Made available in DSpace on 2014-05-06T02:02:26Z (GMT). No. of bitstreams: 1 000457603-Texto+Completo-0.pdf: 4114697 bytes, checksum: 30488d5fc2e6e62e5cc39c6a00ca84ff (MD5) Previous issue date: 2014 / Objective: To evaluate the association of leptin levels in the maternal plasma, umbilical cord plasma and placental tissue of normotensive and preeclamptic (PE) pregnant women. Patients and methods: Leptin levels were analysed in the maternal plasma, umbilical cord plasma and placental tissue of 50 women with preeclampsia and 67 normotensive pregnant women. Plasma and placental leptin were measured using the MagPlexTH-C microspheres system. Results: Leptin levels were 40 times higher in the maternal plasma and 82 times higher in the placental tissue of patients with preeclampsia in comparison to the controls. The geometric means found were 19. 59 ng/mL and 163. 31 mg/g in the PE group, and 13. 96 ng/mL and 89. 95 mg/g in the normotensive group, respectively. Analysis of the umbilical cord plasma showed no significant difference between the groups. The mean ratios found after adjustment for maternal age, BMI and gestational age were: maternal plasma (MR=1. 40; 95% CI: 1. 00 - 1. 97, p=0. 049), fetal plasma (MR=1. 33; 95% CI: 0. 85- 2. 09, p=0. 216) and placenta (MR=1. 82; 95% CI: 1. 11 - 2. 98, p=0. 019).Conclusion: Leptin values found in patients with preeclampsia are significantly increased in maternal plasma and placental tissue in comparison to the control. The extremely high levels in the placenta are believed to have resulted from studies that specifically aimed to evaluate biomarkers. / Objetivo: Avaliar a associação dos níveis de leptina no plasma materno, plasma do cordão umbilical e tecido placentário de gestantes normotensas e com pré-eclâmpsia (PE).Pacientes e métodos: Foram analisados os níveis de leptina no plasma materno, plasma do cordão umbilical e tecido placentário de 50 gestantes com pré-eclâmpsia e 67 gestantes normotensas. A leptina foi mensurada em plasma e placenta utilizando o Sistema MagPlexTH-C - ensaio de microesferas. Resultados: Os níveis de leptina foram 40 vezes maiores no plasma materno e 82 vezes maiores no tecido placentário das pacientes pré-eclâmpticas em comparação aos controles. No grupo Pré-eclâmpsia encontramos as médias geométricas de 19. 59 ng/mL e 163. 31 mg/g e nas normotensas 13. 96 ng/mL e 89. 95 mg/g respectivamente. A análise do plasma do cordão umbilical não mostrou diferença significativa entre os grupos. As razões das médias encontradas após ajuste para idade materna, índice de massa corporal e idade gestacional, foram no plasma materno (rm=1. 40; IC 95%: 1. 00 - 1,97, p=0. 049), no plasma fetal (rm=1. 33; IC 95%: 0. 85- 2. 09, p=0. 216) e na placenta (rm=1. 82; IC 95%: 1. 11 - 2,98, p=0. 019).Conclusão: Os valores de leptina encontrados nas pacientes com pré-eclâmpsia quando comparados ao controle são significativamente maiores no plasma da mãe e no tecido placentário. Os níveis extremamente elevados na placenta são sugestivos de estudos com desenho específico para investigação de biomarcador.

