Despite the unprecedented improvement in child health in last 15 years, burden of stillbirth and neonatal death remain the key challenge in Nepal and the reduction of these deaths will be crucial for reaching the health targets for Sustainable development goal by 2030. The aim of this thesis was to explore the risk factors for stillbirth and neonatal death and change in perinatal outcomes after the introduction of the Helping Babies Breathe Quality Improvement Cycle (HBB QIC) in Nepal. This was a prospective cohort study with a nested case-control design completed in a tertiary hospital in Nepal. Information were collected from the women who had experienced perinatal death and live birth among referent population; a video recording was done in the neonatal resuscitation corner to collect information on the health workers’ performance in neonatal resuscitation.  Lack of antenatal care had the highest association with antepartum stillbirth (aOR 4.2, 95% CI 3.2–5.4), births that had inadequate fetal heart rate monitoring were associated with intrapartum stillbirth (aOR 1.9, CI 95% 1.5–2.4), and babies who were born premature and small-for-gestational-age had the highest risk for neonatal death in the hospital (aOR 16.2, 95% CI 12.3–21.3). Before the introduction of the HBB QIC, health workers displayed poor adherence to the neonatal resuscitation protocol. After the introduction of HBB QIC, the health workers demonstrated improvement in their neonatal resuscitation skills and these were retained until six months after training. Daily bag-and-mask skill checks (RR 5.1 95% CI 1.9–13.5), preparation for birth (RR 2.4, 95% CI 1.0–5.6), self-evaluation checklists (RR 3.8, 95% CI 1.4–9.7) and weekly review and reflection meetings (RR 2.6, 95% 1.0–7.4) helped the health workers to retain their neonatal resuscitation skills. The health workers demonstrated improvement in ventilation of babies within one minute of birth and there was a reduction in intrapartum stillbirth (aOR 0.46, 95% CI 0.32–0.66) and first-day neonatal mortality (aOR 0.51, 95% CI 0.31–0.83).  The study provides information on challenges in reducing stillbirth and neonatal death in low income settings and provides a strategy to improve health workers adherence to neonatal resuscitation to reduce the mortality. The HBB QIC can be implemented in similar clinical settings to improve quality of care and survival in Nepal, but for primary care settings, the QIC need to be evaluated further.

Une diète faible en sodium donnée à des rates lors de la dernière semaine de gestation induit une diminution de l’expansion volumique, du diamètre des artères utérines et du poids des placentas comparativement à des rates témoins. Ces perturbations suggèrent une diminution de la perfusion placentaire affectant l’apport foetal en nutriments. Les ratons naissent avec une restriction de croissance intra-utérine (RCIU). Chez le foetus, le substrat énergétique cardiaque principal est le glucose via la glycolyse. À la naissance, la source principale d’énergie est l’utilisation des acides gras par la β-oxydation. Nous émettons l’hypothèse que dans ce modèle de RCIU, le coeur foetal répond à la diminution d’apport nutritionnel due à une atteinte maternelle en adaptant son métabolisme énergétique cardiaque à la baisse. Les rates gestantes (témoins et recevant la diète faible en sodium) sont sacrifiées au jour 22 de gestation (sur 23). Les coeurs foetaux sont prélevés afin de caractériser les protéines dites « limitantes » in vitro des voies de la glycolyse et de la β-oxydation. Les expressions protéiques de GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2, mesurées par immunobuvardage de type Western, sont similaires entre les coeurs des foetus RCIU et témoins, mâles et femelles. L’expression protéique de CPT1α est diminuée dans les coeurs des femelles RCIU seulement. Il n’existe aucune différence significative entre les différents groupes quant à l’activité enzymatique de PKM1/2. Nos résultats dressent un profil métabolique général suggérant que le sexe du foetus peut avoir un effet sur la réponse cardiaque foetale à une atteinte du volume sanguin maternel causée par la diète restreinte en sodium. Ce profil métabolique semble démontrer une atteinte du catabolisme des lipides. Afin de bien caractériser cette réponse du mécanisme énergétique, l’activité enzymatique des autres enzymes principales de la glycolyse (HK1, HK2, PFK1), le flux intra-mitochondrial d’acyl CoA à travers les CPTs ainsi que la quantité totale d’acétyl CoA devront être quantifiés. / A low sodium diet was given to pregnant rats during the last week of gestation. This diet diminished the maternal expansion of blood volume, the uterine arteries diameter, and placental weight, when compared to their controls. Together, these results suggest a lower placenta perfusion and a decreased output of nutrients to the fetus. The offspring of these pregnant rats were born with an intra-uterine growth retardation (IUGR). The fetal heart utilizes glucose through glycolysis as the major cardiac energy substrate. At birth, the principal source of energy switches to the oxidation of fatty acids, through β-oxydation. We hypothesized that within our IUGR model, the fetal heart could respond to a diminished nutritional intake due to the maternal input when a decreased cardiac energy metabolism was present. The pregnant rats of both groups (controls and on the low sodium diet) were sacrificed on day 22 of a 23 day gestation. The fetal hearts were then analyzed looking for signs of the limiting proteins glycolysis and β-oxidation. The GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2 proteins obtained through a Western immunoblot method were similar between the hearts of the IUGR and their control fetuses, whether they were male or female. The protein expression of CPT1α was lower only in female IUGR fetal hearts. There was no significant difference between the groups with respect to the enzymatic activity of PKM1/2. Our results suggest that the metabolic profile changes with regards to the fetus gender and could affect the fetal cardiac metabolism, due to a lower maternal blood flow caused by a sodium controlled diet, by diminishing its lipid metabolism and sparing glucose metabolism. To characterize the energy metabolism, the enzymatic activity of the other principal limiting enzymes glycolysis (HK1, HK2, PFK1), the intra-mitochondrial flux of acyl CoA through the CPTs and the total quantity of acetyl CoA must also be analyzed.

