Preeclampsia results from incomplete trophoblast invasion of the spiral arteries during early pregnancy. Vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) are critical factors involved in angiogenesis, invasion and hemostasis at the maternal-fetal interface. Both factors are transcriptionally regulated by hypoxia inducible factor (HIF), a heterodimeric complex consisting of HIF-1[beta] and either HIF-1[alpha] or -2[alpha] whose specificity or redundancy in gene regulation is cell-type specific. This study uses siRNA technology to dissect the mechanisms of hypoxia-mediated regulation of PAI-1 and VEGF expression in first trimester trophoblasts. Immortalized first trimester human extravillous trophoblasts (HTR8/SVneo cells) were maintained in serum-free and serum-containing media for 4h (n=3-4), 8h (n=6), 24h (n=5) and 48h (n=5) under normoxic (21% O2) and hypoxic (1-2% O2) conditions to determine a time of maximum induction of both VEGF and PAI-1. Subsequently, cells were maintained for 48h in the presence or absence of siRNA for HIF-1[alpha], HIF-2[alpha], HIF-1[alpha] + -2[alpha], a non-targeting (NT) sequence or Cyclophilin B (CB). Media were then removed, cells lysed, and Western blotting used to assess HIF-[alpha] knockdown. VEGF and PAI-1 levels in the media were quantified by ELISA and results expressed as pg or ng/[micro]g protein. Results from 3 to 8 independent experiments were analyzed using unpaired t-tests. Under hypoxic conditions treatment of cells with HIF-1[alpha], HIF-2[alpha] or HIF -1[alpha] + -2[alpha] siRNA resulted in >90% HIF-Ñ protein knockdown as determined by Western blotting. 48h of hypoxic treatment caused a statistically significant increase in PAI-1 levels (p<0.01) and VEGF levels (p<0.001) compared to normoxic controls. Under hypoxic conditions, PAI-1 levels were 4.75 [plus-minus] 0.46 ng/[micro]g protein and VEGF levels were 7.27 [plus-minus] 1.08 pg/[micro]g protein. Treatment with siRNA to HIF-1[alpha], HIF-2[alpha] and HIF-1[alpha] + -2[alpha] significantly reduced PAI-1 levels to 3.3 [plus-minus] 0.35 (p<0.02), 3.1 [plus-minus] 0.38 (p<0.03) and 2.4 [plus-minus] 0.19 (p<0.003), respectively. No significant difference in PAI-1 reduction was noted between the three HIF siRNA conditions. Under hypoxic conditions, levels of VEGF in cells treated with siRNA to HIF-1[alpha] (5.79 [plus-minus] 0.55), HIF-2[alpha] (5.50 [plus-minus] 1.24) and HIF-1[alpha] + -2[alpha] (4.24 [plus-minus] 0.93) were reduced compared to the hypoxic control (7.27 [plus-minus] 1.08), yet these effects did not reach statistical significance. However, when compared with the levels observed in cells treated with NT siRNA (9.90 [plus-minus] .98), all HIF siRNA treatments promoted a significant reduction in VEGF expression (p<0.003, p<0.02 and p<0.003 for HIF-1[alpha], HIF-2[alpha] and HIF-1[alpha]+ -2[alpha], respectively). In conclusion, these results indicate that hypoxia-mediated changes in PAI-1 and VEGF expression in trophoblasts are regulated similarly by both HIF-1[alpha] and HIF-2[alpha]. This provides important insight into the molecular mechanisms regulating hemostasis and trophoblast invasion as well as their potential dysfunction in pregnancies complicated by preeclampsia

Background: Although the prevalence of pneumonia in pregnancy is reported to be less than 1%, the pregnant state and risk factors associated with the development of pneumonia adversely influence the outcome of pregnancy. KwaZulu-Natal is at the epicenter of the dual epidemics of tuberculosis and HIV-1 and the impact of these diseases occurring concurrently in pregnant women at King Edward VIII hospital (KEH), South Africa have been described previously. The impact of antenatal pneumonia in HIV-1 infected and uninfected women however has not been described in the study population and was investigated. Methods: Pregnant women with clinical and radiological evidence of pneumonia were recruited from the antenatal clinic and labour ward at KEH. The study was conducted prospectively between January and December 2000. The clinical profile of these women and the causative organisms were determined. In addition the impact of HIV-1 infection, maternal immunosuppression and maternal pneumonia on obstetric and perinatal outcomes were evaluated. Mothers diagnosed with tuberculosis and multi drug resistant tuberculosis were hospitalised at King George V hospital until delivery. Results: Twenty nine women were diagnosed with antenatal pneumonia (study arm) with Mycobacterium tuberculosis the only causative organism isolated. A control arm of 112 pregnant women was also studied. Maternal and perinatal mortality was restricted to the study arm with