Τα τελευταία χρόνια τόσο σε διεθνές όσο και σε εθνικό επίπεδο έχει δοθεί βαρύτητα στην ανίχνευση της εμβρυϊκής υποξίας κατά τη διάρκεια της κύησης και του τοκετού, καθώς είναι σαφής η άμεση συσχέτισή της με βραχυπρόθεσμες και απώτερες επιπλοκές του νεογνού. Η επιτυχής έκβαση ενός τοκετού εξαρτάται κυρίως από τον έγκαιρο εντοπισμό της δημιουργίας της εμβρυϊκής υποξίας και η ανάγκη για την υλοποίηση υπολογιστικών συστημάτων για την έγκαιρη διάγνωσή της είναι συνεχής και αυξανόμενη. Στα πλαίσια της διδακτορικής διατριβής σχεδιάστηκε και αναπτύχθηκε ένα πρωτότυπο σύστημα διάγνωσης της πρόωρης οξέωσης του εμβρύου κατά τη διάρκεια του τοκετού, το οποίο βασίστηκε στην επεξεργασία του εμβρυϊκού καρδιακού ρυθμού και στην ανάλυση της εμβρυϊκής παλμικής οξυμετρίας. Στόχος του συγκεκριμένου συστήματος είναι να αποτελέσει ένα βοηθητικό σύστημα διάγνωσης της εμβρυϊκής υποξίας και να συμβάλει στη λήψη αποφάσεων σχετικά με το χρόνο αποπεράτωσης του τοκετού, με σκοπό την πρόληψη άμεσων και απώτερων σοβαρών νεογνικών επιπλοκών. Ειδικότερα, η υλοποίηση του προτεινόμενου συστήματος βασίστηκε στην εφαρμογή του συνεχούς μετασχηματισμού κυματιδίων και της προσαρμοστικής προσέγγισης με τη χρήση του αλγορίθμου matching pursuit για την ανάδειξη της «κρυμμένης» πληροφορίας που μεταφέρει ο εμβρυϊκός καρδιακός ρυθμός στις πολύ χαμηλές συχνότητες. Συνδυάζοντας τα αποτελέσματα των παραπάνω τεχνικών επεξεργασίας, και ιδιαίτερα του αλγορίθμου matching pursuit, με τον προσδιορισμό του συνολικού χρόνου χαμηλού κορεσμού του αρτηριακού εμβρυϊκού αίματος, υλοποιήθηκε, με τη χρήση ενός διαμεριστικού αλγορίθμου, το προτεινόμενο σύστημα. Η ανάπτυξη αυτού του συστήματος αποτελεί μια καινοτόμα και πολλά υποσχόμενη προσέγγιση στην προσπάθεια της διάγνωσης της εμβρυϊκής υποξίας δεδομένου ότι παρουσιάζει υψηλή ειδικότητα και θετική προγνωστική αξία συμβάλοντας στην επίλυση του σοβαρότερου μειονεκτήματος της κλασσικής καρδιοτοκογραφίας που είναι η χαμηλή τιμή των αντίστοιχων προγνωστικών δεικτών. / In the last few years the research community has given great attention to the detection of antepartum and intrapartum fetal hypoxia, given its direct impact on both short- and long-term neonatal morbidity and mortality. The successful completion of labor depends mainly on the prompt identification of fetal hypoxia. The development of computational systems for the early diagnosis of restricted fetal oxygen supply is therefore of critical importance. This thesis involves the design and development of an innovative system for the early detection of acidosis, which was based on the fetal heart rate processing and fetal pulse oximetry analysis. The aim of the system is to comprise a computer-aided diagnostic system of fetal hypoxia and to contribute to the decision making regarding the labor completion time, in order to prevent short- and long-term neonatal complications. Specifically, the development of the system was based on the implementation of continuous wavelet transform and adaptive approximation using the matching pursuit algorithm, in order to reveal the “hidden” information conveyed in the very low frequency range of the fetal heart rate. The system involves the combination of the results of the above-mentioned processing techniques, and especially of the matching pursuit algorithm, along with the calculation of the duration of fetal arterial low oxygen saturation, applying a commonly used clustering algorithm. The proposed system is an innovative and promising approach towards the early diagnosis of fetal hypoxia, given its high specificity and positive predictive value, thus effectively addressing the major drawback of clinical cardiotocography.