INTRODUÇÃO: Gastrosquise é um defeito no fechamento da parede abdominal do feto que está relacionado a elevadas taxas de óbito intrauterino por mecanismos ainda desconhecidos. Em fetos normais, basicamente, todos os parâmetros da frequência cardíaca fetal (FCF) analisados na cardiotocografia computadorizada (CTGc) apresentam uma mudança significativa no decorrer da gestação. OBJETIVO: Descrever as características da FCF e o comportamento dos parâmetros avaliados pela CTGc anteparto, no período de 28 a 36 semanas de gestação. MÉTODOS: Estudo retrospectivo realizado na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de janeiro de 2012 a junho de 2015, envolvendo pacientes com gestação única, feto vivo e portador de gastrosquise isolada que foram submetidas à avaliação antenatal pela CTGc (Sistema FetalCare). Os parâmetros avaliados foram: número de movimentos fetais por hora, frequência cardíaca fetal basal (FCF), desacelerações, acelerações, episódios de alta e baixa variação e variação de curto prazo. A análise não paramétrica para medidas repetidas (ANOVA não paramétrica) foi utilizada para análise comparativa dos parâmetros da CTGc em cada idade gestacional avaliada. RESULTADOS: O estudo envolveu 87 gestantes com média de 3,5 (1-9) avaliações cardiotocográficas por paciente. O número de avaliações cardiotocográficas em cada idade gestacional foi >= 20, exceto para a idade de 29 semanas (n = 16). Os principais parâmetros da FCF avaliados pela CTGc como a FCF basal e o STV não apresentaram mudança significativa. Apenas dois parâmetros da CTGc apresentaram mudança significativa no período avaliado: o número de exames com presença de episódios de baixa variação da FCF aumentou no decorrer da gestação (p = 0,019); e o número de acelerações acima de 15 batimentos por minuto aumentou no evoluir das idades gestacionais estudadas (p = 0,001). Nenhum dos outros parâmetros avaliados pela CTGc apresentou mudança significativa no decorrer do período avaliado: o número de movimentos fetais por hora (p = 0,244), a FCF basal (p = 0,606) e o STV (p = 0,145). CONCLUSÃO: O comportamento da FCF dos fetos com gastrosquise difere do padrão apresentado por fetos normais, já que a maioria dos parâmetros da FCF avaliados pela CTGc de fetos com gastrosquise não apresentou mudança significativa no período gestacional avaliado / INTRODUCTION: Fetal gastroschisis is an abdominal wall defect associated with high rates of intrauterine death of unknown mechanisms. In normal fetuses, basically all computerized cardiotocography (cCTG) parameters present a significant change across gestation. OBJECTIVE: To describe the antepartum cCTG parameters between 28 to 36 weeks gestation. METHODS: Retrospective study, accomplished in the Obstetrics Department of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil between January 2012 and June 2015, involving singleton pregnancies, with alive fetus and isolated gastroschisis that underwent to cCTG (System 8002-Sonicaid) during the antenatal care. The cCTG parameters evaluated were: number of fetal movements per hour, baseline fetal heart rate (FHR) decelerations, accelerations, episodes of high and low variation and short-term variation. A non-parametric analysis for repeated measures (nonparametric ANOVA) was used for comparative analysis of the mean distribution of each cCTG parameters throughout the study period. RESULTS: The study involved 84 pregnant women with a mean of 3.5 (1 - 9) cCTG records per patient. The number of records in each gestational age was >= 20 except for the weeks 29 (n = 16). The cCTG parameters that presented significant change during the study period were: increase in the number of records with episodes of low variation (p = 0.019); and increase in the number of accelerations higher than 15 beats per minute (p = 0.001). None of the others analyzed parameters showed significant changes during the study period, the number of movements/hr (p = 0,244), basal FHR (p = 0,606) and the STV (p = 0,145). CONCLUSION: Only two of the cCTG parameters changed significantly during the study period. Therefore, it seems that the behavior patterns of cCTG parameters, in gastroschisis fetuses, are not similar to the normal fetuses

INTRODUÇÃO: Gastrosquise é um defeito no fechamento da parede abdominal do feto que está relacionado a elevadas taxas de óbito intrauterino por mecanismos ainda desconhecidos. Em fetos normais, basicamente, todos os parâmetros da frequência cardíaca fetal (FCF) analisados na cardiotocografia computadorizada (CTGc) apresentam uma mudança significativa no decorrer da gestação. OBJETIVO: Descrever as características da FCF e o comportamento dos parâmetros avaliados pela CTGc anteparto, no período de 28 a 36 semanas de gestação. MÉTODOS: Estudo retrospectivo realizado na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de janeiro de 2012 a junho de 2015, envolvendo pacientes com gestação única, feto vivo e portador de gastrosquise isolada que foram submetidas à avaliação antenatal pela CTGc (Sistema FetalCare). Os parâmetros avaliados foram: número de movimentos fetais por hora, frequência cardíaca fetal basal (FCF), desacelerações, acelerações, episódios de alta e baixa variação e variação de curto prazo. A análise não paramétrica para medidas repetidas (ANOVA não paramétrica) foi utilizada para análise comparativa dos parâmetros da CTGc em cada idade gestacional avaliada. RESULTADOS: O estudo envolveu 87 gestantes com média de 3,5 (1-9) avaliações cardiotocográficas por paciente. O número de avaliações cardiotocográficas em cada idade gestacional foi >= 20, exceto para a idade de 29 semanas (n = 16). Os principais parâmetros da FCF avaliados pela CTGc como a FCF basal e o STV não apresentaram mudança significativa. Apenas dois parâmetros da CTGc apresentaram mudança significativa no período avaliado: o número de exames com presença de episódios de baixa variação da FCF aumentou no decorrer da gestação (p = 0,019); e o número de acelerações acima de 15 batimentos por minuto aumentou no evoluir das idades gestacionais estudadas (p = 0,001). Nenhum dos outros parâmetros avaliados pela CTGc apresentou mudança significativa no decorrer do período avaliado: o número de movimentos fetais por hora (p = 0,244), a FCF basal (p = 0,606) e o STV (p = 0,145). CONCLUSÃO: O comportamento da FCF dos fetos com gastrosquise difere do padrão apresentado por fetos normais, já que a maioria dos parâmetros da FCF avaliados pela CTGc de fetos com gastrosquise não apresentou mudança significativa no período gestacional avaliado / INTRODUCTION: Fetal gastroschisis is an abdominal wall defect associated with high rates of intrauterine death of unknown mechanisms. In normal fetuses, basically all computerized cardiotocography (cCTG) parameters present a significant change across