Rozprawy doktorskie na temat „Premature rupture of fetal membranes”

The problem. Group B Streptococci (GBS) are one of the most frequent causes of life-threatening infections in newly born infants, who acquire the micro-organism while passing through the genital tracts of their asymptomatic colonized mothers. Some previous studies have suggested that maternal genital colonization by GBS is associated with preterm rupture of the fetal membranes and preterm delivery. In this thesis both a prevalence study and a historical cohort study were conducted, to investigate the prevalence of maternal GBS colonization at 28 weeks of gestation, and whether there is an association between colonization and preterm rupture of the fetal membranes. Background information. Different rates for maternal GBS colonization during pregnancy have been reported, ranging from 4.6% up to 40%. The association between maternal GBS colonization and preterm rupture of the membranes has been reported in some studies, but other studies have not supported this view, which led to differsnces in opinions and the lack of a specific conclusion. The variations in the findings of these studies may have been due to several factors, which include differences in cultured sites and phase of pregnancy at which culture was obtained, in addition to the wide variations in the definition of premature rupture of the membranes used by various authors. (Abstract shortened by UMI.)

Aquesta tesi es centra en la creació d'un sistema de segellat que permet taponar els forats de la membrana corioamniótica produïts per l'instrumental quirúrgic de mínima invasió en operacions fetals. Actualment, amb la millora de les tècniques d'imatge per al diagnòstic fetal que s'utilitzen per fer el seguiment de l'embaràs, ha augmentat la detecció d'anomalies fetals i, per tant, també la necessitat de dur a terme intervencions quirúrgiques amb les que accedir directament al fetus de forma segura. Ja des de fa alguns anys, per a realitzar cirurgies de la manera menys invasiva possible s'utilitza la fetoscòpia. Tècnica en la que mitjançant la inserció d'un trocar a través de la cavitat abdominal som capaços d'introduir les eines necessàries per dur a terme la cirurgia fetal corresponent. Tot i així, l'accés al fetus des d'un sol punt limita les possibilitats de la tècnica, en contraposició de si es tingués accés des de diversos punts, ja que permetria abordar al fetus des de diversos eixos. Un dels problemes associats a les cirurgies fetals és la presència romanent de l'orifici a la membrana corioamniótica un cop s'extreu el trócar i finalitza l'operació, ja que per si sola és incapaç de regenerar-se. La permanència de l'orifici, sobretot en les primeres hores, pot causar diferents patologies. Des d’oligohidramnios, corioamnionitis, hipoplàsia pulmonar del fetus, ..., fins trencament de la membrana corioamniótica, que pot cursar amb la mort del fetus. Aquest trencament de la membrana rep el nom de Ruptura Prematura de les Membranes a Preterme per causes iatrogèniques (iPPROM) i és una de les complicacions més comuns durant l'embaràs. L'objectiu d'aquest treball és crear un pegat que permeti el segellat d'aquests orificis i que es redueixi de manera significativa el risc de pèrdua de líquid amniòtic i el trencament de la membrana corioamniótica durant els primers dies després de la fetoscòpia. El desenvolupament del sistema de segellat s'ha dividit en tres parts, en que els experiments, avenços i resultats s'han obtingut de forma semi-paral·lela fins a obtenir un prototip final de dispositiu mèdic: d'una banda, desenvolupar un adhesiu amb propietats bioadhesives en medi humit i que s'activa en entrar en contacte amb el propi líquid amniòtic; d'altra banda, el substrat on estarà disposat l’adhesiu, i que junts actuen com un pegat; i finalment un sistema d'inserció que permeti la col·locació d'aquest pegat de la forma més ràpida i segura possible per part de l'equip mèdic partícip en la cirurgia.
Esta tesis se centra en la creación de un sistema de sellado que permite taponar los orificios de la membrana corioamniótica producidos por el instrumental quirúrgico de mínima invasión en operaciones fetales. Actualmente, con la mejora de las técnicas de imagen para el diagnóstico fetal que se utilizan para hacer el seguimiento del embarazo, ha aumentado la detección de anomalías fetales y, por lo tanto, también la necesidad de llevar a cabo intervenciones quirúrgicas con las que acceder directamente al feto de forma segura. Ya desde hace algunos años, para realizar cirugías de la manera menos invasiva posible se utiliza la fetoscopia: técnica en la que mediante la inserción de un trócar a través de la cavidad abdominal somos capaces de introducir las herramientas necesarias para llevar a cabo la cirugía fetal correspondiente. Aun así, el acceso al feto desde un solo punto limita las posibilidades de la técnica, en contraposición de si se tuviera acceso desde varios puntos, ya que permitiría abordar al feto desde varios ejes.   Uno de los problemas asociados a las cirugías fetales es la presencia remanente del orificio en la membrana corioamniótica una vez se extrae el trócar y finaliza la operación, ya que por sí sola es incapaz de regenerarse. La permanencia del orificio, sobre todo en las primeras horas, puede causar diferentes patologías. Desde oligohidramnios, corioamnionitis, hipoplasia pulmonar del feto, …, hasta rotura de la membrana corioamniótica, que cursa con la muerte del feto, si éste aún no es viable. Esta rotura de la membrana recibe el nombre de Rotura Prematura de las Membranas a Pretérmino por causas iatrogénicas (iPPROM) y es una de las complicaciones más comunes durante el embarazo. El objetivo de este trabajo es crear un parche que permita el sellado de estos orificios y que se reduzca de forma significativa la pérdida de líquido amniótico y el riesgo de rotura de la membrana corioamniótica durante los primeros días tras la fetoscopia. El desarrollo del sistema de sellado se ha dividido en tres partes, cuyos experimentos, avances y resultados se han obtenido de forma semiparalela hasta obtener un prototipo final de dispositivo médico. Por un lado, el desarrollo de un adhesivo con propiedades bioadhesivas en medio húmedo y que se activa al entrar en contacto con el líquido amniótico; por otro lado, el sustrato donde de depositará el adhesivo, y que juntos actúan como un parche; y finalmente un sistema de introducción que permita la colocación de este parche de la forma más rápida y segura posible por parte del equipo médico partícipe en la cirugía.
This thesis is focused on the creation of a sealing system that blocks the orifices of the chorioamniotic membrane produced by minimally invasive surgical instruments during fetal operations. Currently, with the improvement of imaging techniques for fetal diagnosis used to monitor pregnancy, the detection of fetal anomalies has increased. In this scenario, it is essential to develop surgical procedures to directly access the fetus in a safer manner. Over the past few years, the use of fetoscopy has provided lees invasive surgical procedures. Fetoscopy is a technique in which, by inserting a trocar through the abdominal cavity, we are able to introduce the necessary instruments to perform the corresponding fetal surgery. Even so, the access to the fetus from a single point limits the possibilities of the technique, as opposed to having access from several points, since it would allow the fetus to be approached from several axes.   One of the problems associated with fetal surgeries is the remaining presence of the orifice in the chorioamniotic membrane once the trocar is removed. The permanence of the orifice, especially in the first hours after surgery, can cause different pathologies: oligohydramnios, chorioamnionitis, pulmonary hypoplasia of the fetus, etc., and also the rupture of the chorioamniotic membrane, which could result in fetal death. This rupture of the membrane is called iatrogenic preterm preterm premature rupture of membranes (iPPROM) and is one of the most common complications during pregnancy. The aim of this work is to create a patch that allows the sealing of these orifices and significantly reduces the leakage of amniotic liquid and the risk of chorioamniotic membrane rupture during the first days after fetoscopy. The development of the sealing system has been divided into three parts, which experiments, advances and results have been obtained in a semi-parallel process until a final medical device was obtained: on the one hand, the development of an adhesive with bioadhesive properties in a wet environment, which is activated when it comes into contact with the amniotic fluid itself; on the other hand, the substrate where the adhesive will be placed and which acts as a patch; and finally, an insertion system that allows the placement of this patch as quickly and safely as possible by the medical team involved in the surgery.

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Introdução: O Trabalho de Parto Pré-Termo (TPP) e a Rotura Prematura de Membranas Pré-Termo (RPM-PT) acarretam severas complicações para o binômio materno-fetal. Entre os fatores de risco associados ao TPP e à RPM-PT, a predisposição genética vem ganhando importância. Contudo, a associação entre genes polimórficos, ancestralidade e a patogênese do TPP e da RPM-PT permanece alusiva. Objetivo: Determinar a associação entre marcadores informativos de ancestralidade (AIMs) e polimorfismos de nucleotídeo único (SNPs) dos genes da Interleucina-1 beta (IL1B), IL6, Receptor de IL6 (IL6R), Fator de Necrose Tumoral Alfa (TNFA), Receptor de TNF alpha (TNFR), IL10, Receptor Toll-like 2 (TLR2), TLR4, Metaloproteinase 9 (MMP9), Inibidor de Metaloproteinase 1 (TIMP1) e TIMP2 maternos e fetais e o TPP e a RPM-PT. Pacientes e Métodos: Foram coletados swabs bucais de gestantes com TPP e/ou RPM-PT e DE seus filhos (TPP: 137 mulheres e 88 filhos; RPM-PT: 64 mulheres e 44 filhos) atendidas no Hospital das Clínicas da Faculdade de Medicina de Botucatu, UNESP, entre os anos de 2003 e 2014. O grupo controle foi constituído por 201 mulheres que tiveram gestações resolvidas a termo e seus 201 filhos, pareadas ao grupo caso por idade materna e sexo do recém-nascido. O DNA total foi extraído dos swabs bucais e submetido à identificação de AIMs por análise de fragmentos e genotipagem de SNPs utilizando Taqman® SNP Genotyping Assays (Applied Biosystems) e Reação em Cadeia da Polimerase (PCR). O software Structure v2.3.4 foi utilizado para estimar mistura étnica materna. Teste de desequilíbrio de ligação e proporção da Hardy-Weinberg foram testados com Genepop 3.4 e haplótipos inferidos com Phase. Os dados sociodemográficos e biológicos foram comparados utilizando os testes de χ2, teste exato de Fisher, Regressão Logística, Manova, Mann-Whitney e Odds Ratio. Resultados: Nas amostras maternas, o TPP foi associado a maior...
Introduction: A genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. Objective: To evaluate the association between Ancestry Informative Markers (AIM) and Single Nucleotide Polymorphisms (SNPs) in Interleukin-1 beta (IL1B), IL6, IL6 Receptor (IL6R), Tumor Necrosis Factor Alpha (TNFA), TNF Receptor (TNFR), IL10, Toll Like Receptor 2 (TLR2), TLR4, Metalloproteinase 9 (MMP9), Tissue Inhibitors of Metalloproteinase 1 (TIMP1) and TIMP2 genes and the susceptibility to PTL and PPROM in Brazilian women. Patients and Methods: Oral swabs were collected from women with PTL and/or PPROM and their babies (PTL: 137 women and 88 babies; PPROM: 64 women and 44 babies) seen at the Botucatu Medical School's Hospital, between 2003 and 2014. Control group included 402 mother-babies pairs of term deliveries, matched to case group by age and newborn gender. After DNA extraction, AIMs were identified by fragment analysis and SNPs by Taqman® SNP Genotyping Assays (Applied Biosystems) and Polymerase Chain Reaction (PCR). The software Structure v2.3.4 was used to estimate ethnic admixture of mothers. Linkage Disequilibrium and Hardy-Weinberg proportions were tested with Genepop 3.4 and haplotypes inferred using Phase. Mann-Whitney, χ2, Fisher's exact test, Logistic Regression models, Odds Ratio and Manova were used in data analysis. Results: Regarding maternal samples, PTL was associated to European ancestry and smoking and African ancestry was protective. Regarding ancestry analysis, self-reported ethnicity only explained 20% and 15% of the global variation in African and European contributions, respectively. Fetal IL10-592 C and IL10-819 C were also associated to PTL. Maternal alleles IL10-1082 G and TLR2 A increased the risk ...

