El objetivo del estudio fue determinar las principales diferencias en los resultados perinatales entre gestantes con embarazo prolongado y evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios en comparación con gestantes con embarazo prolongado sin evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios. En el Instituto Nacional Materno Perinatal de Lima – Perú se realizó un estudio observacional, retrospectivo y transversal comparando 50 gestantes con embarazo prolongado con evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios con 70 gestantes con embarazo prolongado sin evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios. El análisis estadístico se realizó con el programa SPSS 14.0. La incidencia de embarazo prolonagado fue 0,73%. El 41,7% de gestantes con embarazo prolongado tuvo evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios. El 38,3% (n igual 46) de gestantes con embarazo prolongado presentó resultado perinatales adversos. Existió mayor riesgo de resultados perinatales adversos en embarazos prolongados con evidencia ultrasonográfica de calcificaciones placentarias y oligohidramnios (OR 4,58; 95% IC 2,74 – 7,65).

Las HSMG son causa importante de morbimortalidad materna y perinatal especialmente en países en desarrollo y se presentan con una frecuencia entre 2 y 6 % y sus causas primarias son obstétricas, el desprendimiento prematuro de la placenta y la placenta previa. La etiología es multifactorial, pero determinadas condiciones se asocian a mayor incidencia de esta complicación como son alteraciones endometriales ó miometriales los que se dan en la edad madura, multiparidad, antecedente de cesárea, legrados uterino, miomas uterino, y cuando hay aumento relativo de la masa placentaria como en los gemelares, fetos de altura, y tabaquismo y en casos de Abruptio, también la hipertensión inducida por el embarazo, ruptura prematura de membranas y traumas. El objetivo general del trabajo es identificar los factores de riesgo que se asocian a las causas de hemorragia en esa etapa del embarazo, y la incidencia acumulada. Los resultados del estudio son que la incidencia general de las HSMG: 1.26%, la incidencia acumulada del Desprendimiento Prematuro de Placenta: 0.55% y de la Placenta Previa: 0.69%. Son factores de riesgo para placenta previa, la edad gestacional menor de 36 semanas, situación transversa, la anemia severa, peso menor de 2500gr de los recién nacidos y el número de transfusiones; y para desprendimiento prematuro de la placenta, además de la anteriores, la hipertensión inducida por el embarazo y la muerte fetal intraútero. En ambos casos el factor de riesgo protector destacable es el control prenatal.

Thesis (Ph. D.)--University of Chicago, Committee on Genetics, June 2001. / Includes bibliographical references. Also available on the Internet.

Mémoire du D.E.S. : Biologie médicale : Nantes : 2007. Thèse d'exercice : Pharmacie : Nantes : 2007. / Bibliogr.