a maternal mortality ratio of 99 per 100 000 live births and a perinatal mortality rate of 240 per 1000 births. Pneumonia was significantly associated with a negative overall obstetric outcome in the presence of HIV- l infection, antenatal care, anaemia and second trimester booking status. In addition, the presence of pneumonia was significantly associated with maternal mortality. There was a highly significant association between exposure to pneumonia and poor neonatal outcome. Maternal pneumonia, maternal HIV infection and the presence of medical and obstetric conditions were significantly associated with low birth weight and neonatal pneumonia. Further, maternal pneumonia (p <0.001) and concurrent HIV infection (p=0.002) was significantly associated with neonatal death. Conclusion: The presence of pneumonia in the antenatal period impacts negatively on maternal and neonatal morbidity and mortality. Health care providers must maintain a high degree of suspicion when managing a pregnant woman with unresolving upper respiratory tract symptoms and refer timeously for further investigation. Pneumonia and in particular pulmonary tuberculosis associated with HIV co- infection in pregnancy is a threat to mother and baby. Therefore in areas endemic for TB and HIV infection, it may be prudent to screen HIV positive pregnant women for symptoms suggestive of pneumonia and thereby identify women requiring further investigations such as sputummicroscopy and cultures, and a screening chest radiograph. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2007.

[Truncated abstract] This thesis explores the risk factors and perinatal outcomes associated with prelabour rupture of membranes, with a particular focus on the environmental context. Prelabour rupture of membranes is defined as the rupture of fetal membranes before the onset of labour. It is a relatively common obstetric endpoint, occurring in approximately 8-10% of pregnant women at term (PROM) and in up to 40% of all preterm deliveries (pPROM). Despite the high prevalence of the condition, the biological mechanisms and risk factors, and in particular the role of environmental predictors, behind the development of PROM and pPROM remain largely unclear. A record-based prevalence design was used to analyse a population of 16,229 nulliparous, Caucasian women residing in Perth, Western Australia who gave birth to a single newborn during 2002-2004. Maternal age, socioeconomic status and threatened preterm labour during pregnancy were identified as risk factors for prelabour rupture of membranes. Term PROM was significantly associated with fetal distress (OR 1.19; 95%CI 1.00-1.43) and post-partum haemorrhage (OR 1.99; 95%CI 1.60-2.48). A number of perinatal complications were observed to be associated with the presentation of preterm PROM, including prolapsed cord (OR 13.95; 95%CI 4.57-42.61), ante-partum haemorrhage (OR 3.29; 95%CI 2.20-4.91), post-partum haemorrhage (OR 2.12; 95%CI 1.54-2.91), low birth weight (OR 17.79; 95%CI 13.87-22.82), very low birth weight (OR 20.01; 95%CI 14.12-28.35) and stillbirth (OR 5.42; 95%CI 2.87-10.21). However, the outcomes were similar between pPROM patients and other preterm deliveries, indicating that the complications arose due to the timing of the delivery. In contrast though, the risk factors between the two outcomes varied which may suggest that a different aetiological pathway exists between preterm PROM and other preterm deliveries. The frequency of complications decreased with increasing gestational age at delivery until the pregnancy reached full-term, whereupon an increase in gestational age at delivery resulted in an increased risk of fetal distress and post-partum haemorrhage. This finding is novel and may have important implications for the management of prelabour rupture of membranes, specifically with regard to the relative risks and benefits of expectant management (that is, the patient is admitted to an obstetric facility or hospital and closely monitored) versus planned delivery. ... This study represents the first attempt to investigate the potential associations between environmental risk factors and prelabour rupture of membranes. The results of the thesis provide a substantial contribution to our knowledge on prelabour rupture of membranes, including findings of direct relevance to clinical practice as well as a potentially contributing environmental exposure pathway. These original findings suggest a possible preventative approach to reducing the occurrence and associated morbidity of prelabour rupture of membranes may be feasible, and should be pursued if future research confirms the preliminary findings of this thesis.