gestation. OBJECTIVE: To describe the antepartum cCTG parameters between 28 to 36 weeks gestation. METHODS: Retrospective study, accomplished in the Obstetrics Department of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil between January 2012 and June 2015, involving singleton pregnancies, with alive fetus and isolated gastroschisis that underwent to cCTG (System 8002-Sonicaid) during the antenatal care. The cCTG parameters evaluated were: number of fetal movements per hour, baseline fetal heart rate (FHR) decelerations, accelerations, episodes of high and low variation and short-term variation. A non-parametric analysis for repeated measures (nonparametric ANOVA) was used for comparative analysis of the mean distribution of each cCTG parameters throughout the study period. RESULTS: The study involved 84 pregnant women with a mean of 3.5 (1 - 9) cCTG records per patient. The number of records in each gestational age was >= 20 except for the weeks 29 (n = 16). The cCTG parameters that presented significant change during the study period were: increase in the number of records with episodes of low variation (p = 0.019); and increase in the number of accelerations higher than 15 beats per minute (p = 0.001). None of the others analyzed parameters showed significant changes during the study period, the number of movements/hr (p = 0,244), basal FHR (p = 0,606) and the STV (p = 0,145). CONCLUSION: Only two of the cCTG parameters changed significantly during the study period. Therefore, it seems that the behavior patterns of cCTG parameters, in gastroschisis fetuses, are not similar to the normal fetuses

L’analyse visuelle du rythme cardiaque fœtal (RCF) est une excellente méthode de dépistage de l’hypoxie fœtale. Cette analyse visuelle est d’autre part sujette à une variabilité inter- et intra-individuelle importante. L’hypoxie fœtale au cours du travail s’exprime par des anomalies du RCF. La sous-évaluation de la gravité d’un RCF entraine une prise de risque indue pour le fœtus avec une augmentation de sa morbi-mortalité et sa surévaluation entraine un interventionnisme obstétrical inutile avec une augmentation du taux de césariennes. Ce dernier point pose par ailleurs en France un problème de santé publique.L’analyse automatisée du signal RCF permet de diminuer la variabilité inter- et intra-individuelle et d’accéder à d’autres paramètres calculés visant à augmenter la valeur diagnostique. Les critères d’analyse morphologiques du RCF (ligne de base, nombre d’accélérations, nombre et typage des ralentissements, variabilité à long terme (VLT)) ont été décrits ainsi que d’autres tels que les surfaces des ralentissements, les indices de variabilité à court terme (VCT) et les analyses fréquentielles. Il n’en demeure pas moins que la définition de la ligne de base, à partir de laquelle sont repérés les accélérations et les ralentissements reste, dans certains cas, difficile à établir.L’objectif principal de la thèse est d’établir un modèle prédictif de l’acidose fœtale à partir d’une analyse automatisée du RCF. L’objectif secondaire est de déterminer la pertinence des différents paramètres élémentaires classiques (CNGOF 2007) (fréquence de base, variabilité, accélérations, ralentissements) et celle d’autres paramètres inaccessible à l’œil (indices de variabilité à court terme, surfaces des ralentissements, analyse fréquentielle…). Par la suite, nous voulons identifier des critères de décision qui aideront à la prise en charge obstétricale.Nous proposons d’aborder l’analyse automatisée du RCF pendant le travail par l’intermédiaire d’une étude cas-témoins ; les cas étant des tracés RCF de nouveau-nés en acidose néonatale (pH artériel au cordon inférieur ou égal à 7,15) et les témoins, des tracés RCF de nouveau-nés sans acidose (pH artériel au cordon supérieur ou égal à 7,25). Il s’agit d’une étude monocentrique à la maternité de l’hôpital Saint Vincent de Paul, GHICL – Lille, sur notre base de données « Bien Naitre » (archivage numérique des tracés RCF depuis 2011), comptant un un nombre suffisant de cas sur ce seul centre. La maternité Saint Vincent de Paul (GHICL) présente depuis 2011 environ 70 cas par an d’acidose néonatale (pHa ≤ 7,10) (3,41%). Le logiciel R sera utilisé pour l’analyse statistique / Visual analysis of the fetal heart rate FHR is a good method for screening for fetal hypoxia but is not sufficiently specific. The visual morphological analysis of the FHR during labor is subject to inter- and intra-observer variability – particularly when the FHR is abnormal. Underestimating the severity of an FHR leads to undue risk-taking for the fetus with an increase in morbidity and mortality and overvaluation leads to unnecessary obstetric intervention with an increased rate of caesarean section. This last point also induces a French public health problem.FHR automated analysis reduces inter and intra-individual variability and accesses other calculated parameters aimed at increasing the diagnostic value. The FHR morphological analysis parameters (baseline, number of accelerations, number and typing of decelerations, long-term variability (LTV)) were described as well as others such as the decelerations surfaces, short-term variability (STV) and frequency analyzes. Nevertheless, when attempting to analyze the FHR automatically, the main problem is computation of the baseline against which all the other parameters are determined.Automatic analysis provides information on parameters that cannot be derived in a visual analysis and that are likely to improve screening for fetal acidosis during labor.The main objective of the thesis is to establish a predictive model of fetal acidosis from a FHR automated analysis. The secondary objective is to determine the relevance of the classical basic parameters (CNGOF 2007) (baseline, variability, accelerations, decelerations) and that of other parameters inaccessible to the eye (indices of short-term variability, surfaces of decelerations, frequency analysis ...). Later, we want to identify decision criteria that will help in the obstetric care management.We propose to validate FHR automated analysis during labor through a case-control study; cases were FHR recordings of neonatal acidosis (arterial cord pH less than or equal to 7.15) and controls, FHR recordings of neonatal without acidosis (arterial cord pH upper than or equal to 7.25). This is a monocentric study at the maternity hospital of Saint Vincent de Paul Hospital, GHICL - Lille, on our « Well Born » database (digital archiving of RCF plots since 2011), with a sufficient number of cases on this only center. Since 2011, the Saint Vincent de Paul hospital (GHICL) has had about 70 cases per year of neonatal acidosis (pHa less than or equal to 7.10) (3.41%). The R software will be used for statistical analysis.

