OBJETIVO: Analisar as freqüências de malformações congênitas detectadas ao nascimento no Rio Grande do Sul, enfocando especialmente aquelas passíveis de Diagnóstico Pré-Natal através do Estudo Morfológico Fetal, para sugerir, ao final, uma rotina mínima de exame ultra-sonográfico fetal. MÉTODOS: Inicialmente realizou-se um estudo descritivo de base populacional dos bancos de dados oficiais do Rio Grande do Sul referentes aos defeitos congênitos no estado. Foi delimitado o período de 2001 a 2005, sendo incluídos todos recém-nascidos vivos que foram registrados ao nascimento como portadores de uma ou mais anomalias congênitas na Declaração de Nascidos Vivos. Foram incluídos também os nascidos vivos falecidos com menos de um ano, com causa mortis atribuída a um defeito congênito e os óbitos fetais cuja Declaração de Óbito registrou defeitos congênitos. Para fins deste estudo, foram analisados 25 defeitos ou grupos de defeitos, levando em conta suas prevalências relatadas na literatura, gravidade, possibilidade de diagnóstico pré-natal ou no exame do recém-nascido. A seguir foram estudadas as possibilidades de Diagnóstico Pré-Natal dos principais defeitos congênitos através da ultra-sonografia, tendo como base na literatura atual e buscando-se elaborar uma rotina mínima de exame fetal. RESULTADOS: Os 25 defeitos ou grupos de defeitos representaram 81,74% do total dos 6.236 recém nascidos com defeitos identificados no nascimento. No período de 2001-2005 nasceram no estado 765.230 bebês, com média anual de 153.046. A ocorrência geral de defeitos diagnosticados no nascimento no período foi de 0,81%, sendo relatadas as freqüências específicas daqueles 25 defeitos. Identificou-se que 787 casos de defeitos congênitos que faleceram no 1º ano de vida não foram diagnosticados ao nascimento. Calculou-se que para cada caso de cardiopatia diagnosticado no nascimento cerca de 3 casos não foram percebidos e faleceram no 1º ano de vida. Estes cálculos foram expressivos também para trissomias do 13 e 18 (3:1) e sistema nervoso central (1,28:1). CONCLUSÕES: A análise das freqüências de defeitos congênitos no Rio Grande do Sul mostrou que 25 defeitos ou grupo de defeitos representam mais de 80% do total das ocorrências no estado. Alguns defeitos congênitos registrados ao nascimento no Campo 34 da Declaração de Nascidos Vivos parecem estar subestimados, especialmente aqueles cujo diagnóstico necessita de exames especializados, como as cardiopatias congênitas. Este estudo sugere que com a avaliação ultra-sonográfica de 18 planos da anatomia fetal se pode rastrear a maioria dos defeitos congênitos do nosso meio. / OBJECTIVE: To analyze the frequency of congenital defects detected at birth in Rio Grande do Sul, focusing mainly on those that can be diagnosed prenatally by a Fetal Morphological Ultrasound Study, and finally, to suggest a minimum routine for fetal ultrasonographic examination. METHODS: Initially a population-based descriptive study was performed of the Rio Grande do Sul (RS) state official database referring to congenital defects in the state. The period from 2001 to 2005 was delimited, and all livebirths recorded in the Declaration of Livebirths as having one or more congenital anomalies were included. Babies born alive who died at less that one year of age were also included if their cause of death was attributed to a congenital defect, and the fetal deaths when the Death Declaration recorded congenital defects. For the purposes of this study, 25 defects or groups of defects were analyzed, taking into account their prevalence reported in the literature, severity, possibility of prenatal diagnosis or diagnosis during the examination of the newborn. Next the possibilities of Prenatal Diagnosis of the main congenital defects by ultrasound were studied based on the current literature and trying to create a minimum routine for a fetal examination. RESULTS: The 25 defects or groups of defects were 81.74% of the total of 6,236 newborns with defects identified at birth. During the 2001-2005 period, 765,230 babies were born in the state, with an annual mean of 153,046. The overall occurrence of defects diagnosed at birth during the period was 0.81%, and the specific frequencies of those 25 defects were reported. It was found that 787 cases with congenital defects that died in the first year of life were not diagnosed at birth. It was calculated that for each case of cardiopathy diagnosed at birth, about 3 cases were not perceived, and died during the 1st year of life. These calculations were also important for trisomies 13 and 18 (3:1) and the central nervous system (1.28:1). CONCLUSIONS: The analysis of frequencies of congenital defects or groups of defects that represents more than 80% of them. Some congenital defects recorded in the Declaration of Livebirths at field number 34 seams to be underestimates, like the congenital cardiopathies. This study suggest that with the ultrasonographic evaluation of 18 planes of fetal anatomy the majority of congenital defects can be traced.

