abstract: Hypertensive disorders of pregnancy (HDP) affect up to 5%-15% of pregnancies around the globe, and form a leading cause of maternal and neonatal morbidity and mortality. HDP are progressive disorders for which the only cure is to deliver the baby. An increasing trend in the prevalence of HDP has been observed in the recent years. This trend is anticipated to continue due to the rise in the prevalence of diseases that strongly influence hypertension such as obesity and metabolic syndrome. In order to lessen the adverse outcomes due to HDP, we need to study (1) the natural progression of HDP, (2) the risks of adverse outcomes associated with these disorders, and (3) the optimal timing of delivery for women with HDP. In the first study, the natural progression of HDP in the third trimester of pregnancy is modeled with a discrete-time Markov chain (DTMC). The transition probabilities of the DTMC are estimated using clinical data with an order restricted inference model that maximizes the likelihood function subject to a set of order restrictions between the transition probabilities. The results provide useful insights on the progression of HDP, and the estimated transition probabilities are used to parametrize the decision models in the third study. In the second study, the risks of maternal and neonatal adverse outcomes for women with HDP are quantified with a composite measure of childbirth morbidity, and the estimated risks are compared with respect to type of HDP at delivery, gestational age at delivery, and type of delivery in a retrospective cohort study. Furthermore, the safety of child delivery with respect to the same variables is assessed with a provider survey and technique for order performance by similarity to ideal solution (TOPSIS). The methods and results of this study are used to parametrize the decision models in the third study. In the third study, the decision problem of timing of delivery for women with HDP is formulated as a discrete-time Markov decision process (MDP) model that minimizes the risks of maternal and neonatal adverse outcomes. We additionally formulate a robust MDP model that gives the worst-case optimal policy when transition probabilities are allowed to vary within their confidence intervals. The results of the decision models are assessed within a probabilistic sensitivity analysis (PSA) that considers the uncertainty in the estimated risk values. In our PSA, the performance of candidate delivery policies is evaluated using a large number of problem instances that are constructed according to the orders between model parameters to incorporate physicians' intuition. / Dissertation/Thesis / Doctoral Dissertation Industrial Engineering 2018

Präeklampsie ist weltweit eine der Hauptursachen perinataler Morbidität und Mortalität für Mutter und Kind. Es wird vermutet, dass unterschiedliche pathophysiologische Mechanismen je nach Zeitpunkt des Auftretens der Präeklampsie vorliegen. Eine Unterscheidung zwischen früher, mittlerer und später Präeklampsie scheint relevant für Screening, klinische Manifestation und Management der Erkrankung zu sein. Ziel dieser Studie ist es die drei Typen der Präeklampsie bezüglich Risikofaktoren, Entbindungsmodalität und maternaler und neonataler Morbiditäten und Mortalitäten zu charakterisieren und zusätzlich mit denen der Gestationshypertonie und chronischen Hypertonie zu vergleichen. In einem retrospektiven Studienaufbau wurden 1089 Einlingsschwangerschaften mit hypertensiver Schwangerschaftserkrankung, deren Entbindung in einem Zeitraum von 10 Jahren (2003-2012) erfolgte, analysiert. Die maternalen und neonatalen Charakteristika der verschiedenen Gruppen hypertensiver Schwangerschaftserkrankungen wurden miteinander verglichen. Es wurden deskriptive und analytische (Chi-quadrat-Test und U-Test) statistische Methoden verwendet. Es zeigten sich signifikant unterschiedliche maternale Komorbiditäten und Risikofaktoren in den untersuchten Gruppen hypertensiver Schwangerschaftserkrankungen. Für die Mehrzahl der untersuchten Parameter waren Fälle mit Präeklampsie häufiger durch Morbidität und Mortalität