Objective: To identify the epidemiological characteristics of early fetal and neonatal deaths in maternal near miss patients and the associated elements to this outcome. Method: Cross-sectional study including 79 women with features near miss, identified in a one-year period, and their newborns. Semi-structured interviews and the study of patients’ records were conducted. The variables were analyzed through simple frequency and percentage. To evaluate the association between those variables, the Fisher’s Exact Test was used. For the multivariate analysis the perceptual map constructed from the multiple correspondence examination was used, using the variables that were significant to 20%. Results: Amongst the near miss mothers, hypertensive disorders (severe pre-eclampsia, eclampsia, hypertension) totalized 32 cases (40,5%) and, of those, 14 (58,3%) had fetal and neonatal adverse outcome (p 0,046). The highest prevalence of fetal and neonatal adverse outcome was derived from cesarean delivery (20, 83,3%), of women with 2 or 3 children (11, 45,8%), and without previous stillbirths (17, 70,8%), this last variable with significance p 0,038. In the fetal and neonatal adverse outcome analysis significant levels were verified in newborns admitted in Neonatal Intensive Care Unit (17, 70,8%, p < 0,001); children with gestational age < 32 weeks (10, 41,6%, p < 0,001); birth weight < 2500 (16, 66,7%, p 0,001); APGAR score at 5 minutes < 7 (9, 52,9%, p < 0,001); neonatal asphyxia, 9 (50,00%, p < 0,001); and early respiratory distress syndrome, 13 (72,2%, p 0,002). Conclusion: The characteristic of early fetal and neonatal deaths in maternal near miss patients had a close association with fetal and neonatal adverse outcome. Among the mothers with hypertensive disorders the significant characteristics to the outcome in newborns were prematurity, neonatal asphyxia and early respiratory distress syndrome. / Objetivo: Identificar as características epidemiológicas dos óbitos fetais e neonatais precoces em pacientes com near miss materno e os fatores associados a este desfecho. Método: Estudo transversal, cuja população foi composta por 79 mulheres com características de near miss (NM), identificadas no período de um ano, e dos seus respectivos recém-nascidos. Foram realizadas entrevistas semiestruturadas e investigação dos prontuários. As variáveis foram analisadas por meio de frequências simples e percentual. Para avaliar associação entre as variáveis, utilizou-se o teste Exato de Fisher. Para análise multivariada, foi usado o mapa perceptual construído a partir da análise de correspondência múltipla e utilizadas as variáveis que foram significativas a 20%. Resultados: Entre as mães classificadas com NM, as desordens hipertensivas (pré-eclâmpsia grave, eclâmpsia, hipertensão) totalizaram 32 casos (40,5%) e, destes, 14 (58,3%) tiveram desfecho fetal e neonatal adverso (DFNA) com p-valor =0,046. A maior prevalência de DFNA foi proveniente de parto cesáreo (20, 83,3%), de mulheres com dois a três filhos (11, 45,8%) e sem natimortos anteriores (17, 70,8%), verificando-se significância para esta última variável p =0,038. Na análise dos DFNA, foi observada significância estatística para os recém-nascidos admitidos na UTIN (17, 70,8%, p <0,001); crianças com idade gestacional < 32 semanas (10, 41,6%, p <0,001); peso ao nascer < 2500 (16, 66,7%, p =0,001); APGAR de 5 minutos < 7 contabilizaram 9 (52,9%, p <0,001); asfixia neonatal, 9 (50%, p <0,001); e desconforto respiratório precoce, 13 (72,2%, p =0,002). Conclusão: As características dos óbitos fetais e neonatais precoces em pacientes com near miss materno tiveram associação forte com o desfecho fetal e neonatal adverso. Nas mães com desordens hipertensivas, as características estatisticamente significantes para o desfecho entre os recém-nascidos foram a prematuridade, asfixia neonatal e desconforto respiratório precoce.

The consequences of early embryonic insults and how they affect subsequent life reflects the emerging concept of "fetal programming". The aim of this project is to study the effects of embryonic insults as they subsequently manifest themselves in adults, with emphasis on the heart and vasculature. My experiments establish that fetal programming operates on the bobwhite quail inducing similar changes as those observed in mammalians and other birds. The quail's fast development provides reliable data in a short period of time than other avian models (e.g. domestic chicken). Data on quail showed a correlation between egg mass and hatchling mass; where small eggs produce small hatchlings but a high mortality made it impractical as a stressor for this study. Hypoxia was used as a stressor during embryonic incubation, where it induced a low hatching weight in quail that was not observable in adult birds. Morphological measurements demonstrated an increased ventricular collagen content and reduced ventricular lumen in birds in adults incubated in hypoxia consistent with hypertension. The hematological analyzes showed few differences indicating organ remodeling instead of hematopoietic compensation. The assessment of vascular reactivity pointed out an impaired endothelium dependent relaxation commonly associated to hypertension in birds and mammals. Fetal programming could be a widespread response to an adverse prenatal environment in endotherms and the resulting data from this work contributes to our understanding of fetal programming in vertebrates and its long term consequences.