Une diète faible en sodium donnée à des rates lors de la dernière semaine de gestation induit une diminution de l’expansion volumique, du diamètre des artères utérines et du poids des placentas comparativement à des rates témoins. Ces perturbations suggèrent une diminution de la perfusion placentaire affectant l’apport foetal en nutriments. Les ratons naissent avec une restriction de croissance intra-utérine (RCIU). Chez le foetus, le substrat énergétique cardiaque principal est le glucose via la glycolyse. À la naissance, la source principale d’énergie est l’utilisation des acides gras par la β-oxydation. Nous émettons l’hypothèse que dans ce modèle de RCIU, le coeur foetal répond à la diminution d’apport nutritionnel due à une atteinte maternelle en adaptant son métabolisme énergétique cardiaque à la baisse. Les rates gestantes (témoins et recevant la diète faible en sodium) sont sacrifiées au jour 22 de gestation (sur 23). Les coeurs foetaux sont prélevés afin de caractériser les protéines dites « limitantes » in vitro des voies de la glycolyse et de la β-oxydation. Les expressions protéiques de GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2, mesurées par immunobuvardage de type Western, sont similaires entre les coeurs des foetus RCIU et témoins, mâles et femelles. L’expression protéique de CPT1α est diminuée dans les coeurs des femelles RCIU seulement. Il n’existe aucune différence significative entre les différents groupes quant à l’activité enzymatique de PKM1/2. Nos résultats dressent un profil métabolique général suggérant que le sexe du foetus peut avoir un effet sur la réponse cardiaque foetale à une atteinte du volume sanguin maternel causée par la diète restreinte en sodium. Ce profil métabolique semble démontrer une atteinte du catabolisme des lipides. Afin de bien caractériser cette réponse du mécanisme énergétique, l’activité enzymatique des autres enzymes principales de la glycolyse (HK1, HK2, PFK1), le flux intra-mitochondrial d’acyl CoA à travers les CPTs ainsi que la quantité totale d’acétyl CoA devront être quantifiés. / A low sodium diet was given to pregnant rats during the last week of gestation. This diet diminished the maternal expansion of blood volume, the uterine arteries diameter, and placental weight, when compared to their controls. Together, these results suggest a lower placenta perfusion and a decreased output of nutrients to the fetus. The offspring of these pregnant rats were born with an intra-uterine growth retardation (IUGR). The fetal heart utilizes glucose through glycolysis as the major cardiac energy substrate. At birth, the principal source of energy switches to the oxidation of fatty acids, through β-oxydation. We hypothesized that within our IUGR model, the fetal heart could respond to a diminished nutritional intake due to the maternal input when a decreased cardiac energy metabolism was present. The pregnant rats of both groups (controls and on the low sodium diet) were sacrificed on day 22 of a 23 day gestation. The fetal hearts were then analyzed looking for signs of the limiting proteins glycolysis and β-oxidation. The GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2 proteins obtained through a Western immunoblot method were similar between the hearts of the IUGR and their control fetuses, whether they were male or female. The protein expression of CPT1α was lower only in female IUGR fetal hearts. There was no significant difference between the groups with respect to the enzymatic activity of PKM1/2. Our results suggest that the metabolic profile changes with regards to the fetus gender and could affect the fetal cardiac metabolism, due to a lower maternal blood flow caused by a sodium controlled diet, by diminishing its lipid metabolism and sparing glucose metabolism. To characterize the energy metabolism, the enzymatic activity of the other principal limiting enzymes glycolysis (HK1, HK2, PFK1), the intra-mitochondrial flux of acyl CoA through the CPTs and the total quantity of acetyl CoA must also be analyzed.