betroffen waren. Patientinnen mit früher Präeklampsie fielen durch einen signifikant höheren mittleren arteriellen Druck vor Entbindung, eine erhöhte Kaiserschnittrate, eine ausgeprägtere Proteinurie und eine häufigere Korrelation zu HELLP-Syndrom, Eklampsie und vorzeitige Plazentalösung auf. Die Häufigkeit pathologischer Doppleruntersuchungen in den Arteriae uterinae und der Arteria umbilicalis verhielt sich umgekehrt proportional zur Schwangerschaftswoche zum Zeitpunkt der Entbindung. Ein nachteiliges fetales Outcome bezogen auf die perinatale und neonatale Mortalität, Beatmung über einen längeren Zeitraum als 24 Stunden, RDS-Syndrom, fetale Wachstumsrestriktion und Verlegung auf eine neonatologische Intensivstation trat unter früher Präeklampsie häufiger als unter mittlerer und bei mittlerer häufiger als unter später Präeklampsie auf. Das neonatale Outcome von Feten unter der 33. SSW war nicht vom Ausmaß der mütterlichen hypertensiven Erkrankung abhängig. Die späte Präeklampsie viel durch günstigere Outcomes als die Gestationshypertonie und chronische Hypertonie auf. Die Ergebnisse der Studie unterstützen die These, dass unterschiedliche pathophysiologische Mechanismen Präeklampsie bedingen können und dass frühe, mittlere und späte Präeklampsie entweder verschiedene Erkrankungen sind, oder die Präeklampsie eine Erkrankung darstellt, die durch verschiedene Einflussfaktoren ein unterschiedlich starkes Ausmaß annimmt. Das Gestationsalter ist demnach das entscheidende Kriterium für die klinische Ausprägung. Die unterschiedlichen Risikoprofile der einzelnen Formen hypertensiver Schwangerschaftserkrankungen fordern ein angepasstes klinisches Management.

Introdução: As doenças hipertensivas da gestação (DHG) são a principal causa de morte materna em todo o mundo. A pré-eclâmpsia ocorre em 3-5% das gestações, acrescentando maior morbimortalidade. Apesar da importância em saúde pública dessa patologia, sua patogênese não está totalmente esclarecida. Acredita-se que uma disfunção na placentação ocasione um estado de estresse oxidativo, contribuindo para manifestação clínica da doença. O selênio é um antioxidante presente no organismo cujas concentrações séricas tendem a diminuir na gestação normal, e a sua deficiência vem sendo relacionada às DHG. Entretanto, estudos prévios mostram resultados conflitantes. O objetivo deste estudo é correlacionar os níveis séricos de selênio com DHG na nossa população, considerando um possível fator de proteção deste mineral. Métodos: Foi realizado um estudo caso-controle, incluindo 32 gestantes normotensas, 20 hipertensas (hipertensão crônica e gestacional) e 38 pacientes com pré-eclâmpsia. Todas pacientes foram oriundas do pré-natal ou admissão obstétrica do Hospital de Clínicas de Porto Alegre. O selênio sérico foi dosado no momento da inclusão do estudo. As pacientes foram acompanhadas até o momento da alta após o parto. O nível de significância adotado foi de 5% (p≤0,05) e as análises foram realizadas no programa SPSS versão 18. Resultados: As pacientes não diferiram quanto à idade materna, etnicidade, anos de estudo, paridade e prevalência de tabagismo. Pacientes normotensas apresentaram menor índice de massa corporal e foram incluídas no estudo mais precocemente. Além disso, estas pacientes apresentaram maior prevalência de outras comorbidades, excluindo hipertensão. Pacientes com pré-eclâmpsia tiveram níveis de pressão arterial sistólica mais altos no momento da admissão. Uso contínuo de medicações e história de DHG em gestações anteriores foi mais comum no grupo de pacientes com pré-eclâmpsia. Os níveis séricos de selênio não apresentaram diferença significativa entre os grupos, sendo uma média de 56,4±15,3μg/L no grupo controle, 53,2±15,2μg/L no grupo hipertensão e 53,3±16,8μg/L no grupo com pré-eclâmpsia (P=0,67). Das pacientes com préeclâmpsia, 52,6% apresentaram pré-eclâmpsia grave. Os níveis séricos de selênio destas pacientes também não diferiram significativamente do grupo controle (P=0,77). Pré-eclâmpsia foi associada a interrupção mais precoce da gestação e menor peso de nascimento (P<0,05), entretanto não houve diferença