Orientador: Marcus Antônio Rossi Feliciano / Resumo: Objetivou-se avaliar e descrever as características ultrassonográficas (modo B, Doppler e elastrográfica) de tecidos materno-fetais (pulmão, fígado, rins, placentônio e cérvix) em ovelhas gestantes de parto natural ou prematuro induzido; verificar diferenças de achados entre os tipos de parto e, correlacionar com os valores obtidos dos sinais específicos do parto e impedância do muco vaginal, visando predizer a proximidade do processo de parturição. Trinta ovelhas Santa Inês adultas foram selecionadas e divididas em dois grupos: Parto Normal-GPN (n=15); e Parto Prematuro Induzido-GPPI (n=15). Os animais foram avaliados a cada 12 horas até o momento da parturição (última semana gestacional), as ovelhas pertencentes ao GPN a partir do 143º dia de gestação e as do GPPI, a partir do 135º dia de gestação (dia correspondente à indução do parto com betametasona e antiprogestágeno aglepristona). Foram avaliadas as estruturas pulmonares, renais e hepática dos conceptos, placêntonio e cérvix, obtendo-se as caraterísticas ultrassonográficas convencional e Doppler (placentônio e artéria uterina), elastografia quantativa (velocidade de cisalhamento – m/s), além dos batimentos cardíacos fetais, impedância do muco vaginal e, presença de sinais específicos e comportamentais do parto (edema vulvar, isolamento, ingurgitamento de úbere e temperatura vulvar). O nível de significância utilizado foi de 5% (p < 0,05) para todos os testes estatísticos realizados. A temperatura vulvar média foi maior... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to evaluate and describe the ultrasonographic characteristics (B mode, Doppler and elastographic) of maternal-fetal tissues (lung, liver, kidneys, placentonium and cervix) in pregnant ewes with normal and induced preterm parturition; to verify differences of findings between the types of lambing and to correlate with the values obtained from specific signs of lambing and impedance of vaginal mucus, aiming to predict the proximity of the parturition process. Thirty adult Santa Inês sheep were selected and divided into two groups: Parturition at term-GPN (n=15); and Induced pre-term parturition-GPPI (n=15). The animals were evaluated every 12 hours until the moment of parturition (last gestational week), the ewes belonging to the GPN from the 143rd day of gestation and those of the GPPI from the 135th day of gestation (day corresponding to the induction of lambing with betamethasone and antiprogestin aglepristone). Pulmonary, renal and hepatic structures of the concepts,, placentonium and cervix were evaluated, obtaining the conventional ultrasound and Doppler ultrasound characteristics (placentonium and uterine artery), quantitative elastography (shear velocity - m / s), in addition to fetal heart rate, impedance of vaginal mucus and presence of specific and behavioral signs of lambing (vulvar edema, isolation, udder engorgement and vulvar temperature). The significance level used was 5% (p <0.05) for all statistical tests performed. Mean vulvar tempe... (Complete abstract click electronic access below) / Doutor

Aim: To explore how pregnant women experience fetal movements in late pregnancy. Specific aims were:  to study women’s experiences during the time prior to receiving news that their unborn baby had died in utero (I), to investigate women’s descriptions of fetal movements (II), investigate the association between the magnitude of fetal movements and level of prenatal attachment (III), and to study women’s experiences using two different self-assessment methods (IV). Methods: Interviews, questionnaires, and observations were used. Results: Premonition that something had happened to their unborn baby, based on a lack of fetal movements, was experienced by the participants. The overall theme “something is wrong” describes the women’s insight that the baby’s life was threatened (I). Fetal movements that were sorted into the domain “powerful movements” were perceived in late pregnancy by 96 % of the participants (II). Perceiving frequent fetal movements on at least three occasions per 24 hours was associated with higher scores of prenatal attachment in all the three subscales on PAI-R. The majority (55%) of the 456 participants reported average occasions of frequent fetal movements, 26% several occasions and 18% reported few occasions of frequent fetal movements, during the current gestational week.  (III). Only one of the 40 participants did not find at least one method for monitoring fetal movements suitable. Fifteen of the 39 participants reported a preference for the mindfetalness method and five for the count-to-ten method. The women described the observation of the movements as a safe and reassuring moment for communication with their unborn baby (IV). Conclusion:  In full-term and uncomplicated pregnancies, women usually perceive fetal movements as powerful. Furthermore, women in late pregnancy who reported frequent fetal movements on several occasions during a 24-hour period seem to have a high level of prenatal attachment. Women who used self-assessment methods for monitoring fetal movements felt calm and relaxed when observing the movements of their babies. They had a high compliance for both self-assessment methods. Women that had experienced a stillbirth in late pregnancy described that they had a premonition before they were told that their baby had died in utero.