Orientador: Márcia Guimarães da Silva
Coorientador: Steven Witkin
Banca: Leandro Gustavo de Oliveira
Banca: Erick da Cruz Castelli
Banca: Rodrigo Paupério Soares de Camargo
Banca: Gisele Alboreghetti Nair
Resumo: Introdução: O Trabalho de Parto Pré-Termo (TPP) e a Rotura Prematura de Membranas Pré-Termo (RPM-PT) acarretam severas complicações para o binômio materno-fetal. Entre os fatores de risco associados ao TPP e à RPM-PT, a predisposição genética vem ganhando importância. Contudo, a associação entre genes polimórficos, ancestralidade e a patogênese do TPP e da RPM-PT permanece alusiva. Objetivo: Determinar a associação entre marcadores informativos de ancestralidade (AIMs) e polimorfismos de nucleotídeo único (SNPs) dos genes da Interleucina-1 beta (IL1B), IL6, Receptor de IL6 (IL6R), Fator de Necrose Tumoral Alfa (TNFA), Receptor de TNF alpha (TNFR), IL10, Receptor Toll-like 2 (TLR2), TLR4, Metaloproteinase 9 (MMP9), Inibidor de Metaloproteinase 1 (TIMP1) e TIMP2 maternos e fetais e o TPP e a RPM-PT. Pacientes e Métodos: Foram coletados swabs bucais de gestantes com TPP e/ou RPM-PT e DE seus filhos (TPP: 137 mulheres e 88 filhos; RPM-PT: 64 mulheres e 44 filhos) atendidas no Hospital das Clínicas da Faculdade de Medicina de Botucatu, UNESP, entre os anos de 2003 e 2014. O grupo controle foi constituído por 201 mulheres que tiveram gestações resolvidas a termo e seus 201 filhos, pareadas ao grupo caso por idade materna e sexo do recém-nascido. O DNA total foi extraído dos swabs bucais e submetido à identificação de AIMs por análise de fragmentos e genotipagem de SNPs utilizando Taqman® SNP Genotyping Assays (Applied Biosystems) e Reação em Cadeia da Polimerase (PCR). O software Structure v2.3.4 foi utilizado para estimar mistura étnica materna. Teste de desequilíbrio de ligação e proporção da Hardy-Weinberg foram testados com Genepop 3.4 e haplótipos inferidos com Phase. Os dados sociodemográficos e biológicos foram comparados utilizando os testes de χ2, teste exato de Fisher, Regressão Logística, Manova, Mann-Whitney e Odds Ratio. Resultados: Nas amostras maternas, o TPP foi associado a maior...
Abstract: Introduction: A genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. Objective: To evaluate the association between Ancestry Informative Markers (AIM) and Single Nucleotide Polymorphisms (SNPs) in Interleukin-1 beta (IL1B), IL6, IL6 Receptor (IL6R), Tumor Necrosis Factor Alpha (TNFA), TNF Receptor (TNFR), IL10, Toll Like Receptor 2 (TLR2), TLR4, Metalloproteinase 9 (MMP9), Tissue Inhibitors of Metalloproteinase 1 (TIMP1) and TIMP2 genes and the susceptibility to PTL and PPROM in Brazilian women. Patients and Methods: Oral swabs were collected from women with PTL and/or PPROM and their babies (PTL: 137 women and 88 babies; PPROM: 64 women and 44 babies) seen at the Botucatu Medical School's Hospital, between 2003 and 2014. Control group included 402 mother-babies pairs of term deliveries, matched to case group by age and newborn gender. After DNA extraction, AIMs were identified by fragment analysis and SNPs by Taqman® SNP Genotyping Assays (Applied Biosystems) and Polymerase Chain Reaction (PCR). The software Structure v2.3.4 was used to estimate ethnic admixture of mothers. Linkage Disequilibrium and Hardy-Weinberg proportions were tested with Genepop 3.4 and haplotypes inferred using Phase. Mann-Whitney, χ2, Fisher's exact test, Logistic Regression models, Odds Ratio and Manova were used in data analysis. Results: Regarding maternal samples, PTL was associated to European ancestry and smoking and African ancestry was protective. Regarding ancestry analysis, self-reported ethnicity only explained 20% and 15% of the global variation in African and European contributions, respectively. Fetal IL10-592 C and IL10-819 C were also associated to PTL. Maternal alleles IL10-1082 G and TLR2 A increased the risk ...
Doutor

Orientadores: Antonio Wilson Sallum, Jose Guilherme Cecatti
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Este estudo teve por objetivo avaliar a prevalência de doença periodontal em uma amostra de gestantes de baixo risco gestacional, os fatores a ela associados, e sua correlação com a ocorrência de resultados perinatais adversos, como parto pré-termo, recém-nascido de baixo peso, recém-nascido pequeno para a idade gestacional e amniorrexe prematura. Trata-se de um estudo de coorte com 334 gestantes fazendo acompanhamento pré-natal no Hospital das Clínicas da UNICAMP, que aceitaram participar voluntariamente e tiveram um único exame periodontal realizado no dia da consulta pré-natal. Os dados foram coletados da anamnese, do exame clínico periodontal e de informações relativas à gestação, parto e puerpério. Os parâmetros clínicos periodontais foram: índice de placa, índice de sangramento gengival à sondagem, profundidade de sondagem, nível de inserção clínica periodontal e retração gengival. As gestantes foram divididas em dois grupos: as com periodontite moderada a grave (P2-P4), e as sem doença ou com doença periodontal leve (P0-P1), pela classificação do índice WS. Avaliaram-se também a idade, paridade, raça, escolaridade, estado civil, hábitos alimentares, índice de massa corpórea (IMC), número de consultas de pré-natal, fumo, uso de bebidas e drogas, uso de medicação, vaginose bacteriana e doenças sistêmicas. Inicialmente foi utilizada uma abordagem analítica de corte transversal para a identificação de fatores associados à ocorrência de doença periodontal na gestação. Depois utilizou-se uma abordagem de estudo de coorte propriamente dito, estimando-se o risco de ocorrência dos resultados perinatais desfavoráveis (parto pré-termo, recém-nascido de baixo peso, recém-nascido pequeno para a idade gestacional e amniorrexe prematura, variáveis dependentes principais do estudo) em função da condição periodontal. Foram analisadas as distribuições de freqüência das variáveis independentes pelas categorias de doença periodontal, estimando-se a Razão de Prevalência e seu IC95% para abordagem transversal. Foi então realizada a análise uni e multivariada para a estimativa do risco de ocorrência das variáveis perinatais desfavoráveis na abordagem de coorte, calculando-se a Razão de Risco e seu IC95% para cada uma delas. Foi estabelecido o nível de significância de 5%. A prevalência de periodontite moderada a grave nas 334 gestantes foi de 47%, e se associou significativamente com a idade gestacional mais avançada ao exame periodontal (17-24 semanas: RP 1,40, IC95% 1,01-1,94; e 25-32 semanas: RP 1,52, IC95% 1,10-2,08), com a idade materna entre 25 e 29 anos (RP 1,65, IC95% 1,02-2,68), com a obesidade (RP 1,38, IC95% 1,04-1,82) e com a presença de sangramento gengival (ORajustado 2,01 - IC95% 1,41-2,88). Foram coletados os dados do parto de 327 gestantes e, entre elas, a doença periodontal esteve associada a um maior risco de ocorrência de parto pré-termo (RR 3,47 IC95% 1,62-7,43), de RN de baixo peso (RR 2,93 IC95% 1,36-6,34) e de amniorrexe prematura (RR 2,48 IC95% 1,35-4,56) na análise multivariada. A prevalência de doença periodontal entre gestantes de baixo risco gestacional é alta e associada com a maior idade gestacional, obesidade e sangramento gengival. A doença periodontal foi um fator de risco para a ocorrência de parto pré-termo, RN de baixo peso e de amniorrexe prematura
Abstract: This study was aimed to evaluate the prevalence of periodontal disease in a sample population of low-risk pregnant women, the factors associated with it and its correlation with the occurrence of adverse perinatal outcomes, including preterm births, low birth weigth, small for gestational age babies and premature rupture of the membranes. This cohort study included 334 pregnant women under prenatal care at the Hospital das Clinicas of the University of Campinas, Brazil, who voluntarily accepted to participate and had one single periodontal examination performed in the same day of a prenatal visit. Data was collected from anamnesis, periodontal clinical exam, and from information regarding pregnancy, delivery and postpartum. The clinical periodontal parameters were: plaque index, bleeding on probing index, probing pocket depth, clinical attachment level and gingival recession. Pregnant women were divided into two groups: those with moderate-to-severe periodontitis (P2-P4) and those with no disease or only mild disease (P0-P1), according to the WS classification index. Age, parity, race/color, years of schooling, marital status, number of prenatal visits, dietary habits, BMI (body mass index), smoking habits, use of alcohol and drugs, use of medication and presence of systemic diseases d bacterial vaginosis were also evaluated. Initially a cross sectional analytic approach was used for identifying factors associated with the occurrence of periodontal disease during pregnancy. After that, a real cohort approach was used, with the estimate of the risk of adverse perinatal outcomes (preterm birth, low birth weight, small for gestational age baby and premature rupture of membranes, the main dependent variables of this study) according to the condition of periodontal disease. Distribution of independent variables within the two groups was analyzed by calculating prevalence ratios and their respective 95% confidence intervals for the cross sectional approach. Uni and multivariate analysis for the estimation of the risk of adverse perinatal outcomes were performed for the cohort approach. The Risk Ratior and its 95%CI were estimated for each outcome. The significance level assumed was 5%. The prevalence of moderate to severe periodontitis in 334 pregnant women was 47%, and it was significantly associated with more advanced gestational age at periodontal examination (17-24 weeks: PR 1.40, 95%CI 1.01-1.94; and 25-32 weeks: PR 1.52, 95%CI 1.10 ¿ 2.08), with maternal age between 25 - 29 years (PR 1.65, 95%CI 1.02 ¿ 2.68), with obesity (PR 1.38, 95%CI 1.04 ¿ 1.82) and with the presence of gingival bleeding (ORadjusted 2.01, 95%CI 1.41 ¿ 2.88). The data of 327 deliveries were collected and, among them, the periodontal disease was associated to a higher risk of preterm birth (RR 3.47 95%CI 1.62-7.43), of low birth weight (RR 2.93 95%CI 1.36-6.34) and of premature rupture of membranes (RR 2.48 95%CI 1.35-4.56) in the multivariate analysis. The prevalence of periodontal disease among low-risk pregnant women is high and it is associated with more advanced gestational age, obesity and gingival bleeding. Periodontal disease was a risk factor for the occurrence of preterm birth, low birth weight and premature rupture of membranes
Mestrado
Periodontia
Mestre em Clínica Odontológica