Mycotoxin contamination in food commodities is an age-old problem. Due to the detrimental impact of mycotoxins on human health, exposure to mycotoxins and their health implications have been increasingly recognized. Ochratoxin A (OTA), one of the mycotoxins, has been found to cause diverse toxicities in animals, with potential impact on human health. OTA has been reported to be teratogenic and interfere with steroidogenesis in vivo. Chronic exposure of pregnant women to OTA may be hazardous for the human foetus, especially when endocrine and developmental toxicities are taken into consideration. Accordingly, in the first part of this project, I hypothesized that OTA may interfere with enzymes involved in human placental steroidogenesis. By evaluation of human placental 3β–hydroxysteroid dehydrogenase/isomerase (3β-HSD) at both mRNA and protein (hormonal) levels, my results showed that OTA could up-regulate 3β-HSD1 expression in human placental cells with concentration relevant to human exposure. This study is the first to report the endocrine disruption potential of OTA in human placental cells. As several mycotoxins have been demonstrated previously to cross human placental barrier and OTA has been associated with developmental toxicity in vivo, I further hypothesized that OTA may be transferred through human placenta and accumulate in foetal compartment. In the second part of this project, human perfused placenta was used to investigate the placental toxicokinetics of OTA using concentrations found in serum of pregnant women. Findings from this study clearly showed that the transfer of OTA through term human placenta was minimal, contradicting the existing epidemiological studies reporting higher foetal OTA levels than maternal. This is the first study where transplacental kinetics of OTA has been studied in human perfused placenta. To assess the relevance of the study findings, it is very important to provide information on maternal OTA exposure during pregnancy. Currently there is limited information regarding OTA exposure of pregnant women. The third part of this project aimed at evaluating the frequency and level of exposure to OTA in pregnant women from Egypt, where exposure to dietary mycotoxins is common due to the environmental conditions. Biomonitoring of both serum and urinary OTA levels showed that more than 70% of pregnant women were exposed to OTA with a geometric mean of 0.27 ng/ml in serum and 37.21 pg/mg creatinine in urine indicating frequent exposure of this subpopulation. As an ultimate aim, maternal-foetal risk assessment served as a conclusive part of this project to predict and evaluate both maternal and foetal risk of exposure to OTA during pregnancy. Data from the exposure of pregnant women in Egypt to OTA were further ultilized to conduct maternal-foetal risk assessment in relation to OTA exposure. Based on the refined Klaassen equation for exposure estimation during pregnancy and the benchmark dose approach for risk assessment, this subpopulation of pregnant women generally was not exposed to OTA in a high-risk manner. However, considering the suspected chronic exposure beginning from early pregnancy with high foetal susceptibility and diverse toxic effects, and in particular the potential endocrine disruption of OTA, keeping OTA exposure to a minimum is recommended. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Pre-eclampsia, often described as toxaemia of pregnancy, historically represents one of the most widely investigated conditions relating to human reproduction. To date no firm cure has been found and a clear, well defined mechanism has not been ascribed to the pathogenesis of the disease. Researchers seem to focus on single pathways in isolation of others. The disease rather represents a multitude of possible underlying pathologies nvolving genetics, immune dysregulation, vascular maladaptation, and sociobiological factors thus complicating the approach to treatment. However, a central theme is the presence of reduced placental perfusion resulting in a hypoxic and/or ischaemic placenta and the subsequent secretion of various factors that initiate the maternal syndrome. It is within this context that we examine how an intervention such as increasing placental perfusion may represent a promising treatment strategy for this disease. We sought to manipulate the vasodilatory mechanisms of the uterine vasculature using sildenafil citrate and a flavonoid extracted from Eriosema kraussianum (Kr2), in Sprague-Dawley rats that exhibited preeclampsia-like manifestations. Both treatment regimens improved fetal outcomes and reduced blood pressure amplification and proteinuria. They also reduced the plasma concentrations of the two anti-angiogenic factors; sFlt1 and sEng. Only sildenafil citrate improved nitric oxide levels which was expected, suggesting that Kr2 causes vasodilation by some other mechanism. Nevertheless, both compounds improved both pup and placental weights, suggesting that they also improve utero-placental perfusion. These findings that selective uterine vascular dilation improves placental perfusion may be promising in averting possible death to mothers and their babies from pre-eclampsia especially in low resource environments. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2011.

Adequate maternal, intervillous and fetal blood flow are all necessary for fetal wellbeing. Compromise to any part of this exchange would be detrimental to pregnancy outcome. Preeclampsia is associated with reduced maternal spiral artery flow, resulting in reduced placental perfusion. This in turn creates an ischemic environment which may pre-dispose morphological changes in placental villi. This pilot study utilized morphometric image analysis to examine some features of the fetal component of the placenta in normotensive (NT) and pre-eclamptic (PE) groups. The features examined included: density of placental villi (expressed as percentage of field area occupied by placental tissue); stem vessel carrying capacity (expressed as percentage of stem villus area occupied by vessel lumina); the thickness of the stem arterial walls relative to artery size (expressed as percentage of artery area occupied by arterial wall) and the extent of fibrosis associated with villi (expressed as percentage of field area occupied by fibrosis). The results were as follows: density of placental villus arrangement NT:51.89±6.19, PE:64.78±6.93 (P<0.001); carrying capacity of stem villi NT:17.20±11.78, PE:8.67±8.51 (P<0.001); relative thickness of stem villi arterial walls NT:74.08±12.92, PE: 86.85±10.55 (P<0.001); and extent of fibrosis NT:0.727±0.310, PE:1.582±0.707 (P<0.001). These significant differences between normotensive and pre-eclamptic placentae suggest possible fetal maladaptations in response to the intervillous ischemia, compounding the existing maternal compromise to materno-fetal exchange. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2012.