OBJETIVO: Analisar as freqüências de malformações congênitas detectadas ao nascimento no Rio Grande do Sul, enfocando especialmente aquelas passíveis de Diagnóstico Pré-Natal através do Estudo Morfológico Fetal, para sugerir, ao final, uma rotina mínima de exame ultra-sonográfico fetal. MÉTODOS: Inicialmente realizou-se um estudo descritivo de base populacional dos bancos de dados oficiais do Rio Grande do Sul referentes aos defeitos congênitos no estado. Foi delimitado o período de 2001 a 2005, sendo incluídos todos recém-nascidos vivos que foram registrados ao nascimento como portadores de uma ou mais anomalias congênitas na Declaração de Nascidos Vivos. Foram incluídos também os nascidos vivos falecidos com menos de um ano, com causa mortis atribuída a um defeito congênito e os óbitos fetais cuja Declaração de Óbito registrou defeitos congênitos. Para fins deste estudo, foram analisados 25 defeitos ou grupos de defeitos, levando em conta suas prevalências relatadas na literatura, gravidade, possibilidade de diagnóstico pré-natal ou no exame do recém-nascido. A seguir foram estudadas as possibilidades de Diagnóstico Pré-Natal dos principais defeitos congênitos através da ultra-sonografia, tendo como base na literatura atual e buscando-se elaborar uma rotina mínima de exame fetal. RESULTADOS: Os 25 defeitos ou grupos de defeitos representaram 81,74% do total dos 6.236 recém nascidos com defeitos identificados no nascimento. No período de 2001-2005 nasceram no estado 765.230 bebês, com média anual de 153.046. A ocorrência geral de defeitos diagnosticados no nascimento no período foi de 0,81%, sendo relatadas as freqüências específicas daqueles 25 defeitos. Identificou-se que 787 casos de defeitos congênitos que faleceram no 1º ano de vida não foram diagnosticados ao nascimento. Calculou-se que para cada caso de cardiopatia diagnosticado no nascimento cerca de 3 casos não foram percebidos e faleceram no 1º ano de vida. Estes cálculos foram expressivos também para trissomias do 13 e 18 (3:1) e sistema nervoso central (1,28:1). CONCLUSÕES: A análise das freqüências de defeitos congênitos no Rio Grande do Sul mostrou que 25 defeitos ou grupo de defeitos representam mais de 80% do total das ocorrências no estado. Alguns defeitos congênitos registrados ao nascimento no Campo 34 da Declaração de Nascidos Vivos parecem estar subestimados, especialmente aqueles cujo diagnóstico necessita de exames especializados, como as cardiopatias congênitas. Este estudo sugere que com a avaliação ultra-sonográfica de 18 planos da anatomia fetal se pode rastrear a maioria dos defeitos congênitos do nosso meio. / OBJECTIVE: To analyze the frequency of congenital defects detected at birth in Rio Grande do Sul, focusing mainly on those that can be diagnosed prenatally by a Fetal Morphological Ultrasound Study, and finally, to suggest a minimum routine for fetal ultrasonographic examination. METHODS: Initially a population-based descriptive study was performed of the Rio Grande do Sul (RS) state official database referring to congenital defects in the state. The period from 2001 to 2005 was delimited, and all livebirths recorded in the Declaration of Livebirths as having one or more congenital anomalies were included. Babies born alive who