Les phtalates sont des composés chimiques utilisés depuis des décennies comme plastifiants dans de nombreux produits du quotidien, notamment les emballages alimentaires, les jouets et les dispositifs médicaux. Toutefois, ces substances sont également reconnues comme des perturbateurs endocriniens, avec des effets potentiellement néfastes sur la santé humaine, en particulier sur la reproduction. Leur lien avec des complications telles que les naissances prématurées et les troubles du développement fœtal a suscité une forte inquiétude. En réponse à cette situation, des plastifiants alternatifs, comme le DINCH (1,2-cyclohexanedicarboxylic acid diisononyl ester), ont été développés pour remplacer les phtalates. Cependant, les impacts à long terme de ces alternatives sur la santé, notamment sur les membranes fœtales, restent à élucider.Le DINCH est aujourd'hui utilisé dans des produits ciblant des populations sensibles, comme les femmes enceintes et les nourrissons. Bien qu'ils soient considérés comme des substances prometteuses, il subsiste un manque de données suffisantes pour garantir leur innocuité, en particulier concernant leur impact potentiel sur la grossesse. Parmi les complications liées à la grossesse, la rupture prématurée des membranes fœtales (PPROM) constitue un facteur majeur de naissances prématurées, touchant environ 3 % à 4 % des grossesses et contribuant pour 50 % des accouchements prématurés. Le rôle que pourrait jouer les plastifiants, qu'ils soient phtalates ou non, dans la survenue de cette pathologie est encore peu étudié.Ce travail de thèse se concentre sur l'exploration des effets de ces plastifiants non-phtalates, et plus particulièrement du DINCH et son métabolite le MINCH (1,2-cyclohexanedicarboxylic acid mono-4-méthyloctyl ester) sur la physiologie des membranes fœtales humaines. Plus précisément, l'étude se penche sur l'impact de ces substances sur le récepteur nucléaire PPARγ, un acteur crucial dans le maintien de la grossesse et la régulation des processus inflammatoires. PPARγ joue un rôle central dans le développement placentaire et la protection contre l'inflammation, deux éléments essentiels pour le bon déroulement de la grossesse. L'objectif principal de ce travail est d'évaluer si ces plastifiants alternatifs perturbent cette voie de signalisation et pourraient, ainsi, compromettre l'intégrité des membranes fœtales, favorisant alors leur rupture prématurée.Les expériences ont été réalisées sur un modèle de cellules épithéliales amniotiques humaines pour explorer la toxicité potentielle des plastifiants, ainsi que leurs effets sur l'expression et l'activité de PPARγ. Les résultats indiquent que le DINCH et son métabolite MINCH n'entraînent pas de perturbations majeures de l'activité de PPARγ contrairement à certains phtalates.En conclusion, cette étude ouvre la voie à une meilleure compréhension des risques potentiels des plastifiants non-phtalates sur la santé reproductive. Bien que les résultats obtenus semblent encourageants quant à l'innocuité du DINCH et du MINCH, il est crucial de mener des études complémentaires pour s'assurer de leur sécurité à long terme, notamment en ce qui concerne la prévention de la rupture prématurée des membranes fœtales et des naissances prématurées qui en résultent. Il soulève également l'importance d'informer les femmes enceintes sur les risques potentiels liés à l'exposition aux plastifiants, qu'ils soient phtalates ou non, et d'encourager auprès de cette population des pratiques visant à limiter leur exposition durant la grossesse
Phthalates are chemical compounds that have been used for decades as plasticizers in various everyday products, including food packaging, toys, and medical devices. However, these substances are also recognized as endocrine disruptors, with potentially harmful effects on human health, particularly reproduction. Their link to complications such as preterm births and fetal developmental disorders has raised significant concerns. In response, alternative plasticizers like DINCH (1,2-cyclohexanedicarboxylic acid diisononyl ester) have been developed to replace phthalates. However, the long-term impacts of these alternatives on health, particularly on fetal membranes, remain unclear.DINCH is now used in products targeting sensitive populations, such as pregnant women and infants. Although these substances are considered promising, there remains a lack of sufficient data to guarantee their safety, particularly regarding their potential impact on pregnancy. Among pregnancy-related complications, preterm premature rupture of membranes (PPROM) is a major factor in preterm births, affecting approximately 3% to 4% of pregnancies and contributing to 50% of preterm deliveries. The role that plasticizers, whether phthalates or non-phthalates, may play in this pathology is still underexplored.This thesis focuses on exploring the effects of these non-phthalate plasticizers, specifically DINCH and its metabolite MINCH (1,2-cyclohexanedicarboxylic acid mono-4-methyloctyl ester), on the physiology of human fetal membranes. More precisely, the study examines the impact of these substances on the nuclear receptor PPARγ, a key player in maintaining pregnancy and regulating inflammatory processes. PPARγ plays a central role in placental development and inflammation control, both essential for a successful pregnancy. The main objective of this work is to assess whether these alternative plasticizers disrupt this signaling pathway and, thus, compromise the integrity of fetal membranes, potentially leading to their premature rupture.Experiments were conducted using a model of human amniotic epithelial cells to explore the potential toxicity of the plasticizers, as well as their effects on PPARγ expression and activity. The results indicate that DINCH and its metabolite MINCH do not cause major disruptions to PPARγ activity contrary to phthalate.In conclusion, this study paves the way for a better understanding of the potential risks associated with non-phthalate plasticizers on reproductive health. Although the results obtained seem encouraging regarding the safety of DINCH and MINCH, it is crucial to conduct further studies to ensure their long-term safety, particularly concerning the prevention of premature rupture of fetal membranes and the resulting preterm births. This study also highlights the importance of informing pregnant women about the potential risks associated with exposure to plasticizers, whether phthalates or non-phthalates, and encouraging practices to limit their exposure during pregnancy

The aim of the research was to find new potential biomarkers of preterm premature rupture of membranes. The amniotic fluid and fetal membranes peptidic composition was analyzed using a fully automated 2D liquid chromatographic system coupled to mass spectrometry. A comparison of peptidomes of amniotic fluid and amniochorionic membranes with preterm premature rupture and term intact membranes was performed. Ten proteins from amniotic fluid were identified as potential biomarkers for PPROM. The created map of amniotic fluid peptides and proteins depending on the gestational age is important for proteomics-based identification of biomarkers for fetal abnormalities and other pregnancy complications.
Mokslinio darbo metu siekta nustatyti potencialius priešlaikinio neišnešioto vaisiaus dangalų plyšimo biožymenis. Panaudojant dvidimensinę skysčių chromatografiją bei masių spektrometriją išanalizuota vaisiaus vandenų ir dangalų peptidinė sudėtis. Ištirti ir palyginti amniochorioninės membranos ir vaisiaus vandenų peptidai bei su jais siejami baltymai, kai prieš laiką plyšta neišnešioto vaisiaus dangalai arba vaisius išnešiojamas iki numatyto gimdymo termino ir dangalai išlieka sveiki. Išanalizavus skirtumus, nustatyti nauji galimi priešlaikinio neišnešioto vaisiaus dangalų plyšimo biožymenys.

[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.

Die nicht-invasive Analyse der fetalen Herzratenvariabilität mittels abdominaler Elektrokardiographie stellt eine neue Methode zur Beurteilung des fetalen Zustandes dar. Die Herzratenvariabilität gilt hier als ein sensitives Maß der autonomen Regulation. Bereits mit Beginn der zweiten Schwangerschaftshälfte ist es möglich, über das mütterliche Abdomen ein fetales Elektrokardiogramm abzuleiten und einer Herzratenvariabilitätsanalyse zuzuführen. Das Untersuchungskollektiv dieser Arbeit umfasste Frauen mit frühem vorzeitigem Blasensprung als Modell einer pathologischen Alteration des fetalen Zustandes sowie Frauen mit normalen Schwangerschaften zwischen der 20. und 28. Schwangerschaftswoche. Die technische Umsetzung und Analyse der fetalen Herzratenvariabilität erfolgte in Kooperation mit dem Institut für Biomedizinische Technik der TU Dresden. Insgesamt wurden 25 Datensätze der Auswertung zugeführt. Eine Reifung des autonomen Nervensystems des Feten mit ansteigendem Gestationsalter konnte mittels der Herzratenvariabilitätsanalyse gezeigt werden. Zur Risikostratifizierung der Feten bei frühem vorzeitigem Blasensprung konnten bei der Betrachtung der Herzratenvariabilitätsparameter keine signifikanten Unterschiede zum Normalkollektiv erhoben werden. Die Analyse der Parameter erfolgte hierbei unabhängig von den fetalen Verhaltenszuständen. Es konnte gezeigt werden, dass die nicht-invasive Analyse der Herzratenvariabilitätsanalyse methodisch und technisch in der Lage ist, den Fetalzustand und dessen Alterationen zu erfassen.