A hemólise decorrente da doença aloimune desencadeia mecanismos adaptativos hematológicos e hemodinâmicos fetais, com intuito de garantir o suprimento adequado de oxigênio para todos os tecidos e órgãos. Na anemia grave, a sobrecarga imposta ao coração fetal, devido ao fluxo hiperdinâmico, tem sido considerada responsável pela insuficiencia cardiaca, e posterior desenvolvimento de hidropisia fetal. No entanto, a literatura médica ainda apresenta controvérsias acerca da integridade da função cardiaca nesta doença. O índice de performance miocárdico (IPM) é uma ferramenta propedêutica não invasiva, derivada do Doppler pulsátil, que permite avaliar a função cardíaca global (sistólica e diastólica). Objetivo: Estudar a função cardíaca fetal, na doença aloimune, utilizando o índice de performance miocárdica. Métodos: Foram seguidos, prospectivamente, fetos únicos, de gestantes sensibilizadas pelo antígeno eritrocitário D, sem malformações estruturais, na Clinica Obstétrica, Hospital das Clinicas da Faculdade de Medicina de São Paulo. A cada avaliação ultrassonográfica, o IPM foi investigado por meio de Doppler pulsátil, com janela de 2-4mm, filtro>190Hz e velocidade de varredura que permitisse observar de 3 a 4 ciclos cardíacos simultâneos no ecrã. O IPM corresponde à soma dos tempos isovolumétricos (contração e relaxamento) dividido pelo tempo de ejeção do ciclo cardíaco. O IPM do ventrículo equerdo (IPM VE) foi realizado em ciclo único, sendo possível obter seus componentes: tempo de contração isovolumétrico (TCI), tempo de relaxamento isovolumétrico (TRI) e tempo de ejeção (TE). O IPM do ventrículo direito (IPM VD) foi obtido em dois tempos. Os valores obtidos de IPM VE, seus componentes foram convertidos em escore zeta para a idade gestacional. Frente à suspeita de anemia fetal, realizou-se cordocentese com determinação dos níveis de hemoglobina fetal antes e após a transfusão intra-uterina. Os respectivos valores foram convertidos em escore-zeta (Hb zeta). Na análise estatística, foram incluidas avaliações do IPM realizadas com menos de 72 horas antes, e até 24 horas após cada transfusão. Para cada transfusão foi calculada a variação no IPM (delta IPM = IPM antes - IPM após). O nível de significância estatísca adotado foi de 0,05. Análises por regressão linear simples e logística foram utilizadas para examinar a associação entre os valores de IPM e delta IPM e as seguintes variáveis: idade gestacional no procedimento, múltiplos da mediana (MoM) da Vmax ACM, Hb zeta pré e após TIU, volume de sangue transfundido e porcentagem da expansão do volume feto-placentário (EVFP). Resultados: Foram incluidas 14 gestações submetidas a 31 procedimentos de cordocentese para transfusão intra-uterina. A idade gestacional média na 1ª transfusão foi de 28,2 ± 4,1 semanas Em 6 procedimentos, a avaliação do IPM pós transfusional foi incompleta, e esses dados não foram incluídos na análise. Quanto à análise dos dados obtidos nas cordocenteses, observou-se correlação significativa entre os valores de escore zeta de IPM VE (r= 0,59, p <0,001), TRI (r= 0,45, p =0,01) e o TE (r= 0,42, p=0,2) e o escore zeta da hemoglobina fetal. Não foi observada correlação significativa com o escore zeta do TCI (r= 0,35, p=0,054) e do IPM VD (r=0,12, p= 0,53). Quando comparados aos valores observados antes das transfuões intra-uterinas, observou-se aumento significativo do escore zeta de IPM VE após os procedimentos (Delta MPI = 1,10 ± 2,47, p = 0,036). Não foi observada correlação entre os valores de escore zeta de IPM antes e após TIU. Delta MPI do VE se correlacionou inversamente, e de forma significativa, com a idade gestacional no procedimento (r= 0,47, p=0,018), escore zeta IPM VE pré-TIU (r= 0,50, p=0,012) e EVFP (r= 0,41, p=0,044). Conclusões: O desempenho miocárdico do ventriculo esquerdo fetal permanece preservado frente a anemia, e nos casos de anemia moderada e grave encontra-se ainda mais eficiente. Após a realização da transfusão intrauterina, observou-se aumento significativo do índice de performance miocárdica, e este aumento esteve relacionado com idade gestacional no procedimento, valores de IPM pré-transfusionais e a expansão do volume feto-placentário / Fetal anemia is associated with several adaptative mechanisms in order to maintain adequate tissue oxygenation. Circulatory changes play a key role in such circumstances. In severe anemia, the overload imposed on the fetal heart, due to the hyperdynamic flow, has been considered to be responsible for cardiac failure and finally hydrops fetalis. However, cardiac failure in this pathology remains controversy. Myocardial performance index (MPI) is a novel technique, Doppler derived and non-invasive that allows assesses global cardiac function (systolic and diatolic). Objective: Evaluate global cardiac function in alloimune disease through myocardial performance index. Methods: This prospective study was carried out at a tertiary referral center for fetal medicine (Clínica Obstetrica do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo). Women with singleton pregnancies and Rh D alloimmune disease were invited to take part in the study and gave informed consent. Fetal examinations did not show structural abnormalities. At every ultrasonography evaluation, MPI was examined with Doppler sample gate set between 2-4mm, wall motion filter >190Hz and high sweep-speed to allow simultaneous identification of 3-4 cardiac cycles on the screen. MPI is the sum of isovolumetric times (contraction and relaxation) divided by ejection time. Left ventricle MPI (LV MPI) was obtained in a single cycle and the MPI components were obtained: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET). Right ventricle MPI (RV MPI) was obtained in two cycles. The values obtained for LV MPI and its components were converted in zeta score for gestacional age. Cordocentesis was perfomed if fetal anemia