significativa entre os outros desfechos estudados. Conclusão: Não houve diferença significativa na concentração de selênio sérico entre gestantes normotensas e gestantes com doenças hipertensivas da gestação, não sendo possível estabelecer um fator de proteção. / Introduction: The hypertensive disorders of pregnancy (HDP) are the leading cause of maternal death in the world. Preeclampsia occurs in 3-5% of pregnancies, adding greater morbidity and mortality. Despite the importance of this disease in public health, its pathogenesis is not fully understood. It is believed that a dysfunction in the placentation process leads to oxidative stress, contributing to the clinical manifestation of the disease. Selenium is an antioxidant present in the body, which serum concentrations tend to decrease in normal pregnancy. Its deficiency has been related to HDP. However, previous studies have shown conflicting results. The aim of this study is to correlate serum selenium levels with HDP in our population, considering a possible protective factor of this mineral. Methods: We conducted a case-control study, including 32 normotensive pregnant women, 20 with hypertension (chronic and gestational hypertension) and 38 patients with preeclampsia. All patients were derived from antenatal or obstetric admission of Hospital de Clínicas de Porto Alegre. Serum selenium was measured at the time of inclusion in the study. Patients were followed until hospital discharge after delivery. The significance level was 5% (p≤0.05) and analyzes were performed using SPSS version 18. Results: The patients did not differ with regard to maternal age, ethnicity, years of education, parity, and smoking prevalence. Normotensive patients had lower body mass index and were included in the study earlier. In addition, these patients had a higher prevalence of other comorbidities excluding hypertension. Patients with preeclampsia had higher levels of systolic blood pressure on admission. Continuous use of medication and HDP history in previous pregnancies were more common in patients with preeclampsia. Serum selenium levels were not significantly different between groups, with an average of 56.4 ± 15,3 μg/L in the control group, 53.2 ± 15,2 μg/L in the hypertension group and 53.3 ± 16,8 μg/L in the group with preeclampsia (P=0.67). Of patients with preeclampsia, 52.6% had severe preeclampsia. Serum selenium levels of these patients did not differ significantly from the control group (P=0.77). Preeclampsia was associated with earlier interruption of pregnancy and lower birth weight (P<0.05). There was no significant difference between other outcomes studied. Conclusion: There was no significant difference in the concentration of serum selenium between normotensive pregnant women and pregnant women with hypertensive disorders of pregnancy, thus not being possible to establish selenium as a protective factor.

Introdução: As doenças hipertensivas da gestação (DHG) são a principal causa de morte materna em todo o mundo. A pré-eclâmpsia ocorre em 3-5% das gestações, acrescentando maior morbimortalidade. Apesar da importância em saúde pública dessa patologia, sua patogênese não está totalmente esclarecida. Acredita-se que uma disfunção na placentação ocasione um estado de estresse oxidativo, contribuindo para manifestação clínica da doença. O selênio é um antioxidante presente no organismo cujas concentrações séricas tendem a diminuir na gestação normal, e a sua deficiência vem sendo relacionada às DHG. Entretanto, estudos prévios mostram resultados conflitantes. O objetivo deste estudo é correlacionar os níveis séricos de selênio com DHG na nossa população, considerando um possível fator de proteção deste mineral. Métodos: Foi realizado um estudo caso-controle, incluindo 32 gestantes normotensas, 20 hipertensas (hipertensão crônica e gestacional) e 38 pacientes com pré-eclâmpsia. Todas pacientes foram oriundas do pré-natal ou admissão obstétrica do Hospital de Clínicas de Porto Alegre. O selênio sérico foi dosado no momento da inclusão do estudo. As pacientes foram acompanhadas até o momento da alta após o parto. O nível