Objective: to evaluate the risk of obstetric and perinatal outcomes in teenage pregnancy in comparison with adult pregnancy. Methods: retrospective cohort study of 67.693 pregnant women attended in a public hospital in Lima between 2000 and 2010. Obstetric and perinatal outcomes were evaluated. The adolescent group was divided in late adolescents (15-20 years), and early adolescents (<15 years) and was compared among the adult group (20-35 years). Adjusted odds ratios were calculated by education, civil status, prenatal care, previous pregnancies, parity, and pre-gesta-tional BMI. Results: higher risk of cesarean (OR=1,28; CI95%=1,07-1,53) and puerperal infection (OR=1,72; CI95%=1,17-2,53) was found in teenager under 15 years old; as well as higher risk of episiotomy (OR=1,34; CI95%=1,29-1,40) in late teenagers. In addition, this study identified a lower risk of teenage pregnancy for preeclampsia (OR=0,90; CI95%=0,85-0,97), 2nd half-pregnancy bleeding (OR=0,80; CI95%=0,71-0,92), premature rupture of membranes(OR=0,83; CI95%=0,79-0,87), preterm labor (OR=0,87; CI95%=0,80-0,94) and vaginal tearing (OR=0,86; CI95%=0,79-0,93). Conclusion: pregnancy behaves as a risk factor for some obstetric outcomes in the adolescent group, especially in the youngest ones. In addition to maternal age, there are other factors that constitute the need to form multidisciplinary teams to reduce obstetric outcomes in this population.
diego.maticorena@gmail.com
Objetivos: analizar el riesgo de complicaciones obstétricas y perinatales en adolescentes embarazadas en un hospital de Lima, Perú. Métodos: estudio de cohorte retrospectiva de 67.693 gestantes atendidas en el período 2000-2010. Se evaluó complicaciones obstétricas y perinatales. Las adolescentes se clasificaron en tardías (15-19 años) y tempranas (< 15 años) y se compararon con las adultas (20-35 años). Se calculó OR ajustados por educación, estado civil, control prenatal, gestaciones previas, paridad e IMC pregestacional. Resultados: se encontró mayor riesgo de cesárea (OR=1,28; IC95%=1,07-1,53) e infección puerperal (OR=1,72; IC95%=1,17-2,53) en las adolescentes menores de 15 años, así como mayor riesgo (OR=1,34; IC95%=1,29-1,40)de episiotomía en las adolescentes tardías. Asimismo, se identificó un menor riesgo del embarazo adolescente para preeclampsia (OR=0,90; IC95%=0,85-0,97), hemorragia de la 2da mitad del embarazo (OR=0,80; IC95%=0,71-0,92), ruptura prematura de membranas (OR=0,83; IC95%=0,79-0,87), amenaza de parto pretérmino (OR=0,87; IC95%=0,80-0,94) y desgarro vaginal (OR= 0,86; IC95%=0,79-0,93). Conclusión: el embarazo se comporta como factor de riesgo para ciertas complicaciones obstétricas en la población adolescente, especialmente en las adolescentes tempranas. Existen además otros factores, que sumados a la edad materna, constituyen la necesidad de formar equipos multidis-ciplinarios para reducir complicaciones obstétricas en esta población.
Revisión por pares

Introdução: A conduta padrão para gestante com Rotura Prematura das Membranas Amnióticas (ROPREMA) com idade gestacional (IG) inferior a 34 semanas, sem trabalho de parto e sem evidências clínicas de infecção ou sofrimento fetal é a expectante, onde a interrupção só é feita quando se identificam sinais de infecção ou comprometimento fetal, pois as complicações da prematuridade pesam mais. No feto, a infecção intrauterina é também conhecida como Síndrome de Resposta Inflamatória Fetal (SRIF). Já se sabe que em mais de 50% dos casos de ROPREMA pré-termo os fetos desenvolverão a SRIF, e identificá-la torna-se importante no manejo das complicações neonatais. Alguns estudos têm demonstrado que a interrupção da gestação antes das 34 semanas pode ser benéfica para fetos já atingidos pela infecção, não diagnosticada pelos métodos atualmente usados. Objetivos: Verificar se existe associação entre as alterações do Doppler cardíaco e da artéria umbilical e a SRIF, confirmada por sepse neonatal e corioamnionite histológica em pacientes com ROPREMA pré-termo, para interferência no manejo expectante. Métodos: Realizado estudo de coorte controlado com pacientes com gestação única, maiores de 18 anos, com ROPREMA confirmada, atendidas no Centro Obstétrico do Hospital de Clínicas de Porto Alegre (CO – HCPA), com IG entre 24 a 33 semanas e 4 dias, que internaram para conduta expectante, no período de outubro de 2007 a março de 2008. A conduta incluiu uso de corticóide, rastreamento de infecções através do hemograma e realização de perfil biofísico fetal (PBF) diário nestas pacientes de acordo com a rotina. Além disso, realizou-se ecocardiografia fetal com Doppler e estudo Doppler da artéria umbilical a cada 7-10 dias até a interrupção da gestação. Os controles foram pacientes com gestação única de evolução normal, com a mesma IG e com pré-natal em unidade básica de saúde, incluídas com a realização da ecocardiografia fetal, acompanhadas até o nascimento. As placentas com seus anexos foram enviados para exame histopatológico e foram acompanhados os recém-nascidos (RNs) para investigação do diagnóstico de sepse neonatal. Resultados: Foram incluídas 15 pacientes com ROPREMA pré-termo (grupo 1) e 15 controles (grupo 2). A sepse neonatal foi diagnosticada em 73,3% e a corioamnionite histológica confirmou-se como marcador para a SRIF em 86,7% das pacientes do grupo 1 versus 6,7% de sepse e 26,7% de corioamnionite no grupo 2 (P < 0,001 e 0,003, respectivamente), onde também houve casos de ROPREMA a termo, com indução imediata do parto. No grupo 1, o PBF só foi alterado em 30% das pacientes, o hemograma mostrou-se infeccioso em 35%, a infecção ovular clínica só foi diagnosticada em 20%, e 27,3% dos RNs sépticos tiveram sua gestação interrompida somente pela IG limite de 34 semanas. Os parâmetros do Doppler cardíaco como o tempo de ejeção e o índice Tei (índice de desempenho miocárdico) do ventrículo esquerdo mostraram diferença significativa entre os grupos (P=0,003 e 0,007 respectivamente). O índice Tei foi mais alto no grupo 1 do que no grupo 2 (0,628 x 0,508), onde o valor dos controles normais foi semelhante aos valores encontrados na literatura. A média do índice de resistência (IR) da artéria umbilical das pacientes do grupo 1 foi estatisticamente diferente da média utilizada nos exames de ultrassonografia na população, considerando-se a amostra de controles representativa da mesma (0,661 x 0,611; P=0,02). No grupo 1, o IR também mostrou diferença significativa entre os RNs sépticos e os não-sépticos (0,692 x 0,576; P=0,003). Os valores do IR da artéria umbilical das pacientes com ROPREMA cujos RNs foram diagnosticados com sepse neonatal estavam no limite superior da normalidade deste índice de acordo com os achados da literatura. Conclusões: O estudo demonstrou que existem alterações do Doppler cardíaco e da artéria umbilical em pacientes com ROPREMA pré-termo, possivelmente relacionadas com a presença de comprometimento inflamatório fetal confirmado pelo diagnóstico de corioamnionite e sepse neonatal. Este achado pode interferir na atual conduta utilizada no manejo expectante da ROPREMA pré-termo, levando à interrupção da gestação antes de 34 semanas.