was suspicion and fetal hemoglobin levels were determined: before and after intrauterine transfusion. Hemoglobin values were converted into the zeta score (Hb zeta). Statistical analysis included MPI evaluations performed within less than 72 hours before and until 24 hours after every transfusion. Variation in the MPI was calculated for every transfusion (delta MPI = MPI before - MPI after). Significance level was set at 0,05. Linear and regression analyses were made in order to examine association between MPI values and delta MPI gestational age at procedure, fetal ACM multiples of median (MoM), Hb zeta before and after the IUT, volume of blood transfused and percentage of the feto-placental expansion volume (FPEV). Results: 14 pregnancies were included. Overall 31 cordocentesis for intrauterine transfusion were performed at mean gestational age of 28,2 ± 4,1 weeks. In 6 procedures, post transfusion MPI evaluation was incomplete and these data were not included in the analysis. Zeta-score values LV MPI (r= 0,59, p < 0,001), IRT (r= 0,45, p =0,01) and ET (r= 0,42, p=0,02) correlated significantly with fetal hemoglobin zeta score. Left ventricle ICT zeta-score (r= 0,35, p=0,054) and RV MPI (r=0,12, p= 0,53). did not show significant correlation. After intrauterine transfusion, LV MPI z-score ]increases and it was statistical significant (Delta MPI = 1,10 ± 2,47, p = 0,036). No correlation was observed between MPI zeta score values before and after the IUT. Delta LV MPI had inverse and significant correlation with pregnancy age in the proceedings (r= 0,47, p=0,018), LV MPI zeta score before IUT (r= 0,50, p=0,012) and FPEV (r= 0,41, p=0,044). Conclusions: Left ventricle myocardial performance not only remains preserved but is actually enhanced in cases of moderate/severe fetal anemia. After intrauterine transfusion procedure, left ventricle myocardial performance index increases significantly and greater changes are associated with procedures at earlier gestational age, lower pre transfusion MPI z-scores and smaller feto-placental volume expansion

A hemólise decorrente da doença aloimune desencadeia mecanismos adaptativos hematológicos e hemodinâmicos fetais, com intuito de garantir o suprimento adequado de oxigênio para todos os tecidos e órgãos. Na anemia grave, a sobrecarga imposta ao coração fetal, devido ao fluxo hiperdinâmico, tem sido considerada responsável pela insuficiencia cardiaca, e posterior desenvolvimento de hidropisia fetal. No entanto, a literatura médica ainda apresenta controvérsias acerca da integridade da função cardiaca nesta doença. O índice de performance miocárdico (IPM) é uma ferramenta propedêutica não invasiva, derivada do Doppler pulsátil, que permite avaliar a função cardíaca global (sistólica e diastólica). Objetivo: Estudar a função cardíaca fetal, na doença aloimune, utilizando o índice de performance miocárdica. Métodos: Foram seguidos, prospectivamente, fetos únicos, de gestantes sensibilizadas pelo antígeno eritrocitário D, sem malformações estruturais, na Clinica Obstétrica, Hospital das Clinicas da Faculdade de Medicina de São Paulo. A cada avaliação ultrassonográfica, o IPM foi investigado por meio de Doppler pulsátil, com janela de 2-4mm, filtro>190Hz e velocidade de varredura que permitisse observar de 3 a 4 ciclos cardíacos simultâneos no ecrã. O IPM corresponde à soma dos tempos isovolumétricos (contração e relaxamento) dividido pelo tempo de ejeção do ciclo cardíaco. O IPM do ventrículo equerdo (IPM VE) foi realizado em ciclo único, sendo possível obter seus componentes: tempo de contração isovolumétrico (TCI), tempo de relaxamento isovolumétrico (TRI) e tempo de ejeção (TE). O IPM do ventrículo direito (IPM VD) foi obtido em dois tempos. Os valores obtidos de IPM VE, seus componentes foram convertidos em escore zeta para a idade gestacional. Frente à suspeita de anemia fetal, realizou-se cordocentese com determinação dos níveis de hemoglobina fetal antes e após a transfusão intra-uterina. Os respectivos valores foram convertidos em escore-zeta (Hb zeta). Na análise estatística, foram incluidas avaliações do IPM realizadas com menos de 72 horas antes, e até 24 horas após cada transfusão. Para cada transfusão foi calculada a variação no IPM (delta IPM = IPM antes - IPM após). O nível de significância estatísca adotado foi de 0,05. Análises por regressão linear simples e logística foram utilizadas para examinar a associação entre os valores de IPM e delta IPM e as seguintes variáveis: idade gestacional no procedimento, múltiplos da mediana (MoM) da Vmax ACM, Hb zeta pré e após TIU, volume de sangue transfundido e porcentagem da expansão do volume feto-placentário (EVFP). Resultados: Foram incluidas 14 gestações submetidas a 31 procedimentos de cordocentese para transfusão intra-uterina. A idade gestacional média na 1ª transfusão foi de 28,2 ± 4,1 semanas Em 6 procedimentos, a avaliação do IPM pós transfusional foi incompleta, e esses dados não foram incluídos na análise. Quanto à análise dos dados obtidos nas cordocenteses, observou-se correlação significativa entre os valores de escore zeta de IPM VE (r= 0,59, p <0,001), TRI (r= 0,45, p =0,01) e o TE (r= 0,42, p=0,2) e o escore zeta da hemoglobina fetal. Não foi observada correlação significativa com o escore zeta do TCI (r= 0,35, p=0,054) e do IPM VD (r=0,12, p= 0,53). Quando comparados aos valores observados antes das transfuões intra-uterinas, observou-se aumento significativo do escore zeta de IPM VE após os procedimentos (Delta MPI = 1,10 ± 2,47, p = 0,036). Não foi observada correlação entre os valores de escore zeta de IPM antes e após TIU. Delta MPI do VE se correlacionou inversamente, e de forma significativa, com a idade gestacional no procedimento (r= 0,47, p=0,018), escore zeta IPM VE pré-TIU (r= 0,50, p=0,012) e EVFP (r= 0,41, p=0,044). Conclusões: O desempenho miocárdico do ventriculo esquerdo