de significância adotado foi de 5% (p≤0,05) e as análises foram realizadas no programa SPSS versão 18. Resultados: As pacientes não diferiram quanto à idade materna, etnicidade, anos de estudo, paridade e prevalência de tabagismo. Pacientes normotensas apresentaram menor índice de massa corporal e foram incluídas no estudo mais precocemente. Além disso, estas pacientes apresentaram maior prevalência de outras comorbidades, excluindo hipertensão. Pacientes com pré-eclâmpsia tiveram níveis de pressão arterial sistólica mais altos no momento da admissão. Uso contínuo de medicações e história de DHG em gestações anteriores foi mais comum no grupo de pacientes com pré-eclâmpsia. Os níveis séricos de selênio não apresentaram diferença significativa entre os grupos, sendo uma média de 56,4±15,3μg/L no grupo controle, 53,2±15,2μg/L no grupo hipertensão e 53,3±16,8μg/L no grupo com pré-eclâmpsia (P=0,67). Das pacientes com préeclâmpsia, 52,6% apresentaram pré-eclâmpsia grave. Os níveis séricos de selênio destas pacientes também não diferiram significativamente do grupo controle (P=0,77). Pré-eclâmpsia foi associada a interrupção mais precoce da gestação e menor peso de nascimento (P<0,05), entretanto não houve diferença significativa entre os outros desfechos estudados. Conclusão: Não houve diferença significativa na concentração de selênio sérico entre gestantes normotensas e gestantes com doenças hipertensivas da gestação, não sendo possível estabelecer um fator de proteção. / Introduction: The hypertensive disorders of pregnancy (HDP) are the leading cause of maternal death in the world. Preeclampsia occurs in 3-5% of pregnancies, adding greater morbidity and mortality. Despite the importance of this disease in public health, its pathogenesis is not fully understood. It is believed that a dysfunction in the placentation process leads to oxidative stress, contributing to the clinical manifestation of the disease. Selenium is an antioxidant present in the body, which serum concentrations tend to decrease in normal pregnancy. Its deficiency has been related to HDP. However, previous studies have shown conflicting results. The aim of this study is to correlate serum selenium levels with HDP in our population, considering a possible protective factor of this mineral. Methods: We conducted a case-control study, including 32 normotensive pregnant women, 20 with hypertension (chronic and gestational hypertension) and 38 patients with preeclampsia. All patients were derived from antenatal or obstetric admission of Hospital de Clínicas de Porto Alegre. Serum selenium was measured at the time of inclusion in the study. Patients were followed until hospital discharge after delivery. The significance level was 5% (p≤0.05) and analyzes were performed using SPSS version 18. Results: The patients did not differ with regard to maternal age, ethnicity, years of education, parity, and smoking prevalence. Normotensive patients had lower body mass index and were included in the study earlier. In addition, these patients had a higher prevalence of other comorbidities excluding hypertension. Patients with preeclampsia had higher levels of systolic blood pressure on admission. Continuous use of medication and HDP history in previous pregnancies were more common in patients with preeclampsia. Serum selenium levels were not significantly different between groups, with an average of 56.4 ± 15,3 μg/L in the control group, 53.2 ± 15,2 μg/L in the hypertension group and 53.3 ± 16,8 μg/L in the group with preeclampsia (P=0.67). Of patients with preeclampsia, 52.6% had severe preeclampsia. Serum selenium levels of these patients did not differ significantly from the control group (P=0.77). Preeclampsia was associated with earlier interruption of pregnancy and lower birth weight (P<0.05). There was no significant difference between other outcomes studied. Conclusion: There was no significant difference in the concentration of serum selenium between normotensive pregnant women and pregnant women with hypertensive disorders of pregnancy, thus not being possible to establish selenium as a protective factor.

