Ce travail de thèse se propose d’étudier le retard de croissance intra-utérin sous l’angle de la cytogénétique placentaire, avec deux approches distinctes et complémentaires. La première approche visera à réévaluer l’influence des anomalies chromosomiques limitées au placenta sur la croissance fœtale, car des études précédentes ont rapporté des résultats contradictoires à ce sujet. La première partie de ce travail permettra en outre d’étudier l’incidence et l’influence de la disomie uniparentale chez les fœtus issus des grossesses compliquées d’une anomalie chromosomique limitée au placenta. La deuxième approche de notre travail s’intéressera à la longueur de structures chromosomiques particulières, les télomères, au niveau placentaire. Il a récemment été décrit que la longueur des télomères des cellules placentaires était réduite au terme des grossesses compliquées d’un retard de croissance intra-utérin. La longueur télomérique placentaire n’a jamais été évaluée au cours de ces grossesses et pourrait potentiellement être utilisée comme biomarqueur placentaire du retard de croissance intra-utérin. La deuxième partie de ce travail nous permettra également d’évaluer le nombre de copies des régions chromosomiques portant les gènes codant pour les principales sous-unités du complexe enzymatique télomérase et de rechercher la présence d’agrégats télomériques au niveau placentaire en cas de retard de croissance intra-utérin. / This thesis proposes to study intrauterine growth restriction in terms of cytogenetics of placenta, with two distinct and complementary approaches. The first approach will be to reassess the influence of confined placental mosaicism on fetal growth, as previous studies have reported conflicting results on this issue. The first part of this work will also study the influence of fetal uniparental disomy in case of confined placental mosaicism. The second approach of our work will focus on the length of terminal chromosomal structures, telomeres, at the placental level. It has recently been reported that telomere length was reduced in placental cells collected at term in pregnancies complicated by intrauterine growth restriction. Placental telomere length has never been evaluated in ongoing pregnancies and it could potentially be used as a placental biomarker of intrauterine growth restriction. The second part of this work will also focus on the copy number of chromosomal regions carrying genes encoding the main subunits of the telomerase enzyme complex and will look for the presence of placental telomeric aggregates in case of intrauterine growth restriction.

Com o intuito de estudar a histopatologia da placenta na insuficiência grave desse órgão, foram selecionados preparados histológicos de 140 placentas oriundas de gestações com diástole zero (DZ) ou diástole reversa (DR) à dopplervelocimetria das artérias umbilicais, acompanhadas no Setor de Avaliação da Vitalidade Fetal da Clínica Obstétrica do HCFMUSP, de 1992 a 2000. Para tal fim, foram revisadas as lâminas histológicas arquivadas na Divisão de Anatomia Patológica do HCFMUSP. Em etapa inicial, foi efetuado um estudo descritivo das lesões encontradas e relatadas, em freqüência, no grupo de DZ e no grupo de DR. Na segunda etapa, os casos foram discriminados em cinco grupos, segundo uma classificação etiopatogênica, para cotejá-los aos aspectos clínicos como: idade gestacional (IG) no nascimento, ocorrência de restrição do crescimento fetal (RCF), peso do recém-nascido (RN) e peso da placenta. Em complemento, os grupos constituídos foram relacionados à gravidade da insuficiência placentária, confrontando-se os grupos de DZ e DR.A análise histopatológica demonstrou que o infarto viloso foi o tipo de lesão isolada mais freqüente, e que o Grupo 2 (Lesões envolvendo patologia vascular uteroplacentária e dano em vilosidades secundárias), foi o grupo etiopatogênico mais freqüente na população geral. Não houve correlação dos achados histológicos com a IG no nascimento, RCF e peso do RN. Nas placentas gravemente insuficientes (DR), a proporção de infartos vilosos, trombose intervilosa e as lesões pertencentes ao grupo 3 (lesões envolvendo coagulação) foi significativamente maior do que nas de gravidade menor (DZ). O conhecimento mais profundo dos mecanismos fisiopatológicos envolvidos na insuficiência placentária, cujos reflexos se manifestam nos achados histopatológicos, são essenciais para a busca de novas alternativas para promover melhorias na condução desses casos, principalmente no que concerne à instituição de terapêutica específica e adequada. No presente trabalho ficou evidente a importância da presença de lesões envolvendo coagulação como marcadores de gravidade na insuficiência placentária. / Histological features of 140 placentas from pregnancies with absent or reversed end-diastolic velocity flow were selected for the study of placental histopathology in cases of severe failure of the organ. All the pregnancies were followed-up in the Fetal Surveillance Unit of the Department of Obstetrics - HC FMUSP, from 1992 to 2000. For this purpose, the review of the histological features archived in the Department of Pathology - HCFMUSP was performed. The first step of the process involved a descriptive study of the findings reported, in frequency, in the AEDVF and REDVF groups. In the following step, cases were separated into five groups, according to an etiopathogenic classification, for the purpose of comparing clinical aspects such as: gestational age at birth, occurrence of fetal growth restriction, newborn weight and placental weight.In addition, the correlation between those groups and the severity of placental insufficiency/failure was analyzed, and both groups of absent and reversed end-diastolic velocity flow were compared. The histopathological analysis showed that villous infarcts were the most frequent lesion found in the histological features, and Group 2 (lesions involving uteroplacental vascular pathology and secondary villous damage) was the most frequent etiopathogenic group in general population. No correlation was found between the histological findings and gestational age, fetal growth restriction and weight of the newborn. In those placentas in which severe failure was detected, the proportional rate of villous infarcts, intervillous thrombosis and lesions found in Group 3 (lesions involving coagulation) was significantly higher than in those with less severe failure (absent end-diastolic velocity flow). Further studies of the pathophysiological mechanisms of placental insufficiency which result in the histopathological findings are essential for improving the follow-up in those cases, principally when specific and appropriate therapy is considered. In this study, the importance of the presence of lesions presenting coagulation as markers of severity in the placental insufficiency is evident.