fetal permanece preservado frente a anemia, e nos casos de anemia moderada e grave encontra-se ainda mais eficiente. Após a realização da transfusão intrauterina, observou-se aumento significativo do índice de performance miocárdica, e este aumento esteve relacionado com idade gestacional no procedimento, valores de IPM pré-transfusionais e a expansão do volume feto-placentário / Fetal anemia is associated with several adaptative mechanisms in order to maintain adequate tissue oxygenation. Circulatory changes play a key role in such circumstances. In severe anemia, the overload imposed on the fetal heart, due to the hyperdynamic flow, has been considered to be responsible for cardiac failure and finally hydrops fetalis. However, cardiac failure in this pathology remains controversy. Myocardial performance index (MPI) is a novel technique, Doppler derived and non-invasive that allows assesses global cardiac function (systolic and diatolic). Objective: Evaluate global cardiac function in alloimune disease through myocardial performance index. Methods: This prospective study was carried out at a tertiary referral center for fetal medicine (Clínica Obstetrica do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo). Women with singleton pregnancies and Rh D alloimmune disease were invited to take part in the study and gave informed consent. Fetal examinations did not show structural abnormalities. At every ultrasonography evaluation, MPI was examined with Doppler sample gate set between 2-4mm, wall motion filter >190Hz and high sweep-speed to allow simultaneous identification of 3-4 cardiac cycles on the screen. MPI is the sum of isovolumetric times (contraction and relaxation) divided by ejection time. Left ventricle MPI (LV MPI) was obtained in a single cycle and the MPI components were obtained: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET). Right ventricle MPI (RV MPI) was obtained in two cycles. The values obtained for LV MPI and its components were converted in zeta score for gestacional age. Cordocentesis was perfomed if fetal anemia was suspicion and fetal hemoglobin levels were determined: before and after intrauterine transfusion. Hemoglobin values were converted into the zeta score (Hb zeta). Statistical analysis included MPI evaluations performed within less than 72 hours before and until 24 hours after every transfusion. Variation in the MPI was calculated for every transfusion (delta MPI = MPI before - MPI after). Significance level was set at 0,05. Linear and regression analyses were made in order to examine association between MPI values and delta MPI gestational age at procedure, fetal ACM multiples of median (MoM), Hb zeta before and after the IUT, volume of blood transfused and percentage of the feto-placental expansion volume (FPEV). Results: 14 pregnancies were included. Overall 31 cordocentesis for intrauterine transfusion were performed at mean gestational age of 28,2 ± 4,1 weeks. In 6 procedures, post transfusion MPI evaluation was incomplete and these data were not included in the analysis. Zeta-score values LV MPI (r= 0,59, p < 0,001), IRT (r= 0,45, p =0,01) and ET (r= 0,42, p=0,02) correlated significantly with fetal hemoglobin zeta score. Left ventricle ICT zeta-score (r= 0,35, p=0,054) and RV MPI (r=0,12, p= 0,53). did not show significant correlation. After intrauterine transfusion, LV MPI z-score ]increases and it was statistical significant (Delta MPI = 1,10 ± 2,47, p = 0,036). No correlation was observed between MPI zeta score values before and after the IUT. Delta LV MPI had inverse and significant correlation with pregnancy age in the proceedings (r= 0,47, p=0,018), LV MPI zeta score before IUT (r= 0,50, p=0,012) and FPEV (r= 0,41, p=0,044). Conclusions: Left ventricle myocardial performance not only remains preserved but is actually enhanced in cases of moderate/severe fetal anemia. After intrauterine transfusion procedure, left ventricle myocardial performance index increases significantly and greater changes are associated with procedures at earlier gestational age, lower pre transfusion MPI z-scores and smaller feto-placental volume expansion

Αντικείμενο της διατριβής ήταν η ανάπτυξη υπολογιστικών μεθόδων διάγνωσης και εκτίμησης της κατάστασης της υγείας του εμβρύου. Οι προτεινόμενες μεθοδολογίες αναλύουν και εξάγουν πληροφορίες από το σήμα της ΕΚΣ καθώς το συγκεκριμένο σήμα αποτελεί ένα από τα λιγοστά διαθέσιμα εργαλεία για την εκτίμηση της οξυγόνωσης του εμβρύου και της αξιολόγησης της κατάστασης της υγείας του κατά τη διάρκεια του τοκετού. Για την αξιολόγηση των μεθόδων εξετάστηκε η συσχέτιση της Εμβρυϊκής Καρδιακής Συχνότητας (ΕΚΣ) με βραχυπρόθεσμες αξιόπιστες ενδείξεις για την κατάσταση του εμβρύου και πιο συγκεκριμένα χρησιμοποιήθηκε η συσχέτιση της τιμής του pH του αίματος του εμβρύου η οποία αποτελεί μια έμμεση ένδειξη για την ανάπτυξη υποξίας κατά τη διάρκεια του τοκετού. Στα πλαίσια της διατριβής χρησιμοποιήθηκε για πρώτη φορά η μέθοδος της ανάλυσης σε ανεξάρτητες συνιστώσες για την εξαγωγή χαρακτηριστικών από το σήμα της ΕΚΣ. Επίσης προτάθηκαν και χρησιμοποιήθηκαν Κρυφά Μοντέλα Markov σε μια προσπάθεια να «συλληφθεί» η χρονική εξέλιξη του φαινομένου της μεταβολής της κατάστασης του εμβρύου. Επιπλέον προτάθηκαν νέα χαρακτηριστικά εξαγόμενα με τη χρήση του Διακριτού Μετασχηματισμού Κυματιδίου. Με χρήση μιας υβριδική μέθοδος, που βασίζεται στη χρήση εξελικτικής γραμματικής «κατασκευάστηκαν» νέα χαρακτηριστικά παραγόμενα από τα χαρακτηριστικά που είχαν ήδη εξαχθεί με συμβατικές μεθόδους. Επιπρόσθετα στα πλαίσια της διατριβής χρησιμοποιήθηκαν για πρώτη φορά (και η μόνη μέχρι στιγμής) μηχανές διανυσμάτων υποστήριξης για την ταξινόμηση και προτάθηκε και χρησιμοποιήθηκε για πρώτη φορά η μέθοδος βελτιστοποίησης με σμήνος σωματιδίων για τη ρύθμιση των παραμέτρων τους. Τέλος προτάθηκε και χρησιμοποιήθηκε για πρώτη φορά η μέθοδος βελτιστοποίησης με