ondersoeke in SUDI gevalle, was selkultuur resultate verkry van long en lewer weefsel, asook bakteriële kulture van deppers wat van beide longe en hart geneem was tydens die lykskouings. „n Seeplex® RV15 Ace polimerase kettingreaksie (PKR) toets is gebruik om die teenwoordigheid van virusse te ondersoek wat moontlik by die babasterftes betrokke kon wees. Trageale- en longdeppers wat tydens die lykskouings versamel was, was getoets vir 13 ribonukleïensure (RNS) respiratoriese virusse (influenza A and B, human parainfluenza 1-4, human coronavirus [OC43, 229E/NL63], human rhinovirus A, B and C, respiratory syncytial virus A and B, human enterovirus and human metapneumovirus). Resultate: Ons studie het verskeie bekende demografiese risikofaktore vir SUDI bevestig, byvoorbeeld „n ouderdomspiek tussen een en drie maande ouderdom, manlike predominansie, deel van „n bed met ander persone, slaap posisie op die maag, styf toedraai in warm komberse, blootstelling aan sigaretrook voor geboorte en sosio-ekonomiese faktore. Die Seeplex® RV15 Ace toets het tussen een en drie virusse geïdentifiseer in 59.5% (88/148) van die gevalle. Uit die 88 gevalle waarin virusse opgespoor was, was selgs een virus in 75% (66/88) van gevalle gevind en twee en drie virusse in 25% (22/88). Die mees algemene virusse was HRV in 77% (68/88) van gevalle, RSV in 18% (16/88) van gevalle en HCoV in 14% (12/88) van gevalle. Baie van die virusse wat tydens hierdie studie ondersoek was, was ingesluit in die roetine selkultuur toets wat deel vorm van die standaard medies-geregtelike laboratoriumondersoeke in alle SUDI gevalle by die Tygerberg lykshuis, alhoewel die selkulture positief was in slegs 9.5% (14/148) van gevalle. Ons het gevind dat baie respiratoriese virusse potensieel gemisdiagnoseer word wat „n rol kon speel in of bydra tot die dood van sommige SUDI gevalle. Gevolgtrekking: In sommige gevalle waarin SIDS geklassifiseer is as die oorsaak van dood, kan die virusse wat met PKR toetse opgespoor is nie geïgnoreer word nie, veral waar die bevinding ondersteun word deur histologiese bewyse van infeksie. Ons stel dus voor dat die gebruik van PKR toetse die oorsaak van dood klassifikasie kan verander van SIDS na Infeksie in sommige van hierdie gevalle. Verdere navorsing is nodig om die waarde van gelyktydige opsporing van virusse in SUDI gevalle te bepaal wanneer daar geen noemenswaardige histologiese bewyse van infeksie gevind word nie. Dit bevraagteken of die PKR toets dalk te sensitief is en gevolglik vorige en latente virusinfeksies identifiseer wat nie noodwendig 'n rol in die oorsaak van dood speel nie. Die diagnostiese en kliniese waarde van die histologiese beeld in terme van die rol van virusinfeksies as bydraende oorsaak van dood moet verder ondersoek word, veral in jong kinders wie se immuunstelsels nog nie volledig ontwikkel is nie. Indien die werklike voorkoms van virusse in SUDI gevalle en die virus-spesifieke immuunrespons nie bepaal word nie, sal die rol van virus-spesifieke infeksies in hierdie sindroom grootliks onbekend bly. / Harry Crossley Foundation / Poliomyelitis Research Foundation (PRF) / National Health Laboratory Services Research Trust