Introdução: As doenças hipertensivas da gestação (DHG) são a principal causa de morte materna em todo o mundo. A pré-eclâmpsia ocorre em 3-5% das gestações, acrescentando maior morbimortalidade. Apesar da importância em saúde pública dessa patologia, sua patogênese não está totalmente esclarecida. Acredita-se que uma disfunção na placentação ocasione um estado de estresse oxidativo, contribuindo para manifestação clínica da doença. O selênio é um antioxidante presente no organismo cujas concentrações séricas tendem a diminuir na gestação normal, e a sua deficiência vem sendo relacionada às DHG. Entretanto, estudos prévios mostram resultados conflitantes. O objetivo deste estudo é correlacionar os níveis séricos de selênio com DHG na nossa população, considerando um possível fator de proteção deste mineral. Métodos: Foi realizado um estudo caso-controle, incluindo 32 gestantes normotensas, 20 hipertensas (hipertensão crônica e gestacional) e 38 pacientes com pré-eclâmpsia. Todas pacientes foram oriundas do pré-natal ou admissão obstétrica do Hospital de Clínicas de Porto Alegre. O selênio sérico foi dosado no momento da inclusão do estudo. As pacientes foram acompanhadas até o momento da alta após o parto. O nível de significância adotado foi de 5% (p≤0,05) e as análises foram realizadas no programa SPSS versão 18. Resultados: As pacientes não diferiram quanto à idade materna, etnicidade, anos de estudo, paridade e prevalência de tabagismo. Pacientes normotensas apresentaram menor índice de massa corporal e foram incluídas no estudo mais precocemente. Além disso, estas pacientes apresentaram maior prevalência de outras comorbidades, excluindo hipertensão. Pacientes com pré-eclâmpsia tiveram níveis de pressão arterial sistólica mais altos no momento da admissão. Uso contínuo de medicações e história de DHG em gestações anteriores foi mais comum no grupo de pacientes com pré-eclâmpsia. Os níveis séricos de selênio não apresentaram diferença significativa entre os grupos, sendo uma média de 56,4±15,3μg/L no grupo controle, 53,2±15,2μg/L no grupo hipertensão e 53,3±16,8μg/L no grupo com pré-eclâmpsia (P=0,67). Das pacientes com préeclâmpsia, 52,6% apresentaram pré-eclâmpsia grave. Os níveis séricos de selênio destas pacientes também não diferiram significativamente do grupo controle (P=0,77). Pré-eclâmpsia foi associada a interrupção mais precoce da gestação e menor peso de nascimento (P<0,05), entretanto não houve diferença significativa entre os outros desfechos estudados. Conclusão: Não houve diferença significativa na concentração de selênio sérico entre gestantes normotensas e gestantes com doenças hipertensivas da gestação, não sendo possível estabelecer um fator de proteção. / Introduction: The hypertensive disorders of pregnancy (HDP) are the leading cause of maternal death in the world. Preeclampsia occurs in 3-5% of pregnancies, adding greater morbidity and mortality. Despite the importance of this disease in public health, its pathogenesis is not fully understood. It is believed that a dysfunction in the placentation process leads to oxidative stress, contributing to the clinical manifestation of the disease. Selenium is an antioxidant present in the body, which serum concentrations tend to decrease in normal pregnancy. Its deficiency has been related to HDP. However, previous studies have shown conflicting results. The aim of this study is to correlate serum selenium levels with HDP in our population, considering a possible protective factor of this mineral. Methods: We conducted a case-control study, including 32 normotensive pregnant women, 20 with hypertension (chronic and gestational hypertension) and 38 patients with preeclampsia. All patients were derived from antenatal or obstetric admission of Hospital de Clínicas de Porto Alegre. Serum selenium was measured at the time of inclusion in the study. Patients were followed until hospital discharge after delivery. The significance level was 5% (p≤0.05) and analyzes were performed using SPSS version 18. Results: The patients did not differ with regard to maternal age, ethnicity, years of education, parity, and smoking prevalence. Normotensive patients had lower body mass index and were included in the study earlier. In addition, these patients had a higher prevalence of other comorbidities excluding hypertension. Patients with preeclampsia had higher levels of systolic blood pressure on admission. Continuous use of medication and HDP history in previous pregnancies were more common in patients with preeclampsia. Serum selenium levels were not significantly different between groups, with an average of 56.4 ± 15,3 μg/L in the control group, 53.2 ± 15,2 μg/L in the hypertension group and 53.3 ± 16,8 μg/L in the group with preeclampsia (P=0.67). Of patients with preeclampsia, 52.6% had severe preeclampsia. Serum selenium levels of these patients did not differ significantly from the control group (P=0.77). Preeclampsia was associated with earlier interruption of pregnancy and lower birth weight (P<0.05). There was no significant difference between other outcomes studied. Conclusion: There was no significant difference in the concentration of serum selenium between normotensive pregnant women and pregnant women with hypertensive disorders of pregnancy, thus not being possible to establish selenium as a protective factor.