Orientador: Lígia Maria S. S. Rugolo
Banca: Cleide Enoir Petean Trindade
Banca: José Carlos Peraçoli
Banca: Maria Fernanda Branco de Almeida
Banca: Lilian dos Santos Rodrigues Sadeck
Resumo: A rotura prematura de membranas pré-termo (RPM-PT) é uma das principais causas de morbimortalidade perinatal e fator de risco para infecção neonatal precoce. As citocinas pró-inflamatórias TNF-α, IL-8 e a antiiflamatória IL-10 são importantes mediadores da resposta imune, e na situação de risco infeccioso podem ser adjuvantes úteis no diagnóstico de infecção neonatal. Investigar se os níveis de TNF-α, IL-8 e IL-10 em sangue de cordão umbilical são marcadores de infecção precoce em prematuros advindos de gestações com RPM-PT. Estudo clínico, prospectivo e do tipo teste diagnóstico, realizado no Serviço de Obstetrícia e Neonatologia da Faculdade de Medicina de Botucatu, envolvendo prematuros de gestantes com rotura de membranas ≥ 12 horas. As citocinas TNF-α, IL-8 e IL-10 foram dosadas em sangue de cordão umbilical pelo método ELISA. Conforme a evolução clínica e laboratorial dos recém-nascidos foram constituídos dois grupos: Infectado e Não infectado, os quais foram comparados quanto às variáveis perinatais e neonatais por análise estatística univariada; com significância em 5%. A acurácia do teste diagnóstico foi obtida pela curva ROC, sendo calculados: sensibilidade, especificidade, valor preditivo positivo (VPP) e negativo (VPN). Foram estudados 55 prematuros: 27 infectados e 28 não infectados. O tempo de rotura não diferiu entre os grupos (54 x 29 hs; p=0,102) mas, no grupo infectado corioamnionite clínica e histológica foi mais frequente; a idade gestacional (31 x 33 semanas; p<0,001) e o peso de nascimento (1707 x 2109g; p=0,003) foram menores; a morbidade foi maior desde o nascimento com necessidade de assistência mais intensiva e o óbito ocorreu somente nesse grupo. As medianas de TNF-α (3.67 vs 1.76 pg/ml; p =0.084) e IL-10 (0 vs 4.10 pg/ml; p=0.291)... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Preterm premature rupture of membranes (PPROM) is one of the major causes of perinatal morbidity and mortality, and an important risk factor for early-onset neonatal infection. The pro-inflammatory cytokines TNF-α, IL-8 and anti-inflammatory cytokine IL-10 are mediators of immune response and may be helpful as early indicator of neonatal infection in the presence of perinatal risk factor. To evaluate umbilical cord blood levels of TNF-α, IL-8 and IL-10 as markers for early-onset infections in premature infants from pregnancies complicated by PPROM. Clinical, prospective and diagnostic test study performed at Obstetrician and Neonatal Unit of Botucatu School of Medicine, enrolling premature infants from pregnant women with ≥ 12 hours of premature rupture of membranes. TNF-α, IL-8 and IL-10 cytokines were measured in umbilical cord blood by ELISA. According to clinical and laboratorial evaluation patients were classified into two groups: infected and noninfected. Perinatal and neonatal variables were studied. Comparisons between groups were performed by univariate statistical analysis; significance at p <0.05. The diagnostic test accuracy was obtained by ROC curve. Sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated by comparing infected with noninfected group. 55 premature infants were studied: 27 infected and 28 noninfected. There was no difference between the groups in the latency period (54 x 29 hours; p=0,102). In the infected group, clinical and histological chorioamnionitis were more frequent, gestational age (31 x 33 weeks; p<0,001) and birth weight(1707 x 2109g; p=0,003) were lower. Morbidity, mortality and resource use were higher among infected premature infants. The median levels of TNF-α (3.67 vs 1.76 pg/ml; p=0.084)... (Complete abstract click electronic access below)
Doutor

LabPasteur
Objetivos deste estudo: identificar a prevalÃncia e os fatores de risco da colonizaÃÃo materna e infecÃÃo neonatal por streptococcus do grupo B (SGB), em mulheres com trabalho de parto prematuro (TPP) e/ou ruptura prematura de membranas (RPM); medir e comparar taxas de colonizaÃÃo vaginal e anorretal por SGB, comparar taxas de detecÃÃo do SGB em meio de cultura seletivo (Todd-Hewitt) e nÃo seletivo (Stuart) e com cultivo em Ãgar-sangue e Ãgar- CPS. Estudo transversal de 112 mulheres e 220 recÃm-nascidos realizou-se na Maternidade Escola Assis Chateaubriand da Universidade federal do Cearà (MEAC-UFC), de maio de 2008 a julho de 2009. Amostras vaginais e anorretais foram colhidas de cada mulher, usando swabs estÃreis. Em 71 mulheres, 2 swabs (vaginal e anorretal), colocaram-se separadamente em meio de transporte Stuart e 2 swabs (vaginal e anorretal), inocularam-se separadamente em meio seletivo Todd-Hewitt, todos subcultivados em placas de Ãgar-sangue. Outras gestantes do grupo, 41 mulheres, foram investigadas somente em meio seletivo com subcultivo em placas de Ãgar-CPS. Colheu-se hemocultura de cada recÃm-nascido pretermo com algum sinal de infecÃÃo. A taxa de colonizaÃÃo materna de 71 mulheres foi de 4,2% e do grupo de 41, de 17%. Meio seletivo Todd-Hewitt detectou 4,4% e meio nÃo seletivo, 7,2% das culturas positivas para SGB no grupo de 71 mulheres, resultados sem diferenÃa significativa. Amostras vaginais tiveram taxas de detecÃÃo de 10,7% e anorretais de 7,1%, nÃo alcanÃando significÃncia estatÃstica. Houve diferenÃa significativa no isolamento de SGB, entre o meio Ãgar-CPS e o Ãgar-sangue. InfecÃÃo urinÃria mostrou ser importante fator de risco (P < 0,01) e a profissÃo Do lar tambÃm associou-se significativamente com a colonizaÃÃo por SGB Dos RNs incluÃdos no estudo, nenhuma hemocultura teve resultado positivo para SGB, embora apresentassem sinais de infecÃÃo e hemogramas alterados. à possÃvel que o resultado tenha ocorrido pelo fato de que as mÃes tomaram antibiÃticos antes ou durante o trabalho de parto. As taxas de colonizaÃÃo por SGB, em nosso meio, sÃo semelhantes Ãs encontradas em outras regiÃes do Brasil, podendo ser tambÃm, aqui, agente de relevÃncia na sepse neonatal que requer, sÃrias medidas de prevenÃÃo.
The objectives of this study: to identify the prevalence and the risk factors from maternal colonization and neonatal infection from group B Streptococcus in women with preterm labor and/or premature rupture membranes. It measures and compare vaginal and anorectal colonization rates. It compare detection rates with selective and non-selective culture media and it compare detection rates with blood Ãgar and CPS Ãgar. A transversal study of 112 women and 220 newborns was performed at Maternidade Escola Assis Chateaubriand from Universidade Federal do Cearà (MEAC-UFC) from may /2008 to july/2009. Vaginal and anorectal samples from each woman were collected using sterile swabs. In 71 women two swabs (vaginal and anorectal) were placed separately in Stuart transport medium and two swabs (vaginal and anorectal) were inoculated separately in Todd-Hewitt selective medium. All subcultered in blood agar plates. The other pregnancies 41 women were investigated only in selective medium and subcultered in a CPS agar plates. A blood culture was collected from each preterm newborn that with any sign of infection. The maternal colonization rate from 71 women was of 4,2% and from the 41 women group was of 17%. Todd-Hewitt selective medium detected 4,4% and non-selective medium 7,2% GBS positive culture (not statistical relevant âNSR). Vaginal samples had a detection rate of 10,7% and anorectal samples had detection rate of 7,1% ( NSR). Urinary infection and be a housewife showed to be meaningful risk factors (p < 0,05). From the newborns studied none of them had GBS positive blood culture due to the sign of infection and altered hemogram. It,s possible that the result had occurred for the fact that the mothers had taken antibiotic before or during the labor. The GBS women colonization in our environment is similar to the other regions of Brazil. The GBS could be to here an important agent for neonatal infection disease and its necessary to take serious prevent measures.

OBJECTIVE: to study the preditivity of PAMG-1 test for patients with suspected premature rupture of membranes (PROM). METHODS: fifty patients with suspected PROM were selected and allocated them into two groups (25 with PROM and 25 without PROM). All patients were subjected to the PAMG-1 test. The preditivity of PAMG-1 test was evaluated for the time between the exam and birth and days in hospital after delivery. For statistical analysis we used the t test, Mann-Whitney and chi-square. A level of 5% of significance was accepted (p<0,05). RESULTS: the sensitivity, specificity, positive and negative predictive values for the PAMG-1 test were 92%. The rates of false positive and false negative were 8%. The accuracy of the test was found to be 92%. The time between the exam and birth was 29h for patients with positive test and 287,8h for patients with negative test (p=0,0001) and maternal hospitalization was 29h and 130h, respectively (p=0,001). CONCLUSIONS: the PAMG-1 test has high preditivity in suspected cases of premature rupture of amniotic membranes, with low rates of false positive and false negative test results. Moreover, it can reduce the time of maternal hospital stay or avoid maternal hospitalization and thereby reduce public health expenditures.
OBJETIVO: estudar a preditividade diagnóstica do teste da PAMG-1 para pacientes com suspeita de ruptura prematura das membranas amnióticas (RUPREME). MÉTODOS: foram selecionadas consecutivamente 50 pacientes com suspeita de RUPREME e alocadas em dois grupos (25 com RUPREME confirmada pelo exame clínico e 25 com RUPREME descartada pelo exame clínico). Todas as pacientes foram submetidas ao teste da PAMG-1. Foram avaliadas a preditividade do teste da PAMG-1, tempo entre a realização do exame e nascimento e tempo de internação materna. Para a análise estatística foi utilizado o teste t de Student, Mann-Whitney e qui-quadrado. O nível de significância admitido foi p<0,05. RESULTADOS: a sensibilidade, especificidade, valores preditivos positivo e negativo para o teste da PAMG-1 foram de 92%. As taxas de falsos positivo e negativo foram de 8%. A acurácia do teste foi 92%. O tempo entre a realização do exame e nascimento foi 29h nas pacientes com teste da PAMG-1 positivo e 287,8h nas pacientes com teste negativo (p=0,0001) e o tempo de internação materna foi 29h e 130h, respectivamente (p=0,001). CONCLUSÕES: o teste da PAMG-1 apresenta elevada preditividade diagnóstica nos casos de suspeita de ruptura prematura de membranas, com baixas taxas de falsos positivo e negativo. Além disso, pode reduzir o tempo ou evitar a hospitalização materna e dessa forma, reduzir gastos com saúde pública.