Estudos de placentação foram desenvolvidos em quatorze fêmeas de mocós em diferentes fases de gestação. As fêmeas foram pré-anestesiadas associando-se cloridrato de quetamina (15mg/kg) e midazolan (1mg/kg). Em seguida anestesiadas com isoflurano em associação com oxigênio com 100% de saturação. Após a anestesia realizou-se a cirurgia para a exposição das estruturas fetais e a coleta de dados. Macroscopicamente, identificou-se uma placenta discoidal, o saco vitelínico e o âmnio de aspecto transparente e avascular. Microscopicamente, o cordão umbilical apresentou duas artérias, uma veia e o ducto alantoideano, além de uma artéria e uma veia vitelínicas. A placenta mostrou uma relação mesometrial com o útero e apresentou-se constituída por lóbulos delimitados por regiões de interlóbulo e, perifericamente, uma região de sincício marginal contendo locais com espongiotrofoblasto e células trofoblásticas gigantes. A subplacenta esteve composta por lóbulos e por trofoblasto de natureza sincicial e celular. O saco vitelínico apresentou uma porção parietal sustentada pela membrana de Reichert´s e uma porção visceral muito vascularizada. Os estudos de placentação em mocós indicaram a presença de um útero bicórneo, uma placenta corioalantoídea discoidal e labiríntica, com barreira placentária hemocorial de subtipo hemomonocorial separando um fluxo sangüíneo materno-fetal do tipo contracorrente. / Placentation studies of fourteen rock cavy females in different gestation phases were conducted. Females were pre-anesthetized associating ketamine chloridrate (15mg/kg) and midazolan (1mg/kg). Soon afterwards, they were anesthetized by isoflurane inhalation in association with oxygen at 100% saturation. After anesthesia, the surgery allowed to exhibit fetal structures and then data collection was performed. Macroscopically, a discoidal placenta, vitelline sack and the amnion of a transparent aspect and avascular, were identified. Microscopically, the umbilical cord presented two arteries, a vein and the allantoid duct, besides an artery and a vitelline vein. The placenta showed a relationship between the mesometrium and the uterus and was constituted by lobes delimited by interlobular areas and, peripherically, by an area of marginal syncytium containing places with spongiotrophoblast and gigantic trophoblastic cells. The subplacenta was composed by lobules and by a trophoblast of syncytium and cellular nature. The vitelline sack showed a parietal portion sustained by the Reichert´s membrane and a well-vascularized visceral portion. The placentation studies in rock cavies indicated the presence of a bicornuate uterus, a chorioallantoid discoidal and labirynthic placenta, with a hemochorial placental barrier of hemomonochorial subtype separating the maternal-fetal countercurrent sanguine flow.

Le placenta assure les échanges materno-fœtaux et possède une fonction endocrine autonome. Les hormones placentaire lactogène (hPL) et chorionique gonadotrope (hCG) sont synthétisées par le syncytiotrophoblaste. A ce jour, les mécanismes impliqués dans le contrôle de la sécrétion de ces deux hormones ne sont pas connus. In vitro, l’influx d’ions Ca2+ entraîne une augmentation immédiate et soutenue de la libération d’hPL et d’hCG à partir d’explants de placentas à terme. En outre, l’élévation de la concentration extracellulaire en albumine, principale protéine maternelle circulante en contact direct avec le trophoblaste, stimule de manière immédiate et transitoire la libération d’hPL et d’hCG.<p><p>L’objectif de nos travaux a été de vérifier la spécificité de l’activité sécrétagogue de l’albumine au niveau du placenta, de caractériser les messagers cellulaires potentiellement impliqués dans la libération d’hPL et d’hCG, et de définir l’interaction entre l’albumine et le trophoblaste, en utilisant des explants provenant de placentas humains à terme.<p> <p>Nos travaux démontrent que la riposte sécrétoire à l’albumine (5%, m/v) est largement mimée par d’autres agents colloïdaux (dextran et polygéline). Cette stimulation colloïdale de la libération d’hPL et d’hCG impliquerait une mobilisation de Ca2+ à partir de réserves intracellulaires. L’intervention de 3 messagers cellulaires a été envisagée: les IPs/DAG, l’AMPc, et le GMPc. Le fluorure de sodium, la forskoline, ou le nitroprussiate sodique, activateurs connus de la production respective des IPs, de l’AMPc, et du GMPc, augmentent de manière significative les taux placentaires de chacun de ces messagers, sans toutefois affecter la libération d’hPL ou d’hCG. De plus, l’élévation de la concentration extracellulaire en albumine (5%, m/v) ne modifie pas les taux des IPs, de l’AMPc et du GMPc dans les explants placentaires, tandis qu’elle stimule la sécrétion hormonale. Ces systèmes de signalisation, bien que fonctionnels au niveau du trophoblaste, ne joueraient donc pas un rôle majeur dans la régulation de la libération d’hPL et