died at less that one year of age were also included if their cause of death was attributed to a congenital defect, and the fetal deaths when the Death Declaration recorded congenital defects. For the purposes of this study, 25 defects or groups of defects were analyzed, taking into account their prevalence reported in the literature, severity, possibility of prenatal diagnosis or diagnosis during the examination of the newborn. Next the possibilities of Prenatal Diagnosis of the main congenital defects by ultrasound were studied based on the current literature and trying to create a minimum routine for a fetal examination. RESULTS: The 25 defects or groups of defects were 81.74% of the total of 6,236 newborns with defects identified at birth. During the 2001-2005 period, 765,230 babies were born in the state, with an annual mean of 153,046. The overall occurrence of defects diagnosed at birth during the period was 0.81%, and the specific frequencies of those 25 defects were reported. It was found that 787 cases with congenital defects that died in the first year of life were not diagnosed at birth. It was calculated that for each case of cardiopathy diagnosed at birth, about 3 cases were not perceived, and died during the 1st year of life. These calculations were also important for trisomies 13 and 18 (3:1) and the central nervous system (1.28:1). CONCLUSIONS: The analysis of frequencies of congenital defects or groups of defects that represents more than 80% of them. Some congenital defects recorded in the Declaration of Livebirths at field number 34 seams to be underestimates, like the congenital cardiopathies. This study suggest that with the ultrasonographic evaluation of 18 planes of fetal anatomy the majority of congenital defects can be traced.

Abstract The main goal of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment is a healthy mother and a healthy child. The most important complication following IVF/ICSI arises from the increased risk of multiple pregnancies. An elective single embryo transfer (eSET) with the freezing of spare embryos and subsequent treatment with frozen embryo transfer (FET) is the only way to avoid this complication. For this reason, the number of children born after FET is steadily rising. The aim of this study was to provide more detailed evidence on the safety of FET, particularly focusing on serum hormone profiles during the first trimester weeks of singleton pregnancies after IVF/ICSI fresh embryo transfer (ET), after FET during a natural menstrual cycle, and after spontaneous conception. Another part of this study compared the perinatal outcomes, congenital anomalies (CAs), and morbidity of singletons born after FET and IVF/ICSI fresh ET. The reference group was those born after spontaneously conceived (SC) pregnancies. In the clinical prospective study, the maternal serum estradiol and progesterone levels in pregnancies after fresh ET (n=39) were higher during early pregnancy weeks than in FET (n=30) and SC pregnancies (n=41), while the hormonal profiles after FET did not differ from SC pregnancies. In the large register study, FET children (n=1830) were found to have a reduced risk for adverse perinatal outcomes, such as preterm birth, a low birthweight, and being small