Thesis (MA)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: The objective of this thesis is to review and synthesize the scientific literature on cognitive and neuropsychological deficits associated with children who were exposed to alcohol prenatally and to highlight possible areas of future attention. High incidences of Fetal Alcohol Syndrome has been reported especially in patients from low socio-economic areas. The highest reported incidence is found in the Western Cape province in South Africa. The devastating part of FAS is that its affects are entirely preventable. Alcohol is a physical and a behavioural teratogen. Prenatal alcohol exposure causes structural damage to the central nervous system and the brain that is vulnerable throughout the pregnancy. A dose-response association exist as exposure to heavier amounts of alcohol can cause more harm. The timing and pattern of alcohol consumption also plays a role. To date though, no "safe" level of alcohol consumption during pregnancy can be advocated. Various neuropsychological decrements are found in individuals with fetal alcohol syndrome or alcohol related neuro-developmental deficits as evaluated on standardized tests. Mental retardation is commonly found and even individuals with normal IQ's still display other learning disabilities. IQ's remain stable over the life span. Along with impaired intellectual functioning they also struggle with mathematical tasks especially as their complexity increases. Speech and language development is also delayed in individuals with FAS. There is little variation in the pith and display poor language comprehension. Attentional deficits are also noted and especially impact on academic functioning. Clinically, children often present with ADHD but in-depth studies have revealed that neurobiologically there is some differences as children with FAS struggle more with encoding and shifting of attention as opposed to other patients with ADHD. Difficulties with visual-spatial functioning has also been found. Verbal learning and memory are also impaired in individuals with FAS. Their poor verbal learning are influenced by their shallow level of encoding. Problems with fine motor skills are also noted. It also appear that all executive functions are impaired. They demonstrate poor planning skills, initiation, cognitive shifting, slow information processing, their thinking is concrete and they have poor self-regulatory skills. Behavioural problems include impulsivity, hyperactivity, aggressiveness, poor social skills and impaired judgement. Early intervention is thus essential to lessen the impact of neuro-psychological deficits on functional adaptation. A sensitive battery of neuro-psychological tests are also required to identify all the impairments in affected individuals and to plan more focussed intervention strategies. / AFRIKAANSE OPSOMMING: In hierdie tesis word 'n oorsig aangebied van literatuur wat betrekking het op die disfunksie van kinders wie se moeders tydens swangerskap alkohol misbruik het. Leemtes asook moontlike areas van toekomstige navorsing, is bespreek. 'n Hoe voorkoms van fetale alkohol sindroom (FAS) word gerapporteer, pasiente uit die lae SES gebiede. Die hoogste voorkoms word gerapporteer in die Wes- Kaapse provinsie in Suid Afrika. Wat die probleem meer tragies maak, is die feit dat dit heeltemal voorkombaar is. Alkohol is 'n teratogeen wat fisieke, neurologiese en gedragsimplikasies het. Blootstelling aan alkohol voor geboorte veroorsaak strukturele veranderinge in die sentrale senuweestelsel en die brein. Blootstelling tot hoer volumes van alkohol veroorsaak noodwendig meer skade. Die spesifieke stadium van alkohol-inname tydens die swangerskap, en die moeder se drinkpatroon, speel 'n rol in die neurosielkundige uitkomste. Tot op hede kon geen veilige alkoholsvlak tydens swangerskap vasgestel word nie. Verskeie neurosielkundige uitvalle is gevind in kinders met FAS en ook kinders met alkohol-verwante neurologies ontwikkelings probleme, volgens neurosielkundige toetsing. Verstandelike gestremdheid kom algemeen voor in kinders met FAS. Kinders met FAS wat oor normale intellektuele vernoens beskik ervaar leerprobleme. Die intellektuele inkortings bly stabiel oor die lewenspan. Kinders met FAS ondervind erge probleme met wiskunde, veral wanneer die werk moeiliker raak. Die spraak-en taalontwikkeling wat kinders met FAS ervaar sluit in beperkte taalbegrip en intonasie. Hulle kort aandagspan affekteer veral hulle akademiese funksionering. Die aandagsteuring van kinders met FAS en kinders met aandagstekort-hiperaktiwiteit versteuring verskil neuro-biologies. Verdere verskille bestaan ook aangesien kinders met FAS spesifiek sukkel met swak enkoderingsvermoe en om kognitiewe aanpassings te maak. Visueel-ruimtelike verrnoe van kinders met FAS is ook benadeel. Hulle sukkel ook met verbale leer en hulle geheue is ook ingekort. Die inkortings dui op 'n oppervlakkige enkoderingsvermoe. Probleme met fyn-motoriese vaardighede is ook gevind, volgens toetseing. Toetse wat gemik is om uitvoerende funksies te evalueer, het verskeie uitvalle aan die lig gebring. Probleme in abstrakte redenering, beplanning, impulsiwiteit, self-regulering, en die lnlslerlnq en prosessering van informasie. Gedragsprobleme soos swak sosialiseringsvaardighede, aggresiwiteit, swak oordeel en hiperaktiwiteit. Die wye neurosielkundige uitvalle wat voorkom in kinders met FAS noodsaak vroee intervensie om die langtermyn-impak daarvan te verminder. Hiervoor word 'n sensitiewe battery neurosielkundige toetse benodig wat al die kognitiewe uitvalle kan identifiseer.