L’inflammation joue un rôle central dans la rupture des membranes fœtales (MF), que celle-ci ait lieu à terme ou prématurément, mais l’ensemble des mécanismes reste encore à élucider. Dans ce contexte, les études sur les inflammasomes, un des acteurs clés de l’inflammation, se sont récemment intensifiées. Ces plateformes intracellulaires, formées suite à un signal pro-inflammatoire, sont impliquées dans la mise en place et la propagation d’une réaction inflammatoire. Leur fonction au sein des MF commence à être décrite mais de nombreuses zones d’ombre persistent. L’objectif de ce travail a donc été de compléter la caractérisation des processus inflammatoires dépendant des inflammasomes dans les MF, en se focalisant sur les inflammasomes de type NLRP.Les inflammasomes NLRP sont constitués d’un récepteur NLRP, de l’adaptateur ASC et de la pro-caspase-1. Après avoir vérifié la présence de ces acteurs dans les MF à terme, un intérêt particulier a été porté à l’inflammasome de type NLRP7. En effet, sa fonction a déjà été étudiée dans la sphère placentaire mais jamais dans les MF. La stimulation de cellules épithéliales amniocytaires primaires avec un ligand spécifique de l’inflammasome NLRP7 a permis de montrer (i) l’augmentation du niveau protéique des trois acteurs de cet inflammasome (NLRP7, ASC et pro-caspase-1), (ii) la formation de l’inflammasome par co-localisation entre NLRP7 et ASC, (iii) l’activation de cet inflammasome montré par le clivage de deux effecteurs terminaux, la pro-caspase-1 et la gasdermine D. Ces résultats indiquent pour la première fois que les MF sont capables de mettre en jeu la signalisation de l’inflammasome NLRP7 en réponse à un signal pro-inflammatoire.En parallèle, deux activateurs naturels de l’inflammasome NLRP7 ont été identifiés pour la première fois dans les MF humaines à terme : il s’agit de Mycoplasma salivarium et Mycoplasma fermentans. Leur présence suggère le fait que l’inflammasome NLRP7 puisse jouer un rôle majeur dans les processus inflammatoires au sein des MF. L’ensemble de ce travail suggère donc fortement l’implication de l’inflammasome NLRP7 dans la physiopathologie de la rupture des membranes fœtales humaines, qui pourrait être une cible thérapeutique potentielle pour prévenir les ruptures prématurées des membranes fœtales
Inflammation plays a pivotal role in term or preterm fetal membranes (FM) rupture, but the detailed mechanisms remain unclear. In this context, studies on inflammasomes, one of the key inflammation actors, recently intensified. These intracellular platforms, formed following a pro-inflammatory signal, are involved in the establishment and propagation of an inflammatory reaction. Their functions in FM begin to be described but grey areas remain. Thus, the aim of this work was to complete the characterization of inflammasomes-dependent inflammatory processes, focusing on NLRP inflammasomes.NLRP inflammasomes are composed of a NLRP receptor, the adapter ASC and the pro-caspase-1. After verifying the presence of these actors in term human FM, we focused our interest on NLRP7 inflammasome. Indeed, its function has been studied in the placental area but never in FM. The stimulation of primary amnion epithelial cells with an NLRP7 inflammasome specific ligand demonstrated (i) an increased protein level of the three actors of this inflammasome (NLRP7, ASC and pro-caspase-1), (ii) the formation of this inflammasome by NLRP7 and ASC colocalization and (iii) the activation of this inflammasome, by cleavages of two end-effectors, pro-caspase-1 and gasdermin D. These results indicate for the first time that FM are able to activate NLRP7 inflammasome signalization in response to a pro-inflammatory signal. Moreover, two natural activators of NLRP7 inflammasome have been newly identified in term human FM: Mycoplasma salivarium and Mycoplasma fermentans. Their presence suggests that NLRP7 inflammasome could play an essential role in inflammatory processes in FM. All this work strongly suggests the involvement of NLRP7 inflammasome in pathophysiology of human FM rupture, which could be a potential therapeutic target to prevent premature rupture of FM

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A rotura prematura de membranas pré-termo (RPM-PT) é uma das principais causas de morbimortalidade perinatal e fator de risco para infecção neonatal precoce. As citocinas pró-inflamatórias TNF-α, IL-8 e a antiiflamatória IL-10 são importantes mediadores da resposta imune, e na situação de risco infeccioso podem ser adjuvantes úteis no diagnóstico de infecção neonatal. Investigar se os níveis de TNF-α, IL-8 e IL-10 em sangue de cordão umbilical são marcadores de infecção precoce em prematuros advindos de gestações com RPM-PT. Estudo clínico, prospectivo e do tipo teste diagnóstico, realizado no Serviço de Obstetrícia e Neonatologia da Faculdade de Medicina de Botucatu, envolvendo prematuros de gestantes com rotura de membranas ≥ 12 horas. As citocinas TNF-α, IL-8 e IL-10 foram dosadas em sangue de cordão umbilical pelo método ELISA. Conforme a evolução clínica e laboratorial dos recém-nascidos foram constituídos dois grupos: Infectado e Não infectado, os quais foram comparados quanto às variáveis perinatais e neonatais por análise estatística univariada; com significância em 5%. A acurácia do teste diagnóstico foi obtida pela curva ROC, sendo calculados: sensibilidade, especificidade, valor preditivo positivo (VPP) e negativo (VPN). Foram estudados 55 prematuros: 27 infectados e 28 não infectados. O tempo de rotura não diferiu entre os grupos (54 x 29 hs; p=0,102) mas, no grupo infectado corioamnionite clínica e histológica foi mais frequente; a idade gestacional (31 x 33 semanas; p<0,001) e o peso de nascimento (1707 x 2109g; p=0,003) foram menores; a morbidade foi maior desde o nascimento com necessidade de assistência mais intensiva e o óbito ocorreu somente nesse grupo. As medianas de TNF-α (3.67 vs 1.76 pg/ml; p =0.084) e IL-10 (0 vs 4.10 pg/ml; p=0.291)...
Preterm premature rupture of membranes (PPROM) is one of the major causes of perinatal morbidity and mortality, and an important risk factor for early-onset neonatal infection. The pro-inflammatory cytokines TNF-α, IL-8 and anti-inflammatory cytokine IL-10 are mediators of immune response and may be helpful as early indicator of neonatal infection in the presence of perinatal risk factor. To evaluate umbilical cord blood levels of TNF-α, IL-8 and IL-10 as markers for early-onset infections in premature infants from pregnancies complicated by PPROM. Clinical, prospective and diagnostic test study performed at Obstetrician and Neonatal Unit of Botucatu School of Medicine, enrolling premature infants from pregnant women with ≥ 12 hours of premature rupture of membranes. TNF-α, IL-8 and IL-10 cytokines were measured in umbilical cord blood by ELISA. According to clinical and laboratorial evaluation patients were classified into two groups: infected and noninfected. Perinatal and neonatal variables were studied. Comparisons between groups were performed by univariate statistical analysis; significance at p <0.05. The diagnostic test accuracy was obtained by ROC curve. Sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated by comparing infected with noninfected group. 55 premature infants were studied: 27 infected and 28 noninfected. There was no difference between the groups in the latency period (54 x 29 hours; p=0,102). In the infected group, clinical and histological chorioamnionitis were more frequent, gestational age (31 x 33 weeks; p<0,001) and birth weight(1707 x 2109g; p=0,003) were lower. Morbidity, mortality and resource use were higher among infected premature infants. The median levels of TNF-α (3.67 vs 1.76 pg/ml; p=0.084)... (Complete abstract click electronic access below)

Common, complex disorders are polygenic and multifactorial traits representing interactions between environmental, genetic and epigenetic risk factors. More often than not, contributions of these risk factors have been studied individually and this is especially true for complex reproductive traits where application of genomic technologies has been challenging and slow to progress. This thesis explores the potential of genetic and epigenetic components contributing to a better understanding of the biological pathways underlying disease risk in two specific female complex reproductive traits - polycystic ovary syndrome (PCOS) and preterm premature rupture of membranes (PPROM). The PCOS projects focus on characterization of a gene, DENND1A, whose association to PCOS has been established by Genome Wide Association Studies (GWAS) and is known to contribute to PCOS steroidogenic phenotype. In addition, differential microRNAs expression contributing to DENND1A expression regulation in PCOS theca cells was identified. The studies on PPROM utilize a Whole Exome Sequencing approach to identify rare variants in fetal genes contributing to extracellular matrix composition and synthesis contributing to PPROM risk. The results suggest that fetal contribution to PPROM is polygenic and is driven by a significant genetic burden of potentially damaging rare variants in genes contributing to fetal membrane strength and integrity. Tissue and location specific expression patterns of the Chromosome 21 miRNA cluster (miR-99a, miR-125b, let-7c) in fetal membranes from term pregnancies with spontaneous rupture were investigated. The results suggest that these miRNAs play potential roles in fetal membrane rupture and fetal membrane defects associated with T21.