for their gestational age compared with children born after fresh ET (n=2942). However, FET children have an increased risk for being large for their gestational age. The major CAs and morbidity until three years of age did not differ between groups. When compared with SC children (n =31 243), the perinatal outcome was worse and the rates of CAs and morbidity were higher in FET children. The FET cycle seemed to provide a better physiological environment for early fetal development than fresh ET. Further, FET protects against some of the adverse perinatal outcomes of children when compared with fresh ET, but not when it comes to the major CAs and early somatic health. This study provides further evidence of the safety of FET in comparison with fresh ET. This information should further encourage clinicians to implement eSET combined with cryopreservation in their IVF/ICSI program. / Tiivistelmä Koeputkihedelmöityshoidon (in vitro fertilization, IVF ja intracytoplasmic sperm injection, ICSI) tavoitteena on terve äiti ja terve lapsi. Monisikiöraskaus on hoidon komplikaatio, koska siihen liittyy selkeästi kohonnut riski äidille ja lapselle. Yhden alkion siirto, jäljelle jääneiden alkioiden pakastus ja myöhemmin tehtävä pakastetun alkion siirto (PAS) ovat lisänneet IVF/ICSI-hoitojen turvallisuutta ja tehokkuutta. Täten PAS:sta syntyneiden lasten määrä kasvaa. Tutkimuksen tavoitteena on lisätä PAS-hoitojen turvallisuutta tarkastelemalla veren steroidihormonien muutoksia alkuraskaudessa naisilta, jotka olivat tulleet raskaiksi IVF/ICSI-tuorealkion siirroista, luonnollisen kuukautiskierron aikana tehdystä PAS:sta ja luonnollisesti. Lisäksi tutkimuksessa verrattiin PAS- ja IVF/ICSI-tuorealkion siirrosta alkunsa saaneiden lasten terveyttä kolmeen ikävuoteen asti. Viiteryhmän muodostivat luonnollisesti alkunsa saaneet lapset. Kliinisessä prospektiivisessa tutkimuksessa havaittiin naisilla, joilla oli tuorealkion siirrosta alkanut raskaus (n=39), merkittävästi koholla olevat seerumin estradioli- ja progesteronipitoisuudet 7-8 raskausviikolle asti verrattuna naisiin, joilla raskaudet olivat alkaneet PAS:sta (n=30) tai luonnollisesti (n=41). Vastaavasti PAS-raskauksissa hormonipitoisuudet eivät eronneet merkittävästi luonnolliseen raskauteen verrattuna. Laajassa rekisteritutkimuksessa havaittiin PAS-lapsilla (n=1830) olevan pienempi riski ennenaikaisuuteen ja pienipainoisuuteen kuin tuorealkiolapsilla (n=2942). Kuitenkin PAS-lapsilla oli lisääntynyt riski syntyä isokokoisina raskausviikkoihin nähden. Synnynnäisten epämuodostumien ja eri sairauksien esiintyvyyksissä ei ollut eroja. Luonnollisesti alkunsa saaneisiin lapsiin (n= 31 243) verrattaessa, PAS-lapsilla oli vastasyntyneisyyskaudelta lähtien enemmän terveyteen liittyviä ongelmia. Tutkimus osoitti PAS-raskaudessa sikiön kehittyvän alkuviikkoina luonnollisemmassa ympäristössä kuin tuorealkion siirtoraskaudessa. Vaikka suurin osa PAS- ja tuorealkiolapsista oli terveitä, tuorealkiolapsilla oli vastasyntyneisyyskaudella enemmän ongelmia kuin PAS-lapsilla. Muita terveyseroja lasten välillä ei todettu. Tutkimus antaa lisänäyttöä PAS hoidon turvallisuudesta. Alkion pakastamisella voidaan välttää koeputkihedelmöityshoidon riskejä pyrkimällä mahdollisimman usein yhden alkion siirtoon.