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

Non-invasive prenatal diagnosis (NIPD) is a promising approach that is currently being developed. The principle is that fetal material can be detected in maternal plasma and potentially enable women to pursue reliable and timely prenatal diagnosis, whilst eliminating the risk of miscarriage associated with chorionic villus sampling or amniocentesis. However NIPD research has been restricted up until now for the diagnosis of Down syndrome due to the low concentration of free fetal DNA (ffDNA) in maternal plasma. Various methods have been developed in an attempt to increase the concentration of ffDNA. This study uses COLD-PCR (co-amplification at lower denaturation temperature PCR) to analyse potential enrichment of ffDNA over maternal DNA through optimization of the critical denaturation temperature (Td), using Real Time-PCR in an attempt to selectively enrich smaller fetal DNA fragments. Fake fetal DNA was created in two different spike experiments to imitate the natural environment of viable ffDNA. One spike experiment used 5% of fake fetal DNA in a 95% maternal background to represent levels of ffDNA during early pregnancy. The other spike experiment utilized 10% of fake fetal DNA in 90% maternal background to denote late pregnancy. Before running COLD-PCR, various adjustments took place to find the critical Td at which one could run the spike experiment by COLD-PCR. Products of spike experiment were analysed on a genetic analyser for fragment analysis. Melt curve analysis was also performed for the spike experiment to identify the specificity of each sample at each denaturation temperatures. A critical Td (80°C) was identified for the D21S1890 region of chromosome 21 by COLD-PCR. This temperature does allow enrichment of fetal DNA, as fake maternal DNA was undetermined by RT-PCR compared to fake fetal DNA. The spike experiments clearly showed amplification of fake fetal DNA from the mixture of fake fetal and fake maternal DNA at the critical Td of 80°C. Running same samples of spike experiment on genetic analyser identified peaks from all samples at a Td of 95°C, while at a critical Td of 80°C the result showed decreased numbers of maternal peaks, regardless of stutter peaks formation. Melt curve analysis results clearly identified heteroduplex formation in the samples at the critical Td of 80°C. The results represent a good indication for using COLD-PCR in enriching ffDNA for detection by RT-PCR. However, as each individual has only two alleles, the observed results of multiple peaks for fragment analysis were not expected. Further research needs to focus on both eliminating heteroduplex formation and stutter peaks. COLD-PCR has the potential to open a new gateway in NIPD for aneuploidy detection. This method could be particularly useful in the detection of genetic abnormalities in the fetus, in particular Down syndrome and other aneuploidies.

Alloresponses to blood group antigens result from antigen mismatch between donor and recipient during blood transfusion or transplantation and between mother and fetus during pregnancy. During pregnancy, antigen mismatch can result in haemolytic disease of the newborn (HDN), a disease characterised by the development of potentially harmful alloantibodies, which cross the placenta and mediate the destruction of fetal erythrocytes. This project investigates examples of clinically important alloresponses to blood group antigens and, more specifically, characterises the ymphocytes that either drive or regulate these responses. The main aims or this project were to first map alioreactive T-helper cell epitopes and secondly to clone using a novel method, IL-10 secreting blood group specific regulatory cells. The work focussed on two major antigens, the kell (K) 1 and Rhesus (Rh) D antigens.