The role of placental VEGFA in placental development and maternal pregnancy adaptations is unknown. In this thesis, one or both copies of Vegfa was knocked out from the placental spongiotrophoblast region using a mouse Cre-loxP system. Surprisingly, in pregnancies carrying 100% conceptuses with a single deletion of Vegfa from the spongiotrophoblast layer, maternal circulating VEGFA increased by 20% accompanied by a 15% decrease in arterial pressure while no impairment in embryo growth was found. In pregnancies carrying 50% conceptuses with both copies of Vegfa deleted from spongiotrophoblast, 17% of conceptuses had been reabsorbed by late gestation suggesting a function for spongiotrophoblast VEGFA in sustaining early pregnancy. In conclusion, spongiotrophoblast VEGFA affects maternal function during pregnancy but the exact mechanism remains to be defined.

The role of placental VEGFA in placental development and maternal pregnancy adaptations is unknown. In this thesis, one or both copies of Vegfa was knocked out from the placental spongiotrophoblast region using a mouse Cre-loxP system. Surprisingly, in pregnancies carrying 100% conceptuses with a single deletion of Vegfa from the spongiotrophoblast layer, maternal circulating VEGFA increased by 20% accompanied by a 15% decrease in arterial pressure while no impairment in embryo growth was found. In pregnancies carrying 50% conceptuses with both copies of Vegfa deleted from spongiotrophoblast, 17% of conceptuses had been reabsorbed by late gestation suggesting a function for spongiotrophoblast VEGFA in sustaining early pregnancy. In conclusion, spongiotrophoblast VEGFA affects maternal function during pregnancy but the exact mechanism remains to be defined.

Les microARNs (miARNs) participent à la régulation du destin et de la différenciation cellulaire. La littérature fait état d'une variété de miARNs exprimés dans le placenta dont plusieurs sont exprimés uniquement dans les trophoblastes. Par contre, peu de chercheurs ont exploré les fonctions des miARNs dans les cellules placentaires. Dans cette étude, nous avons mis au point une approche fonctionnelle reposant sur l'inhibition d'une enzyme impliquée dans la maturation des miARNs afin d'évaluer l'implication de ceux-ci dans la régulation de la différenciation des trophoblastes in vitro. Ainsi, grâce à la technologie de I'ARNi, l'expression protéique de l'enzyme Drosha a été inhibée jusqu'à 80% dans les choriocarcinomes de la lignée BeWo. Suite à l'inhibition de Drosha, une augmentation significative du taux de fusion cellulaire a été mesurée, mais celle-ci n'a pas été accompagnée d'une augmentation de la sécrétion d'hCG par les cellules BeWo. L'activité globale des miARNs favorise donc le maintien des CT dans un état prolifératif. Des analyses de qRT-PCR subséquentes ont révélé que l'augmentation de la fusion cellulaire mesurée était accompagnée d'un accroissement de l'expression du transcrit de Syncytine-2, une protéine fusiogène connue. Des analyses in silico réalisées à l'aide des logiciels libres MiRanda et TargetScan ont dévoilé que le transcrit de Syncytine-2 serait la cible d'une vingtaine de miARNs dont plusieurs sont membres des familles miR-17, miR-515 et miR-15. En conclusion, cette étude a permis de confirmer que les miARNs ont un rôle essentiel dans la régulation de la différenciation morphologique des cellules BeWo in vitro. Il reste cependant à élucider les mécanismes moléculaires exacts par lesquels les miARNs participent à la différenciation des cellules placentaires. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : placenta, trophoblaste, différenciation, microARNs, fusion, Syncytine-2.