L'objectif de notre projet de recherche est l'exploration de la faisabilité de l'allogreffe des tissus composites (ATC) chez les nouveau-nés ayant des anomalies congénitales sévères de la main ou du visage. Dans la partie bibliographique, nous avons étudié les mécanismes de tolérance néonatale chez la souris, ainsi que la transplantation in utero des cellules souches hématopoïétiques avec des modèles animaux et humains. Ensuite, les propriétés du système immunitaire du nouveau-né humain ont été décrites avec étude des différents protocoles de conditionnement non-myéloablatifs utilisés pour induire une tolérance aux greffes d'organes solides, afin de trouver le type de conditionnement utilisable chez les nouveaux nés pour l'induction de tolérance. La greffe du thymus et de la moelle osseuse vascularisée avec l'ATC ont été également étudiés. Enfin, une revue exhaustive des différentes études d'ATC concernant l'induction de tolérance chez les humains et les larges animaux a été faite. Un premier modèle préclinique expérimental d'ATC a été élaboré chez le porcelet nouveau-né. Des études ultérieures ont par suite étudié les agents immunosuppresseurs ainsi que le régime de conditionnement avec l'administration de cyclosporine A., des thymo-globulines de lapin anti-porc et du mycophénolate mofétil. Un protocole d'induction de tolérance pour l'ATC chez les porcelets nouveau-nés a été rédigé et l'expérimentation sera réalisée courant 2014-2015. Si la tolérance d'ATC spécifique du donneur pourra être induite avec notre protocole, nous allons par la suite élaborer un protocole d'induction de tolérance et un programme d'allogreffe de main applicable chez les nouveau-nés humains / This present research is devoted to the exploration of performing vascularized composite allografts as a treatment for severe congenital hand or face anomalies in neonates or very young infants. The bibliographic studies at first revised the discovery and mechanisms of neonatal tolerance in mice, as well as in utero hematopoietic stem cells transplantation in large-animal models and human fetuses. Then the properties of human neonatal immune system were described; and the non-myeloablative or non-toxic conditioning regimens for solid organ transplant tolerance induction were also studied, in order to give the clue to a applicable conditioning regimen for tolerance induction in neonates. The potent thymus and vascularized bone marrow transplantation in neonatal VCA were considered as advantages. Finally, the researches concerning tolerance induction for VCA in large animal models and in human patients were reviewed. ln experimental studies, the preclinical VCA was firstly established in neonatal swines. Subsequent experiments thus studied the immunosuppressive agents, as well as conditioning regimen, including the administration of cyclosporine A, rabbit anti-pig thymocyte globulin and mycophenolate mofetil for VCA in pig neonates. The findings in these experiments were then concluded. Based on these finding, a general tolerance induction protocol for VCA in neonatal swines was designed and experiment will be performed in year 2014-2015. lf donor-specific tolerance for VCA could be induced with present protocol, we will subsequently elaborate an applicable tolerance induction protocol and hand allotransplantation program in human newborn infants

L’Assistance Médicale à la Procréation est considérée comme une solution thérapeutique en cas d’infertilité. Au-delà des questions économiques et éthiques qui sont soulevées au niveau de la société, l’impact sur la santé des enfants nés grâce à ces techniques pose de nombreuses questions. En effet, ces techniques ont été introduites chez l’homme sans aucun essai clinique ni aucune évaluation sur les effets à long terme sur la santé.Dans ce travail, nous présentons trois études réalisées à partir d’une cohorte de plus de 3000 enfants (singletons et jumeaux) constituée depuis 1994 au sein du service de médecine et de biologie de la reproduction de l’Hôpital Saint Joseph à Marseille. Nous avons évalué différents indicateurs de la santé périnatale (la prématurité, le faible poids et la macrosomie à la naissance, l’hypotrophie et l’hypertrophie pondérales par rapport à l’âge gestationnel et les anomalies congénitales), chez des enfants conçus à partir de différentes techniques : fécondation in vitro classique, fécondation in vitro avec micromanipulation, fécondation après transfert d’embryon congelé et fécondation après vitrification et réchauffement ovocytaire.Nos résultats ont suggéré que l’Assistance Médicale à la Procréation, quelle que soit la technique mise en œuvre, était associée à des problèmes de santé chez les enfants nés grâce à ces techniques. Il est nécessaire de continuer à développer des systèmes de surveillance visant à rendre plus performant le suivi de l’état de santé à long terme des enfants concernés, d’autant plus que de nouvelles techniques et procédés continueront à être développés. / Assisted reproductive technologies are considered as a therapeutic solution in infertility cases. Beyond the economic and ethical questions that arise at the societal level, the impact on children’s health born after these techniques raises many questions. Indeed, these techniques have been introduced to the human without any clinical trial or assessment of long-term health effects. The main interest of this thesis is to contribute to the existing debate on the safety of these techniques regarding children’s health and well-being and to open new perspectives for future research on this subject.This research presents three studies based on a cohort of more than 3000 children (singletons and twins) constituted since 1994 in the Medicine and Reproductive Biology Department at the Saint Joseph Hospital in Marseille. The thesis evaluates various indicators of perinatal health (preterm birth, low birth weight and macrosomia, small and large for gestational age, and congenital anomalies) in children conceived from different techniques: classical In Vitro fertilisation, In Vitro fertilisation with micromanipulation, fertilisation after frozen embryo transfer and fertilisation after vitrified/warmed oocyte.The results suggest that assisted reproductive technologies, regardless of the technique used, were associated with health problems in children born through these techniques. There is a need to continue to develop surveillance systems to improve the long-term monitoring of the health status of children, especially as new techniques and procedures will continue to be developed.