Com o intuito de estudar a histopatologia da placenta na insuficiência grave desse órgão, foram selecionados preparados histológicos de 140 placentas oriundas de gestações com diástole zero (DZ) ou diástole reversa (DR) à dopplervelocimetria das artérias umbilicais, acompanhadas no Setor de Avaliação da Vitalidade Fetal da Clínica Obstétrica do HCFMUSP, de 1992 a 2000. Para tal fim, foram revisadas as lâminas histológicas arquivadas na Divisão de Anatomia Patológica do HCFMUSP. Em etapa inicial, foi efetuado um estudo descritivo das lesões encontradas e relatadas, em freqüência, no grupo de DZ e no grupo de DR. Na segunda etapa, os casos foram discriminados em cinco grupos, segundo uma classificação etiopatogênica, para cotejá-los aos aspectos clínicos como: idade gestacional (IG) no nascimento, ocorrência de restrição do crescimento fetal (RCF), peso do recém-nascido (RN) e peso da placenta. Em complemento, os grupos constituídos foram relacionados à gravidade da insuficiência placentária, confrontando-se os grupos de DZ e DR.A análise histopatológica demonstrou que o infarto viloso foi o tipo de lesão isolada mais freqüente, e que o Grupo 2 (Lesões envolvendo patologia vascular uteroplacentária e dano em vilosidades secundárias), foi o grupo etiopatogênico mais freqüente na população geral. Não houve correlação dos achados histológicos com a IG no nascimento, RCF e peso do RN. Nas placentas gravemente insuficientes (DR), a proporção de infartos vilosos, trombose intervilosa e as lesões pertencentes ao grupo 3 (lesões envolvendo coagulação) foi significativamente maior do que nas de gravidade menor (DZ). O conhecimento mais profundo dos mecanismos fisiopatológicos envolvidos na insuficiência placentária, cujos reflexos se manifestam nos achados histopatológicos, são essenciais para a busca de novas alternativas para promover melhorias na condução desses casos, principalmente no que concerne à instituição de terapêutica específica e adequada. No presente trabalho ficou evidente a importância da presença de lesões envolvendo coagulação como marcadores de gravidade na insuficiência placentária. / Histological features of 140 placentas from pregnancies with absent or reversed end-diastolic velocity flow were selected for the study of placental histopathology in cases of severe failure of the organ. All the pregnancies were followed-up in the Fetal Surveillance Unit of the Department of Obstetrics - HC FMUSP, from 1992 to 2000. For this purpose, the review of the histological features archived in the Department of Pathology - HCFMUSP was performed. The first step of the process involved a descriptive study of the findings reported, in frequency, in the AEDVF and REDVF groups. In the following step, cases were separated into five groups, according to an etiopathogenic classification, for the purpose of comparing clinical aspects such as: gestational age at birth, occurrence of fetal growth restriction, newborn weight and placental weight.In addition, the correlation between those groups and the severity of placental insufficiency/failure was analyzed, and both groups of absent and reversed end-diastolic velocity flow were compared. The histopathological analysis showed that villous infarcts were the most frequent lesion found in the histological features, and Group 2 (lesions involving uteroplacental vascular pathology and secondary villous damage) was the most frequent etiopathogenic group in general population. No correlation was found between the histological findings and gestational age, fetal growth restriction and weight of the newborn. In those placentas in which severe failure was detected, the proportional rate of villous infarcts, intervillous thrombosis and lesions found in Group 3 (lesions involving coagulation) was significantly higher than in those with less severe failure (absent end-diastolic velocity flow). Further studies of the pathophysiological mechanisms of placental insufficiency which result in the histopathological findings are essential for improving the follow-up in those cases, principally when specific and appropriate therapy is considered. In this study, the importance of the presence of lesions presenting coagulation as markers of severity in the placental insufficiency is evident.