d’hCG. <p><p>Nos résultats mettent en évidence une internalisation rapide d’albumine marquée, avec de l’125I ou de la fluorescéïne, dans le syncytiotrophoblaste. Une large fraction de cette albumine est recyclée, intacte, vers la circulation maternelle selon un processus sensible à l’abaissement de la température et indépendant du cytosquelette. L’albumine marquée restant dans les explants placentaires est partiellement dégradée. Trois mécanismes ont été envisagés pour expliquer ces mouvements d’entrée et de sortie de l’albumine au sein du placenta humain: l’endocytose médiée par l’albondine via les caveolae, le système des coated pits clathrine-dépendant, et l’endocytose médiée par la mégaline. Par immunohistochimie, nous avons montré que, dans le tissu placentaire, la caveoline-1, protéine caractéristique des caveolae, est localisée uniquement dans l’endothelium des capillaires fœtaux. La clathrine, au niveau des coated pits, et la mégaline se trouvent au contraire dans le syncytiotrophoblaste. La méthyl-b-cyclodextrine et l’hydrochlorure de chlorpromazine, inhibiteurs d’une endocytose dépendant de la clathrine, réduisent significativement l’internalisation placentaire de l’albumine marquée. Par contre, le DIDS ou le NPPB, susceptibles de perturber l’endocytose médiée par la mégaline, n’affectent pas la captation d’albumine marquée par les explants placentaires. L’albumine pénétrerait donc dans le syncytiotrophoblaste principalement par un processus clathrine-dépendant. La mégaline ne jouerait ici qu’un rôle mineur dans l’entrée de la protéine. Un tel processus de recyclage de l’albumine pourrait être similaire à celui décrit pour les immunoglobulines G au niveau du syncytiotrophoblaste.<p><p>Ces mouvement d’entrée et de sortie de l’albumine ne semblent pas associés à la stimulation de la libération d’hPL et d’hCG par l’albumine. Ils pourraient par contre participer significativement, étant donné leur ampleur, à la nutrition fœtale. L’albumine est en effet un transporteur notoire d’ions et d’acides gras, molécules qui pourraient être acheminées au fœtus via le phénomène de recyclage placentaire de l’albumine mis en évidence par ce travail. /<p><p>The human placenta is the site of all maternal-fetal exchanges, and is also an active endocrine organ. Placental lactogen (hPL) and chorionic gonadotrophin (hCG) hormones are synthesized by the syncytiotrophoblast. So far, the mechanisms involved in the regulation of both hormones secretion remain elusive. In vitro, calcium inflow causes an immediate and sustained rise in the hPL and hCG releases from human term placenta explants. Moreover, increasing the extracellular concentration of albumin, the major maternal plasma protein in direct contact with the human trophoblast, stimulates the hPL and hCG releases in an immediate and transient way.<p><p>Our study have aimed to check the specificity of this secretory effect of albumin, to investigate the potential cellular messengers involved in the hPL and hCG releases, and to define the interaction between albumin and the throphoblast layer, using human term placenta explants.<p><p>Our results indicate that the triggering effect of albumin (5%, w/v) is largely mimicked by two other colloidal agents (dextran and polygelin). This “colloidal” stimulation of the hPL and hCG releases would involve the mobilization of calcium from intracellular pools. Three cellular messengers have been considered to mediate this process: the IPs/DAG, the cAMP, and the cGMP. Sodium fluoride, forskolin, or sodium nitroprusside, known activators of respectively the IPs, cAMP, and cGMP production, significantly increase the placental content of each of those messengers, without modifying the hPL and hCG releases. In addition, raising the extracellular concentration of albumin does not cause any change in the placental level of IPs, cAMP, and cGMP, while stimulating the hormonal release. These three signaling pathways are thus functional in human term trophoblast but do not appear to significantly modulate the hPL and hCG secretions. <p><p>Our findings show that albumin, labeled with 125I or with fluorescein, is rapidly internalized into the syncytiotrophoblast. Thereafter, the intact protein is largely recycled to the maternal circulation, through a temperature-sensitive and cytoskeleton-independent process. The labeled albumin remaining in placental explants is partially degraded. Three different mechanisms could participate to the albumin entry into the human placenta: the albondin-mediated endocytosis via the caveolae, the clathrin-dependent coated pits system, and the megalin-mediated endocytosis. Using immunohistochemistry, caveolin-1, marker of the caveolae, is localized in the endothelium of the fetal capillaries and not in the syncytiotrophoblast. By contrast, clathrin and megalin are observed only in the syncytiotrophoblast. Methyl-b-cyclodextrin, and chlorpromazine hydrochloride, known inhibitors of the clathrin-dependent endocytotic process, significantly reduce the placental uptake of labeled albumin. On the other hand, DIDS or NPPB, able to perturb the megalin-mediated endocytosis, do not affect the labeled albumin uptake. Thus, albumin seems to be internalized into the syncytiotrophoblast mainly through a clathrin-dependent mechanism. Megalin would only play a minor role in this process. Such movements of albumin in the human placenta may be similar to the recycling process reported for IgG at that site.