La déficience intellectuelle (DI) correspond à un défaut des performances intellectuelles et des fonctions adaptatives, débutant dans l’enfance. Il est estimé que 2-3% des individus développeront une DI, ce qui représente un enjeu médical important puisque les personnes avec DI sont fréquemment en situation de dépendance sociale. Dans l’ensemble, on estime majoritaire l’implication de facteurs génétique dans cette pathologie. A ce jour, plusieurs centaines de gènes sont connus pour être responsables de DI. La DI est notamment caractérisée par une extrême hétérogénéité clinique et génétique, qui l’a rendue résistante aux études génétiques classiques. Toutefois, on différencie les DI syndromiques, qui peuvent être cliniquement reconnaissables en raison des anomalies du développement qui lui est associées ; des DI isolées, sans signe distinctif.L’objectif de cette thèse est d’identifier des bases moléculaires de DI par la combinaison de deux approches. La première repose sur l’application systématique d’une recherche de microréarrangements chromosomiques par CGH-array dans un groupe de patients avec DI pour constituer a posteriori des groupes de patients homogènes. La seconde est basée sur une cohorte de patients avec DI syndromique homogène, porteurs d’un syndrome de Shprintzen-Goldberg de diagnostic clinique, étudiée par séquençage haut débit d’exome. Cette thèse définit de nouvelles entités cliniques par l’identification de variations génétiques récurrentes entre plusieurs patients comprenant la description de deux syndromes microdélétionnels, et de deux gènes candidats à la DI. De plus, nous avons pu identifier la base moléculaire du syndrome de Shprintzen-Goldberg par la mise en évidence d’un hotspot mutationnel du gène SKI. / Intellectual disability (ID) corresponds to abnormal intellectual performances and adaptive functions, beginning in childhood. It is estimated that 2-3% of individuals develop a ID, which represents a significant medical challenge since people with ID are frequently in situations of social dependence. Overall, a critical involvement of genetic factors in this disease is suspected. To date, several hundreds of genes are known to be responsible for ID. The ID is particularly characterized by extreme clinical and genetic heterogeneity, that made it resistant to conventional genetic studies. However, it is classicaly separated between syndromic ID, which may be clinically recognizable due to associated congenital anomalies; isolated ID, without disctinctive features.The objective of this thesis was to identify the molecular basis of ID by combining both approaches. The first is based on the systematic identification of chromosomal microrearrangements using array-CGH in a group of patients with ID, to constitute a posteriori homogeneous cohorts. The second is based on a cohort of patients with a clinical diagnosis of Shprintzen-Goldberg syndrome studied by high throughput sequencing.This thesis defines new clinical entities by identifying recurrent genetic variations between different patients including the description of two microdeletionnal syndromes, and two candidate genes to the ID. In addition, we identified the molecular basis for the Shprintzen-Goldberg syndrome by highlighting a mutational hotspot in the SKI gene.