[Truncated abstract] A diagnosis of breast cancer is a life-changing event for any woman. For young women and their families it can be devastating. Women aged less than 45 years make up 20% of new cases of breast cancer diagnosed annually in Australia. With the trend for women to delay pregnancy, young women diagnosed with breast cancer may want at least the option to become pregnant after diagnosis and treatment but little is known about how pregnancy affects breast cancer or how breast cancer affects pregnancy. The aims of this thesis were to investigate how concurrent and subsequent pregnancy affects the development and outcomes of breast cancer and how breast cancer affects a concurrent or subsequent pregnancy. This study describes two groups of women identified from the entire Western Australian population less than 45 years of age when diagnosed with: 1. Gestational breast cancer, defined as breast cancer diagnosed while a woman is pregnant or in the first twelve months after completion of a pregnancy; and 2. Breast cancer who subsequently conceive. This study focused on three main areas; patterns of care and outcomes for women diagnosed with gestational breast cancer and those women diagnosed with breast cancer who subsequently conceived; the imaging and pathological characteristics of gestational breast cancer; and lastly the psychosocial issues associated with gestational breast cancer. ... This result was statistically significant. In an age and staged matched case control study lymph node negativity did not purvey a survival advantage for women diagnosed with gestational breast cancer as it did for the non- gestational breast cancer controls. Women diagnosed with breast cancer who have good prognosis tumours need not necessarily wait two years to become pregnant. In an age matched case control study women diagnosed with gestational breast cancer were more likely to have extensive insitu carcinoma, higher mitotic rates and tumours with medullary like features than their age matched controls. In a Cox's proportional hazards regression model which included pathological characteristics, there was no significant difference in survival for women diagnosed with gestational breast cancer were compared to women diagnosed with non-gestational breast cancers. The psychosocial issues for women diagnosed with gestational breast cancer are similar to other young women diagnosed with breast cancer but the effect on the 9 lives of women dealing with pregnancy and breast cancer simultaneously was much greater. The issues of breast cancer and pregnancy are complex at both a physical and psychological level. Much more research is needed to understand the mechanisms of how pregnancy affects breast cancer and its spread. Women who are pregnant when diagnosed with breast cancer or who consider pregnancy after their diagnosis need unbiased support from those around them. Survival is important but other survivorship issues may be just as important. To translate these findings into clinical practice and offer directions for future research eleven recommendations are proposed.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 46-53).

Orientador: Adriano Dias / Resumo: Análise da incidência, identificação dos casos e distribuição dos critérios para a morbidade materna grave, no Distrito Federal. Utilizou-se para a identificação dos casos os critérios da OMS (2010). Inicialmente, delineou-se um estudo transversal, desenvolvido em nove hospitais públicos do Distrito Federal que são referência para a assistência a gestação e ao parto de risco habitual e alto risco, no período entre 01 de julho de 2013 e 29 de dezembro de 2015, a fim de verificar a incidência e identificar os casos de condições potencialmente ameaçadoras da vida (CPAV) e near miss (NM) por meio de busca ativa dos casos e entrevista direta com a paciente. Identificou-se 174 casos de morbidade materna grave em 62.706 nascidos-vivos, gerando uma incidência de 2,77 casos por mil nascidos-vivos. Dos 174 casos entrevistados, 26 foram classificados como CPAV e 148 como NM correspondendo a incidências de 0,4/1.000 e 2,36/1.000, respectivamente. As condições hemorrágicas foram as condicionantes primárias mais significantes (p<0,001) nos casos de maior gravidade (NM). Concomitantemente, desenvolveu-se um estudo caso-controle para estimar a associação entre os fatores de risco para a ocorrência de morbidade materna grave (MMG) utilizando-se o modelo de regressão logística múltipla hierarquizada. Verificou-se a associação entre cada variável preditora e a variável desfecho por meio do teste do Quiquadrado, em sequência, a análise multivariada foi realizada seguindo a entrada hierarquizada ... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Submitted by DANIELA MENDES DOS SANTOS MAGALHÃES null (danymendes@yahoo.com.br) on 2017-07-26T04:54:14Z No. of bitstreams: 1 Tese Daniela Magalhaes.pdf: 1427419 bytes, checksum: a1e1e559a3794b7205af5fb16ebc0ddd (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-07-26T19:00:45Z (GMT) No. of bitstreams: 1 magalhaes_dms_dr_bot.pdf: 1427419 bytes, checksum: a1e1e559a3794b7205af5fb16ebc0ddd (MD5) / Made available in DSpace on 2017-07-26T19:00:45Z (GMT). No. of bitstreams: 1 magalhaes_dms_dr_bot.pdf: 1427419 bytes, checksum: a1e1e559a3794b7205af5fb16ebc0ddd (MD5) Previous issue date: 2017-05-26 / Outra / Análise da incidência, identificação dos casos e distribuição dos critérios para a morbidade materna grave, no Distrito Federal. Utilizou-se para a identificação dos casos os critérios da OMS (2010). Inicialmente, delineou-se um estudo transversal, desenvolvido em nove hospitais públicos do Distrito Federal que são referência para a assistência a gestação e ao parto de risco habitual e alto risco, no período entre 01 de julho de 2013 e 29 de dezembro de 2015, a fim de verificar a incidência e identificar os casos de condições potencialmente ameaçadoras da vida (CPAV) e near miss (NM) por meio de busca ativa dos casos e entrevista direta com a paciente. Identificou-se 174 casos de morbidade materna grave em 62.706 nascidos-vivos, gerando uma incidência de 2,77 casos por mil nascidos-vivos. Dos 174 casos entrevistados, 26 foram classificados como CPAV e 148 como NM correspondendo a incidências de 0,4/1.000 e 2,36/1.000, respectivamente. As condições hemorrágicas foram as condicionantes primárias mais significantes (p<0,001) nos casos de maior gravidade (NM). Concomitantemente, desenvolveu-se um estudo caso-controle para estimar a associação entre os fatores de risco para a ocorrência de morbidade materna grave (MMG) utilizando-se o modelo de regressão logística múltipla hierarquizada. Verificou-se a associação entre cada variável preditora e a variável desfecho por meio do teste do Quiquadrado, em sequência, a análise multivariada foi realizada seguindo a entrada hierarquizada das variáveis definidas à priori e que produziram estimativas de odds ratio (OR) com valores de p≤0,25 no modelo univariado. O nível mais distal foi constituído de fatores sociodemográficos, o nível mais proximal por cuidados obstétricos e o intermediário os antecedentes clínicos. Neste estudo foram considerados fatores de risco para morbidade materna grave a cor da pele declarada não branca, renda familiar de até dois salários mínimos, não tem companheiro, realizar menos que seis consultas de pré-natal, não estar vinculada a maternidade de referência e a ausência de trabalho de parto na admissão. Neste estudo, a presença de indicadores socioeconômicos precários e o cuidado obstétrico desqualificado apresentaram relação significativa com o risco para morbidade materna grave. / Incidence analysis, case identification and distribution of criteria for severe maternal morbidity in the Federal District. The WHO criteria (2010) were used to identify the cases. Initially, a cross-sectional study was developed in 09 public hospitals of the Federal District there are a reference for the assistance of gestation and delivery at usual risk and high risk, between July 1, 2013 and December 29, 2015, In order to verify the incidence and identify the cases of potentially life threatening conditions (PLTC) and near miss (NM) by means of active case search and direct interview with the patient. We identified 174 cases of severe maternal morbidity in 62,706 live births, generating an incidence of 2.77 cases per thousand live births. Of the 174 interviewed cases, 26 were classified as PLTC and 148 as NM corresponding to incidence of 0.4 / 1,000 and 2.36 / 1,000, respectively. Hemorrhagic conditions were the most significant primary conditioners (p <0.001) in cases of greater severity (NM). Concurrently, a case-control study was developed to estimate the association between risk factors for the occurrence of severe maternal morbidity (SMM) using the hierarchical multiple logistic regression model. The association between each predictor variable and the outcome variable was verified by means of the Qui-square test, in sequence, the multivariate analysis was performed following the hierarchical input of the variables defined a priori and that produced estimates of odds ratio (OR) with values of P≤0,25 in the univariate model. The most distal level was composed of sociodemographic factors, the most proximal level for obstetric care and the intermediate clinical history. In this study, the risk factors for severe maternal morbidity were declared non-white skin, family income of up to two minimum wages, no partner, less than six prenatal consultations, no reference maternity, and Absence of labor on admission. In this study, the presence of precarious socioeconomic indicators and disqualified obstetric care had a significant relation with the risk for severe maternal morbidity.