<p><p>The placental apical recycling of albumin is not associated to the albumin triggering effect on the hPL and hCG releases. This quantitatively significant internalization process may participate to the fetus’ nutrition. Indeed, Albumin carries ions and fatty acid, which could be brought to the fetus via the protein recycling evidenced by our study.<p><p><p> <p> / Doctorat en sciences biomédicales / info:eu-repo/semantics/nonPublished

Fetal growth restriction (FGR) signifies that the fetus has not achieved its growth potential and is associated with increased perinatal mortality and morbidity. The exact aetiology of FGR, in the absence of any identifiable fetal and maternal factors, remains unclear and is attributed to placental insufficiency. The FGR placenta has a characteristic phenotype including: increased resistance in the fetoplacental circulation, an alteration in trophoblast cell turnover and reduced activity of placental nutrient transport systems, the best characterised being the amino acid transporter, system A. The placenta strongly expresses the cortisol inactivating enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 11β-HSD2 activity was reduced in placentas from pregnancies complicated by FGR, suggesting increased exposure of the fetoplacental unit to maternal cortisol. In animal models, excessive exposure to glucocorticoids (GCs) is associated with a reduction in both fetal and placental weight. This reduction in placental weight was associated with abnormalities in placental function, consistent with those observed in the FGR placenta. This PhD investigated whether excess GC exposure during pregnancy is responsible placental insufficiency in human pregnancies and tested the hypotheses that excess GC exposure adversely affects placental vascular tone, trophoblast cell turnover and activity of the amino acid transporter, system A. Term placentas were collected from uncomplicated pregnancies and first trimester placental samples were obtained following elective surgical termination of pregnancy. Wire myography was used to explore the acute and chronic effects of GCs on term chorionic plate artery (CPA) function. The impact of GC treatment on trophoblast cell turnover in both first trimester and term placenta was investigated using the placental explant system. The effect of GCs on the activity of the system A transporter was also investigated in term explants and in isolated cytotrophoblasts where the expression of 11β-HSD2 was reduced using siRNA. Gene microarray studies on first trimester placental explants treated with GCs were utilised to identify genes regulated by GCs. Blunted constriction to thromboxane A2 was observed following acute GC treatment, whilst chronic exposure resulted in enhanced vasoconstriction, mimicking the altered reactivity of CPAs from pregnancies complicated by FGR. GC excess in first trimester placental explants increased apoptosis and decreased proliferation, thereby replicating the disordered turnover of the trophoblast observed in FGR placentas. No demonstrable effect was observed in cell turnover or system A activity in term placental explants treated with GCs, however, these experiments were hindered by the in-vitro regeneration of the syncytiotrophoblast in the model employed. The attenuation of 11β-HSD2 activity observed in FGR placentas was replicated in term primary cytotrophoblasts utilising siRNA to knock-down expression of 11β-HSD2. Preliminary results suggested an increase in system A activity in response to cortisol. Gene microarray studies identified a significant number of genes (~500) that were regulated by dexamethasone, confirming that GCs have an impact on many aspects of placental function. Potential mediators for the characteristic features of the FGR placenta replicated here in response to GC treatment were identified and validated at the mRNA level. The studies described in this thesis support the hypotheses that GC excess within the placenta contributes to the development of raised vascular resistance in the fetoplacental circulation and the disordered trophoblast turnover in placentas from pregnancies complicated by FGR. However, with the preliminary studies performed, the hypothesis that elevated levels of GCs contribute to the reduced placental amino acid transfer by the system A transporter in the FGR placenta can not be confidently disproven.