Orientador: Renato Passini Júnior
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: A prematuridade é um problema complexo de saúde pública, sendo a principal causa de morbidade e mortalidade neonatais, com tendência a aumento nas últimas décadas. Foi proposto um estudo com a participação de vários hospitais do Brasil, a fim de avaliar diversos aspectos envolvidos com a ocorrência do parto pré-termo. Objetivos: descrever os métodos de implementação do Estudo Multicêntrico de Investigação em Prematuridade no Brasil; avaliar a homogeneidade amostral dos casos incluídos; estimar a prevalência e analisar fatores associados à prematuridade espontânea. Métodos: estudo transversal multicêntrico, com componente caso-controle aninhado, em 20 hospitais de referência em três regiões geográficas do Brasil. Foram selecionadas as instituições participantes, elaborado o formulário de coleta de dados, escolhido o sistema eletrônico para inclusão de casos, desenvolvido um programa para a digitação dos dados, elaborados manuais de orientação e padronização da coleta de informações, seguidos de implantação do estudo e análise dos dados obtidos. Foi realizada vigilância prospectiva para identificação de partos pré-termo e estimada sua prevalência, subdividindo-os pelas condições determinantes: trabalho de parto espontâneo, ruptura prematura de membranas e parto terapêutico. Foram estimadas taxas de prevalência ou médias, coeficientes de correlação intraclasse, efeitos do desenho do estudo e média de tamanho de conglomerado para mais de 250 variáveis. O risco de parto pré-termo espontâneo foi estimado com Odds Ratio para vários preditores e a análise por regressão logística não condicional identificou fatores independentemente associados. Resultados: Foram incluídas 5.296 mulheres, sendo 4.150 com partos prematuros (casos) e 1.146 com partos a termo (controles), e avaliados 5.752 recém-nascidos. A taxa geral de prematuridade foi 12,3%. Os coeficientes de correlação intraclasse foram baixos (<0,1) na maioria das variáveis. Comparando 2.682 partos prematuros espontâneos com 1.146 partos a termo, a análise multivariada identificou como fatores de risco para o parto pré-termo: antecedente de parto prematuro, gravidez múltipla, suspeita de insuficiência cervical, malformação fetal, polidrâmnio, sangramento vaginal, número insuficiente de consultas de pré-natal, aborto anterior e infecção do trato urinário. Conclusões: A implantação do Estudo Multicêntrico de Investigação em Prematuridade no Brasil foi a primeira etapa de uma ampla avaliação da prematuridade no país. Os coeficientes de correlação intraclasse indicaram adequada heterogeneidade da amostra estudada. Seus valores poderão ser usados como referência no cálculo de tamanho amostral de estudos futuros na área. A prevalência de partos pré-termo nos centros terciários do Brasil foi alta. Antecedente de parto prematuro, gravidez múltipla, suspeita de insuficiência cervical, malformação fetal, polidrâmnio, sangramento vaginal, número insuficiente de consultas de pré-natal, aborto anterior e infecção do trato urinário foram considerados fatores de risco para parto prematuro espontâneo. A identificação desses fatores pode auxiliar no planejamento de medidas para reduzir a ocorrência de partos pré-termo
Abstract: Background: Preterm birth is the main cause of neonatal morbidity and mortality, resulting in a high likehood of sequelae in surviving children, with a tendency to increase in last decades. A study intending to collect information from hospitals in Brazil on several aspects of preterm birth was proposed. Objectives: To describe the methods used in elaborating and implementing the Brazilian Multicenter Study on Preterm Birth; to evaluate the homogeneity of the sample included in the network; to assess the prevalence of preterm births in Brazil and to identify factors associated with spontaneous preterm birth. Methods: The project consisted of a multicenter cross-sectional study plus a nested case-control study in 20 reference hospitals of three regions of Brazil. The elegible hospitals were selected, forms for data collection were prepared, an electronic system for the inclusion of cases was selected, a program for entering data was developed and the implantation process and data analysis were performed. A prospective surveillance was implemented to identify preterm births, to estimate its prevalence, subdividing into determinats conditions: spontaneous labor, prelabor rupture of membranes or therapeutic birth. Estimated prevalence rates or means, intracluster correlation coefficients, design effects and mean cluster sizes were presented for more than 250 variables. The risk of spontaneous preterm birth was estimated with Odds Ratio for several predictors and a non-conditional logistic regression analysis was then performed to identify independently associated factors. Results: Overall, 5,296 women were included in the study, being 4,150 preterm births (cases) and 1,146 term births (controls), and the total number of studied newborns was 5,752. Overall rate of preterm birth was 12.3%. Intracluster correlation coefficients were low (<0.1) in most variables, showing intracluster heterogeneity. When comparing 2,682 spontaneous preterm births to a sample of 1,146 term births, the multivariate analyzes identified as risk factors for preterm birth: a previous preterm birth, multiple pregnancy, cervical insufficiency, fetal malformation, polyhydramnios, vaginal bleeding, inadequate number of prenatal care visits, previous abortion, and urinary tract infection. Conclusions: The implementation of the Brazilian Multicenter Study on Preterm Birth was the first step of a comprehensive assessment of prematurity in the country. Intracluster correlation coefficients for the outcome variables indicate adequate sample heterogeneity. Their values can be used to calculate the sample size of further studies in the area. The preterm birth rate in tertiary facilities in Brazil was high and the proportion of therapeutic preterm births was over one third. Previous preterm birth, multiple pregnancy, cervical insufficiency, fetal malformation, polyhydramnios, vaginal bleeding, inadequate number of prenatal care visits, previous abortion, and urinary tract infection were considered risk factors to spontaneous preterm birth. Identification of these factors can be worth for planning effective measures to reduce the occurrence of preterm births
Doutorado
Saúde Materna e Perinatal
Doutora em Ciências da Saúde

Orientador: Renato Passini Junior
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Objetivo: estudar a colonização bacteriana endocervical em gestantes com trabalho de parto prematuro e/ou ruptura prematura de membranas (termo e pré-termo). Método: 212 gestantes com trabalho de parto prematuro (TPP) e/ou ruptura prematura de membranas (RPM), internadas no Hospital Estadual Sumaré (Unicamp), foram avaliadas no período de julho de 2002 a janeiro de 2004. Na admissão hospitalar foram coletadas duas amostras do conteúdo endocervical, realizadas bacterioscopia e cultura em meios ágar-sangue ou ágar-chocolate. Foram analisadas associações da colonização endocervical com infecção de trato urinário materno, corioamnionite, uso de antibióticos, dados de parto, sofrimento fetal, prematuridade, infecção e óbito neonatais. Resultados: entre as mulheres estudadas, 74 (35%) tinham TPP e 138 (65%), RPM. A prevalência de colonização endocervical foi de 14,2% (IC=9,5%-18,9%), com resultados similares em TPP e RPM. Na população estudada, o microorganismo mais encontrado foi o estreptococo do grupo B (EGB) (9,4%), sendo também isolados Candida sp (5 casos), Streptococcus sp (2 casos), Streptococcus pneumoniae, Escherichia coli e Enterococcus sp (1 caso de cada). Das bacterioscopias analisadas, os achados mais freqüentes foram baixa prevalência de bacilos de Dodërlein e elevado número de leucócitos. Em mulheres colonizadas houve maior prevalência de infecção de trato urinário (23,8% versus 5,4%; p<0,01), infecção neonatal (25,0% versus 7,3%; p<0,01) e óbito neonatal (dois casos entre as colonizadas; p<0,02), quando comparadas às não-colonizadas. Conclusões: observou-se alta prevalência de colonização endocervical, sem a utilização de meios de cultura seletivos. O EGB foi o principal microorganismo isolado, reforçando a necessidade de triagem deste agente durante a gestação e nas situações de risco estudadas. Um terço das culturas positivas ocorreram por outros agentes. Estudos complementares são necessários para esclarecer a importância destes achados bacteriológicos no canal endocervical e sua associação com complicações gestacionais, sepse e mortalidade neonatais
Abstract: Objective: to study cervical colonization in women with preterm labor and/or premature rupture of membranes. Method: 212 pregnant women with preterm labor and/or premature rupture of membranes (PROM), admitted at Hospital Estadual Sumaré, during the period between July 2002 and January 2004, were studied. Two cervical samples from each woman were collected and bacterioscopy and culture in blood-agar or chocolate-agar plates were performed. Association of cervical microorganisms and urinary infection, chorioamnionitis, antibiotics use, prematurity, neonatal infection and neonatal death were evaluated. Results: the population evaluated consisted of 74 women with preterm labor (35%) and 138 women with PROM (preterm and term). The prevalence of cervical colonization was 14.2% (CI=9.5-18.9%), with similar results in preterm labor or PROM. Group B streptococcus was the most prevalent organism in this population (9.4%). Other organisms isolated were Candida sp, Streptococcus sp, Streptococcus pneumoniae, Escherichia coli and Enterococcus sp. The most common findings of bacterioscopy were a reduced number of lactobacilli and a great number of leukocytes. Endocervical colonization was associated with a higher occurrence of urinary tract infection (23.8% versus 5.4%; p<0.01), early-onset of neonatal infection (25.0% versus 7.3%; p<0.01) and neonatal mortality (2 cases in colonizated women; p<0.02) when compared with a negative culture of endocervical mucus. Conclusions: this study showed high prevalence of endocervical colonization despite of the use of a nonselective culture media. The main microorganism isolated was Group B streptococcus but other organisms were present in one third of studied population. More studies are needed to evaluate the influence of endocervical colonization in obstetrical outcome and in neonatal sepsis and mortality
Mestrado
Tocoginecologia
Mestre em Tocoginecologia

Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg
Background and objectives Prelabour rupture of the membranes (PROM) is a major obstetric problem affecting about 20% of pregnancies. Complications include preterm labour, ascending intrauterine and perinatal infections, and neonatal mortality. Standard guidelines are formulated and continually reviewed to improve the clinical management of PROM and to reduce poor perinatal outcomes associated with this condition. The objectives of this study, conducted using women in Johannesburg as a sample population, were: 1) to audit the implementation of the standard protocol on management of PROM, and 2) to determine the maternal and fetal outcomes of this condition. Methods A cross-sectional descriptive study was done on women admitted to the antenatal wards of Chris Hani Baragwanath Academic Hospital with PROM. Inclusion criteria were that PROM was the main reason for admission, gestation ≥24 weeks, and maternal age 18 years or more. Hospital clinical files were studied for obstetric and clinical characteristics, adherence by doctors to the management protocol, and final outcome including latency period, induction rate, mode of delivery, and neonatal outcome. Results Ninety-seven women participated in the study. Their mean age was 27.0 years, and 37 (38%) were nulliparous. Eighty-five (87%) had attended antenatal clinic. Twenty-nine (30%) were HIV-infected, 23 (79%) of them on highly active antiretroviral treatment. 6 The mean gestational age on admission was 32.8 weeks, with 78 (80%) women having preterm PROM at GA<37 weeks and 52 (54%) at GA <34 weeks. The most frequent methods of diagnosis were visual inspection in 77 (79%), speculum examination in 49 (51%) and ultrasound scan in 81 (84%) of the women. Antibiotics were given to 96 women (99%), and antenatal corticosteroids were used in all women <34 weeks pregnant. No cases of clinical chorioamnionitis were detected. The mean latency from PROM to delivery for women <37 weeks pregnant was 15 days, and for those <34 weeks, it was 19 days. Twenty-nine women (30%) required induction of labour, and 25 (25.8%) had caesarean sections. There were 12 perinatal deaths (with the exclusion of three late neonatal deaths), resulting from prematurity (n=4), congenital anomalies (n=2), neonatal jaundice (n=2), respiratory distress syndrome (n=2) and perinatal asphyxia / hypoxic ischaemic encephalopathy (n=2). There were no recorded cases of either neonatal or puerperal sepsis. Conclusion The study may have under-represented term PROM, so the findings are most applicable to preterm PROM. The condition was mostly managed appropriately within the local protocol, especially in terms of corticosteroid and antibiotic use. Overt or clinically evident chorioamnionitis was not detected. However, the perinatal mortality rate was high, and whatever the causes of perinatal death in this group, it is clear that PROM is a high-risk condition deserving of close clinical attention.