Orientador: Jose Guilherme Cecatti / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T20:54:38Z (GMT). No. of bitstreams: 1 Haddad_SamiraElMaerrawiTebecherane_M.pdf: 6986091 bytes, checksum: 426357180584abd261e39ad98c68b5ff (MD5) Previous issue date: 2009 / Resumo: Introdução: A saúde materna é um dos focos das Metas de Desenvolvimento do Milênio das Nações Unidas para 2015. A manutenção dos altos índices de mortalidade decorre principalmente das dificuldades de acesso aos serviços de saúde e inadequação do manejo das complicações obstétricas em locais pouco desenvolvidos. Por outro lado, a ocorrência da morte materna em locais desenvolvidos é um evento relativamente raro em comparação com o número de casos mórbidos. Neste sentido, o estudo da morbidade materna ganhou relevância. Estudos mostraram que a falta de padronização de critérios definidores de morbidade materna grave, a dificuldade de identificação e relato dessas condições nos registros oficiais e pelas próprias mulheres e a condução de investigações retrospectivas, podem distorcer o número real de casos de morbidade. Sistemas de vigilância eletrônica podem trazer melhorias à investigação, por facilitar o relato e completude das informações e diminuir o tempo de coleta e análise das mesmas. Recentemente, foram divulgados pela Organização Mundial da Saúde o novo conceito de near miss materno e critérios de condições definidoras de gravidade. Com este avanço, o seguimento da vigilância e a elaboração de estratégias de redução do problema mundial da morte materna podem ter sua condução embasada em fonte teórica unificada, dando solidez à investigação e norteando o foco da atenção. Objetivos: Criar uma rede nacional de vigilância de morbidade materna grave no Brasil, com abrangência em todas as regiões geográficas do país, elaborar o planejamento teórico de caracterização da rede de vigilância e descrever os métodos e procedimentos adotados para sua implementação. Métodos: O projeto desenvolvido foi de um estudo transversal multicêntrico para implantação em unidades obstétricas de referência em diversas regiões geográficas do Brasil. Durante um período de doze meses, deve ser realizada a vigilância prospectiva e coleta de dados para a identificação dos casos de near miss materno e de condições potencialmente ameaçadoras da vida, segundo os novos critérios da OMS. A partir da elaboração teórica do projeto, foi realizada a seleção dos centros da rede, revisão dos critérios de morbidade materna grave e formulários de coleta de dados, seleção do sistema eletrônico para inclusão de casos, desenvolvimento das ferramentas específicas do software e hardware, desenvolvimento do material de pesquisa, iniciado processo de implementação e análise de processo. Conclusão: A formação teórica da Rede Nacional de Vigilância de Morbidade Materna Grave foi uma conseqüência da experiência adquirida em diversos estudos na área nos últimos anos. A estrutura teórica é parte de um conceito abrangente de cuidado à saúde materna e perinatal, e a sua implementação é a primeira etapa da execução desse planejamento. A arquitetura do sistema de informação da Rede poderá ser utilizada para novos estudos em saúde reprodutiva e perinatal. / Abstract: Introduction: Maternal health is one of the United Nations Millenium Development Goals for 2015. The maintenance of high levels of mortality is due mostly to difficulties to access health care services and inadequacy on the management of obstetrical complications in least developed regions. Furthermore, the occurence of maternal death in developed regions is a relatively rare event compared to the number of morbid cases. Therefore, the study of maternal morbidity became more relevant. Studies showed that the lack of standardization of severe maternal morbidity criteria, difficulties in identifying and reporting these conditions in the official records and the women themselves and retrospective investigations, can distort the actual number of cases of morbidity. Electronic surveillance systems can bring improvements to research, facilitate reporting and completeness of the information and reduce the time of collection and examination. Recently the concept of maternal near miss and defining criteria of severity have been released by the World Health Organization. With this advance, tracking and surveillance strategies to reduce the global problem of maternal mortality may have their management based on a unified theoretical source, giving strength to the research and guiding the focus of attention. Objectives: To create a national surveillance network of severe maternal morbidity in Brazil covering all geographic regions of the country, to develop the theoretical planning of characterization of the network and to describe the methods and procedures adopted for its implementation. Methods: It was developed a cross sectional multicentric study in reference obstetric units in various geographical regions of Brazil. During a period of twelve months, it should be carried out prospective surveillance and data collection for the identification of cases of maternal near miss and potentially life-threatening conditions, according to the new WHO criteria. After the theoretical development of the project, the network centers were selected, the severe maternal morbidity criteria and data collection forms were reviewed, selection of the software for case inclusion, development of specific tools of the software and hardware, development of the research material, initiated the process of implementation and process analysis. Conclusion: The theoretical development of the Brazilian Network for Surveillance of Severe Maternal Morbidity was a result of experience learned in several studies in this area in recent years. The theoretical framework is part of a comprehensive concept of maternal and perinatal health care, and its implementation is the first step in executing this plan. The system architecture of the network information system may be used for further studies in reproductive and perinatal health. / Mestrado / Tocoginecologia / Mestre em Tocoginecologia