Many researchers in the academic and clinical communities theorise that inflammation may underpin the placental dysfunction to which the majority of fetal growth restriction (FGR) and stillbirth cases are attributed. Villitis of unknown etiology (VUE) is an inflammatory condition of the placenta characterised by lesions of macrophages and T cells in the villous stroma. This study addressed the hypothesis that VUE is a maternal-mediated immune reaction that contributes to FGR and stillbirth by detrimentally affecting placental function. The hypothesis was tested by: 1) completing a systematic review of the literature to confirm implied links of VUE to poor pregnancy outcome, 2) performing a detailed characterisation of the cellular phenotype of VUE in stillbirth, 3) developing an in vitro model of VUE and 4) examining the functional effects of VUE using this model. A systematic review of the literature revealed that VUE occurred in 28.6% of placentas from FGR pregnancies compared to 15.6% of placentas from appropriately grown infants (p < 0.0001), confirming the implied association. There were insufficient published studies to be able to corroborate a link with stillbirth. Elevated numbers of macrophages, CD4 and CD8 T cells were quantified in VUE lesions. There were significant increases in pan-placental CD4 and CD8 T cell presence in placentas from stillborn infants with VUE (p < 0.0001). A greater staining area of pro-inflammatory cytokines interleukin (IL)-2 (p < 0.05) and IL-12 (p < 0.0001) was recorded in VUE lesions and a reduction in the anti-inflammatory cytokine IL-4 in the stillbirth with VUE cohort. Dual immunofluorescence of cell markers and cytokines implies that the immune response in VUE is directed towards Th1-type cell-mediated immunity. An in vitro model of VUE was developed that enabled co-culture of explants with fluorescently labelled T cells isolated from matched maternal whole blood samples. Placental tissue and T cells could be maintained in culture for the required duration of the experiment and placental function was not affected by preparation and culture conditions. In vitro co-culture with maternal T cells resulted in a significant reduction in placental function as measured by hCG secretion (p=0.015). There were significant increases in culture supernatant concentrations of IL-1β (p=0.008), IL-10 (p=0.02), interferon-γ (p=0.02) and IL-1Ra (p=0.05) and tissue lysate concentrations of IL-6 (p=0.008) and IL-1β (p=0.02). Culture of explants with a combination of IL-2, IL-12 and anti-IL-4 significantly reduced hCG secretion compared to control (p=0.03).These studies indicate that VUE involves a Th1-type immune response that may affect placental function, the impact of which might be impaired fetal growth that could contribute to stillbirth. The novel in vitro model facilitates future investigations into the pathophysiology of VUE.

No description available.

Publicación a texto completo no autorizada por el autor / Determina la predicción de la ultrasonografía transvaginal entre las 20 – 26 semanas de gestación mediante la medición de la sobreposición del orificio cervical interno por el borde placentario inferior. En el Instituto Nacional Materno Perinatal de Lima – Perú se realizó un estudio observacional, prospectivo, longitudinal entre el 01 de agosto y el 31 de diciembre del año 2013. El análisis estadístico se realizó con el programa IBM Statistics SPSS 19. Un total de 221 pacientes cumplieron los criterios de inclusión y participaron de la investigación. El valor de la sobreposición del orificio cervical interno por el borde placentario inferior medido por ultrasonografía transvaginal varió entre 3 – 38 mm ( media de 18,9 +/- 7,9 mm) Se observó diferencia altamente significativa (p < 0,001) entre el valor de la sobreposición del orificio cervical interno por el borde placentario inferior medido por ultrasonografía transvaginal que presentaron placenta previa a término (25,6 +/- 4,9 mm) y aquellas sin placenta previa a término (12,8 +/- 4,4 mm). El valor de la sobreposición del orificio cervical interno por el borde placentario inferior medido por ultrasonografía transvaginal demostró una buena capacidad predictora de placenta previa a término (Área bajo la curva ROC 0,98, IC al 95%: 0.97 – 0.99), con una sensibilidad del 91,5%, especificidad de 93,4%, valor predictivo positivo de 93,3%% y valor predictivo negativo de 92,3%. Se concluyó que la sobreposición del orificio cervical interno por el borde placentario inferior medida por ultrasonografía transvaginal predice en forma eficaz la presencia de placenta previa al término. / Trabajo de investigación

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21998号 / 医博第4512号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 柳田 素子, 教授 松田 文彦, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: The placenta is a complex, disk-shaped organ vital to a successful pregnancy and responsible for materno-fetal exchange of vital gases and biochemicals. Instances of compromised placental development or function – collectively termed placenta dysfunction - underlies the most common and devastating pregnancy complications observed in North America, including preeclampsia (PE) and fetal growth restriction (FGR). A comprehensive histopathology examination of the placenta following delivery can help clarify obstetrical disease etiology and progression and offers tremendous potential in the identification of patients at risk of