Die nicht-invasive Analyse der fetalen Herzratenvariabilität mittels abdominaler Elektrokardiographie stellt eine neue Methode zur Beurteilung des fetalen Zustandes dar. Die Herzratenvariabilität gilt hier als ein sensitives Maß der autonomen Regulation. Bereits mit Beginn der zweiten Schwangerschaftshälfte ist es möglich, über das mütterliche Abdomen ein fetales Elektrokardiogramm abzuleiten und einer Herzratenvariabilitätsanalyse zuzuführen. Das Untersuchungskollektiv dieser Arbeit umfasste Frauen mit frühem vorzeitigem Blasensprung als Modell einer pathologischen Alteration des fetalen Zustandes sowie Frauen mit normalen Schwangerschaften zwischen der 20. und 28. Schwangerschaftswoche. Die technische Umsetzung und Analyse der fetalen Herzratenvariabilität erfolgte in Kooperation mit dem Institut für Biomedizinische Technik der TU Dresden. Insgesamt wurden 25 Datensätze der Auswertung zugeführt. Eine Reifung des autonomen Nervensystems des Feten mit ansteigendem Gestationsalter konnte mittels der Herzratenvariabilitätsanalyse gezeigt werden. Zur Risikostratifizierung der Feten bei frühem vorzeitigem Blasensprung konnten bei der Betrachtung der Herzratenvariabilitätsparameter keine signifikanten Unterschiede zum Normalkollektiv erhoben werden. Die Analyse der Parameter erfolgte hierbei unabhängig von den fetalen Verhaltenszuständen. Es konnte gezeigt werden, dass die nicht-invasive Analyse der Herzratenvariabilitätsanalyse methodisch und technisch in der Lage ist, den Fetalzustand und dessen Alterationen zu erfassen.

Pregnancy-related complications such as gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, spontaneous preterm birth, and preterm premature rupture of membranes may have severe consequences for both the mother and the child. The development of reliable early screening methods for pregnancy-related complications has therefore been a long-term goal of obstetrics. New possibilities for prenatal diagnostics have opened with the discovery of circulating microRNAs in maternal plasma. MicroRNAs are short, noncoding, 21 to 23 nucleotides long, single-strand RNAs whose main function is to regulate gene expression. During pregnancy, both common and unique miRNAs are expressed by the placenta, amongst them the miRNAs of the C19MC cluster. Several C19MC miRNAs have been shown to display a different expression profile associated with certain pregnancy-related complications. This thesis identifies the plasma exosomal profiles of six C19MC miRNAs (miR-516-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) in patients in their first trimester of gestation who later developed pregnancy-related complications, and compares them with profiles in patients with normal pregnancies.

The vaginal microbial community is critical to a woman’s health and the health of her family. Bacterial vaginosis (BV) is a polymicrobial syndrome characterized by a shift of the vaginal microbiota from a Lactobacillus dominated community to a dense biofilm containing a complex mixture of organisms. Although BV is an important risk factor for poor reproductive health outcomes, the etiology of BV is poorly understood. Gardnerella vaginalis is a hallmark species of BV. Phylogenetic analysis of cpn60 universal target sequences from metagenomic studies of the vaginal microbiome and from G. vaginalis isolates resolved four subgroups within the species. This subdivision, supported by whole genome similarity comparisons, demonstrated that these subgroups might represent different species. Among a group of African women, only G. vaginalis subgroup B was significantly more abundant in women with BV relative to women with Nugent scores not consistent with BV. To characterize the subgroups further, several phenotypic and molecular factors of G. vaginalis subgroups were assessed. Proteomic profiles of isolates within each subgroup formed unambiguous clusters. Sialidase gene sequences were detected in all subgroups, however enzymatic activity was detected only in subgroup B. Two isolates of subgroup B isolates (N153 and N101) were incapable of growth in 7% CO2. Given the well-known relationship between an anaerobic microbiota and BV, anaerobic isolates of G. vaginalis are potentially important players in the vaginal microbial community. To determine genome content differences that could account for the phenotypic difference, whole genome sequences of four G. vaginalis subgroup B isolates representing facultative and anaerobic phenotypes were determined. Comparison of genomes led to the identification of genes predicted to encode proteins involved in cell wall biogenesis and protection from oxidative damage that might account for the observed phenotypes. The cpn60 universal target based methodology that improved resolution of the vaginal microbiota including G. vaginalis was applied in a prospective study of the vaginal microbiome of women with preterm premature rupture of membranes (PPROM). The objectives were to characterize the vaginal microbiota of women following PPROM, and to determine if microbiome composition at the time of rupture predicts latency duration and perinatal outcomes. Only 13/70 samples collected from 36 women were dominated by Lactobacillus spp., the expected profile for healthy women, while Megasphaera type 1 and Prevotella spp. were detected in all samples. Microbiome profiles at the time of membrane rupture did not cluster by gestational age at PPROM, or latency duration. Microbial profiles were unstable over the latency period, with dramatic shifts in composition between weekly samples, and an overall decrease in Lactobacillus abundance. Mollicutes were detected by PCR in 81% (29/36) of women, and these women had significantly lower gestational age at delivery and correspondingly lower birth weight infants than Mollicutes negative women. Taken together, the results presented in this thesis demonstrate the value of high resolution profiling of the vaginal microbiome using cpn60 UT sequences. The resolution of subgroups within G. vaginalis has potentially significant implications for women's health diagnostics, requiring a shift away from considering G. vaginalis as a single entity. The PPROM study provides foundational information that may lead to the identification of informative sequence patterns, providing clinicians with better tools for expectant management following PPROM.

Η ενδοθηλίνη-1 (ET-1) είναι ένα πεπτίδιο αποτελούμενο από 21 αμινοξέα. Είναι ισχυρός αγγειοσυσπαστικός παράγοντας και μιτογόνο των λείων μυϊκών κυττάρων. Στο πλάσμα ασθενών που πάσχουν από σοβαρού βαθμού υπέρταση ή προεκλαμψία έχουν ανιχνευθεί υψηλές συγκεντρώσεις ΕΤ-1. Ο ακριβής ρόλος της ΕΤ-1 σε σχέση με την ανθρώπινη αναπαραγωγή είναι ακόμη σε μεγάλο βαθμό ένα αίνιγμα. Μητρικές και εμβρυικές συγκεντρώσεις στο πλάσμα της ενδοθηλίνης έχουν μελετηθεί πρόσφατα σε σχέση με την εγκυμοσύνη. Αυτοί περιλαμβάνουν ενδομήτρια καθυστέρηση της ανάπτυξης (IUGR) και προεκλαμψία. Οι ακριβείς μηχανισμοί για αυτές τις παθολογικές διαδικασίες και η αύξηση των συγκεντρώσεων πλάσματος της ενδοθηλίνης είναι ακόμη σε μεγάλο βαθμό άγνωστοι, αν και υπάρχουν στοιχεία που να υποδηλώνουν ότι η ενδοθηλίνη συνδέεται με βλάβη του ενδοθηλίου των κυττάρων. Υπάρχουν τώρα κάποιες ενδείξεις ότι οι αμνιακές συγκεντρώσεις της ενδοθηλίνης είναι αυξημένες σε κυήσεις που σχετίζονται με προ-εκλαμψία. Ο σκοπός αυτής της προοπτικής μελέτης ήταν να καταγράψει την συγκέντρωση ενδοθηλίνης στο αμνιακό υγρό σε γυναίκες με φυσιολογικές κυήσεις συγκριτικά με τις γυναίκες που εμφανίζουν προεκλαμψία , IUGR και προώρη ρήξη εμβρυικων υμένων. Εξετάσθηκε το αμνιακό υγρό που προήλθε από αμνιοπαρακέντηση από 125 γυναίκες κατά το δεύτερο τρίμηνο της εγκυμοσύνης . Τα επίπεδα της ενδοθηλίνης μετρήθηκαν με μια ευαίσθητη και ειδική εξεταση ραδιοανοσοπροσδιορισμού. Η συγκέντρωση στο αμνιακό υγρό της ενδοθηλίνης είναι αυξημένη από το δεύτερο τρίμηνο σε γυναίκες που αργότερα αναπτύσσουν PPROM, PROM, IUGR και προεκλαμψία με στατιστικά σημαντική διαφορά. Έχει αποδειχθεί ότι τα επίπεδα ΕΤ1 συσχετίζονται με το βάρος γέννησης των νεογνών, για τη κυήση που περιπλέκονται με IUGR, με το βάρος γέννησης των νεογνών, και με την ηλικία κύησης για την ομάδα PPROM, κια με το βάρος γέννησης των νεογνών σε κυήσεις με προεκλαμψία. Η διερεύνηση επιπέδων ΕΤ-1 στο αμινιακό υγρό δευτέρου τριμήνου μπορεί να είναι ένας εξαιρετικά σημαντικός χώρος έρευνας στο μέλλον, καθώς θα μπορούσε να ρίξει περισσότερο φως για την πρώιμη ανέυρεση των παθοφυσιολογικων διαδικασιών της πλακουντιακής δυσλειτουργίας.
Endothelin-1 (ET-1) is a peptide consisting of 21 amino acids. It is a strong vasoconstrictor and mitogenic factor with significant activity on to the smooth muscle cells. High concentrations of ET-1 have been detected in plasma of patients with severe hypertension or preeclampsia. The exact role of ET-1 in relation to human reproduction is still largely an enigma. Maternal and fetal plasma concentrations of ET-1 have been studied recently in relation to pregnancy. These include intrauterine growth retardation (IUGR) and preeclampsia. The exact mechanisms of these pathological processes and increased plasma concentrations of ET-1 are still largely unknown, although there is evidence to suggest that ET-1 is associated with impaired endothelial cells. There is now some evidence that amniotic ET-1 concentrations are elevated in pregnancies associated with pre-eclampsia. The purpose of this prospective observational study was to record the ET-1 concentration in second trimester amniotic fluid and compare with the levels in women who develop preeclampsia, IUGR and premature rupture of membranes. The amniotic fluid samples were obtained from 125 women by amniocentesis during the second trimester of pregnancy. The levels of ET-1 were measured with a sensitive and specific radioimmunoassay examination (ELISA). The amniotic fluid concentrations of ET-1 are statistically significantly higher from the second trimester in women who later develop PPROM, PROM, IUGR with preeclampsia. This study showed that ET-1 levels correlated with the birth weight of newborns in the pregnancies complicated by IUGR, the birth weight of newborns and the gestational age for the group PPROM, and with the birth weight of newborns in pregnancies with preeclampsia . Investigating the levels of ET-1 in the second trimester amniotic fluid can be an extremely important research area in the future, and could shed more light on the early discovery of the pathophysiological process of placental dysfunction.