σμήνος σωματιδίων για την εκπαίδευση μιας νέας οικογένειας νευρωνικών δικτύων, των νευρωνικών δικτύων κυματιδίου. Μέσα από τα πειράματα τα οποία διεξήγαμε καταφέραμε να δείξουμε ότι τα δεδομένα της ΕΚΣ διαθέτουν σημαντική πληροφορία η οποία με τη χρήση κατάλληλων προηγμένων μεθόδων επεξεργασίας και ταξινόμησης μπορεί να συσχετιστεί με την τιμή του pH του εμβρύου, κάτι το οποίο θεωρούνταν ουτοπικό στη δεκαετία του 90. / This Dissertation dealt with the development of computational methods for the diagnosis and estimation of fetal condition. The proposed methods analyzed and extracted information from the Fetal Heart Rate (FHR) signal, since this is one of the few available tools for the estimation of fetal oxygenation and the assessment of fetal condition during labor. For the evaluation of the proposed methods the correlation of the FHR signal with short term indices were employed and to be more specific, its correlation with the pH values of fetal blood, which is an indirect sign of the development of fetal hypoxia during labor. In the context of this Dissertation, Independent Component Analysis (ICA) for feature extraction from the FHR signal was used for the first time. Moreover we used Hidden Markov Models in an attempt to “capture” the evolution in time of the fetal condition. Furthermore, new features based on the Discrete Wavelet Transform were proposed and used. Using a new hybrid method based on grammatical evolution new features were constructed based on already extracted features by conventional methods. Moreover, for the first (and only) time, Support Vector Machine (SVM) classifiers were employed in the field of FHR processing and the Particle Swarm Optimization (PSO) method was proposed for tuning their parameters. Finally, a new family of neural networks, the Wavelet Neural Networks (WNN) was proposed and used, trained using the PSO method. By conducting a number of experiments we managed to show that the FHR signal conveys valuable information, which by the use of advanced data processing and classification techniques can be associated with fetal pH, something which was not regarded feasible during the 90’s.

L'analyse de séries temporelles biomédicales chaotiques tirées de systèmes dynamiques non-linéaires est toujours un challenge difficile à relever puisque dans certains cas bien spécifiques les techniques existantes basées sur les multi-fractales, les entropies et les graphes de récurrence échouent. Pour contourner les limitations des invariants précédents, de nouveaux descripteurs peuvent être proposés. Dans ce travail de recherche nos contributions ont porté à la fois sur l’amélioration d’indicateurs multifractaux (basés sur une fonction de structure) et entropiques (approchées) mais aussi sur des indicateurs de récurrences (non biaisés). Ces différents indicateurs ont été développés avec pour objectif majeur d’améliorer la discrimination entre des signaux de complexité différente ou d’améliorer la détection de transitions ou de changements de régime du système étudié. Ces changements agissant directement sur l’irrégularité du signal, des mouvements browniens fractionnaires et des signaux tirés du système du Lorenz ont été testés. Ces nouveaux descripteurs ont aussi été validés pour discriminer des fœtus en souffrance de fœtus sains durant le troisième trimestre de grossesse. Des mesures statistiques telles que l’erreur relative, l’écart type, la spécificité, la sensibilité ou la précision ont été utilisées pour évaluer les performances de la détection ou de la classification. Le fort potentiel de ces nouveaux invariants nous laisse penser qu’ils pourraient constituer une forte valeur ajoutée dans l’aide au diagnostic s’ils étaient implémentés dans des logiciels de post-traitement ou dans des dispositifs biomédicaux. Enfin, bien que ces différentes méthodes aient été validées exclusivement sur des signaux fœtaux, une future étude incluant des signaux tirés d’autres systèmes dynamiques nonlinéaires sera réalisée pour confirmer leurs bonnes performances. / The analysis of biomedical time series derived from nonlinear dynamic systems is challenging due to the chaotic nature of these time series. Only few classical parameters can be detected by clinicians to opt the state of patients and fetuses. Though there exist valuable complexity invariants such as multi-fractal parameters, entropies and recurrence plot, they were unsatisfactory in certain cases. To overcome this limitation, we propose in this dissertation new entropy invariants, we contributed to multi-fractal analysis and we developed signal-based (unbiased) recurrence plots based on the dynamic transitions of time series. Principally, we aim to improve the discrimination between healthy and distressed biomedical systems, particularly fetuses by processing the time series using our techniques. These techniques were either validated on Lorenz system, logistic maps or fractional Brownian motions modeling chaotic and random time series. Then the techniques were applied to real fetus heart rate signals recorded in the third trimester of pregnancy. Statistical measures comprising the relative errors, standard deviation, sensitivity, specificity, precision or accuracy were employed to evaluate the performance of detection. Elevated discernment outcomes were realized by the high-order entropy invariants. Multi-fractal analysis using a structure function enhances the detection of medical fetal states. Unbiased cross-determinism invariant amended the discrimination process. The significance of our techniques lies behind their post-processing codes which could build up cutting-edge portable machines offering advanced discrimination and detection of Intrauterine Growth Restriction prior to fetal death. This work was devoted to Fetal Heart Rates but time series generated by alternative nonlinear dynamic systems should be further considered.