recurrence in subsequent pregnancies, as well as patients at high risk of chronic diseases in later life. However, these types of examinations require a high degree of specialized training and are resource intensive, limiting their availability to tertiary care centers in large city centres. The development of machine learning algorithms tailored to placenta histopathology applications may allow for automation and/or standardization of this important clinical exam – expanding its appropriate usage and impact on the health of mothers and infants. The primary objective of the current project is to develop and pilot the use of machine learning models capable of placental disease classification using digital histopathology images of the placenta. Methods: 1) A systematic review was conducted to identify the current methods being applied to automate histopathology screening to inform experimental design for later components of the project. Of 230 peer-reviewed articles retrieved in the search, 18 articles met all inclusion criteria and were used to develop guidelines for best practices. 2) To facilitate machine learning model development on placenta histopathology samples, a villi segmentation algorithm was developed to aid with feature extraction by providing objective metrics to automatically quantify microscopic placenta images. The segmentation algorithm applied colour clustering and a tophat transform to delineate the boundaries between neighbouring villi. 3) As a proof-of-concept, 2 machine learning algorithms were tested to evaluated their ability to predict the clinical outcome of preeclampsia (PE) using placental histopathology specimens collected through the Research Centre for Women’s and Infant’s Health (RCWIH) BioBank. The sample set included digital images from 50 cases of early onset PE, 29 cases of late onset PE and 69 controls with matching gestational ages. All images were pre-processed using patch extraction, colour normalization, and image transformations. Features of interest were extracted using: a) villi segmentation algorithm; b) SIFT keypoint descriptors (textural features); c) integrated feature extraction (in the context of deep learning model development). Using the different methods of feature extraction, two different machine learning approaches were compared - Support Vector Machine (SVM) and Convolutional Neural Network (CNN, deep learning). To track model improvement during training, cross validation on 20% of the total dataset was used (deep learning algorithm only) and the trained algorithms were evaluated on a test dataset (20% of the original dataset previously unseen by the model). Results: From the systematic review, 5 key steps were found to be essential for machine learning model development on histopathology images (image acquisition and preparation, image preprocessing, feature extraction, pattern recognition and classification model training, and model testing) and recommendations were provided for the optimal methods for each of the 5 steps. The segmentation algorithm was able to correctly identify individual villi with an F1 score of 80.76% - a significantly better performance than recently published methods. A maximum accuracy of 73% for the machine learning experiments was obtained when using textural features (SIFT keypoint descriptors) in an SVM model, using onset of PE disease (early vs. late) as the output classification of interest. Conclusion: Three major outcomes came of this project: 1) the range of methods available to develop automated screening tools for histopathology images with machine learning were consolidated and a set of best practices were proposed to guide future projects, 2) a villi segmentation tool was developed that can automatically segment all individual villi from an image and extract biologically relevant features that can be used in machine learning model development, and 3) a prototype machine learning classification tool for placenta histopathology was developed that was able to achieve moderate classification accuracy when distinguishing cases of early onset PE and late onset PE cases from controls. The collective body of work has made significant contributions to the fields of placenta pathology and computer vision, laying the foundation for significant progress aimed at integrating machine learning tools into the clinical setting of perinatal pathology.

The placenta and fetal intestines are two key nutrient transport organs that sustain and nurture growing fetus. Insufficient placental development and consequently inadequate fetal nutrient supply can lead to IUGR resulting in low birth weight offspring. Our experimental objectives were to investigate the effects of elevated maternal nutrition, IUGR, and E2 supplementation during mid-gestation (in an attempt to rescue IUGR offspring) on placental and fetal intestinal cell proliferation, angiogenic gene expression, and vascularity. Limited responsiveness in placental development and vascularization to E2 supplementation was observed, likely due to inappropriate timing or dose of E2. However, maternal E2 supplementation increased fetal small intestinal length and GUCY1b3 mRNA expression, suggesting that E2 supplementation has positive effects on IUGR fetal intestinal growth. In conclusion, understanding molecular mechanisms associated with IUGR and possible effects of E2 supplementation in rescuing IUGR may lead to enhanced human health and livestock production efficiency.