Infant mortality (IM) rates in the United States remains high. The higher rates of IM among specific groups in the United States is believed to be fueled by the high rates of adverse birth outcomes including low birthweight (LBW) and preterm births (PTB) among these groups. Adverse birth outcomes have also been linked to the presence of hypertensive disorders during pregnancy. The purpose of this cross-sectional study was to explore the association between hypertensive disorders during pregnancy and adverse birth outcomes and the impact of the residential neighborhood of expectant mothers on this association. The life course health development theory guided the framework for this study. Study data were obtained from the 2010 New York City birth records and the 2010 US Census. Descriptive statistics and logistic regression analysis were used to address the 3 research hypotheses of the study. The study found that prepregnancy hypertension (HTN) (AOR: 2.84 & 3.25), gestational HTN (AOR: 2.28 & 3.33) and eclampsia (AOR: 4.41 & 6.70) were significantly associated with PTB and LBW respectively. Neighborhood segregation was not significant for PTB (AOR: 1.01) or LBW (AOR: 1.03). Neighborhood poverty was significant for PTB (AOR: 0.86) but not for LBW (AOR: 1.05). Neighborhood segregation and poverty had significant moderating effects on the prepregnancy HTN (p = 0.00), gestational HTN (p = 0.00), eclampsia (p = 0.00) and PTB and LBW association. Results from this study can help to address disparities in birth outcomes among women of differing races and ethnicities and thereby contribute to positive social change.

Introduction: Gestational diabetes (GDM) affects one in three pregnancies and women with GDM have a 10-fold higher risk of developing type-2 diabetes during their lifetime. Similarly, hypertensive disorders (HPD) of pregnancy affect up to one in seven pregnancies and have a 4-fold increase in the risk of hypertension and a 2-fold risk of cardiovascular diseases (CVD) over the lifetime. Primary care (PC) transitions are critical for the management of GDM and HDP to reduce the long-term risk of developing type-2 diabetes, hypertension, and CVD. Despite clinical guidelines recommending PC follow-up for continuous and sustainable care practice, only 50% of postpartum mothers transition to PC within 12 months. Few studies examine this issue and none in South Carolina. Therefore, our study uses Medicaid Claims data to examine the extent to which postpartum mothers with GDM and HDP transition to PC within 12 months of childbirth. Methods: We examined cross-sectional data of Medicaid women with a live birth in the years 2017 and 2018 in South Carolina. Women above the age of 20, receiving postpartum services within 12 months of delivery were included in the study. Primary care visits was the outcome variable of interest. Any women with at least one primary care visit (Family/General Practice Physician visit) claim in the 12 months following birth were considered as a primary care transition. GDM, HDP, and both (GDM &HDP) were the primary independent variables of interest. Results: In 14,273 postpartum mothers, the prevalence of GDM, HDP, and both (GDM & HDP) were found to be 10.02%, 15.05%, and 3.60% respectively. Among the women with GDM, 47.02% had visited PC compared to 35.02% of women without GDM (p<0.001). Similarly, 48.12% of women with HDP visited PC compared to 34.23% of women without HDP (p<0.001). In addition, 52.66% of women with both (GDM & HDP) visited PC compared to 35.72% of women without both (GDM & HDP) (p<0.001). After adjusting for maternal age, ethnicity, residence, and pay category, women with GDM were 1.43 times more likely to visit PC as compared to the women with no GDM (95% CI: 1.27–1.61). Similarly, the odds of visiting PC by women with HDP was 1.67 times higher as compared to women without HDP (95% CI: 1.51 – 1.84). Conclusion: In this study, postpartum mothers with GDM and HDP had higher odds of PC visits compared with those without GDM and without HDP respectively. This is positive. However, the overall percentage of women visiting PC with chronic disease was lower than 50%. To change health outcomes among women with chronic diseases like GDM and HDP, lifelong screening and disease management are needed. It is necessary to link postpartum mothers with PC to improve illness management and raise screening adherence. However, more barriers preventing under-resourced women from receiving PC should be analyzed and addressed.

Präeklampsie ist weltweit eine der Hauptursachen perinataler Morbidität und Mortalität für Mutter und Kind. Es wird vermutet, dass unterschiedliche pathophysiologische Mechanismen je nach Zeitpunkt des Auftretens der Präeklampsie vorliegen. Eine Unterscheidung zwischen früher, mittlerer und später Präeklampsie scheint relevant für Screening, klinische Manifestation und Management der Erkrankung zu sein. Ziel dieser Studie ist es die drei Typen der Präeklampsie bezüglich Risikofaktoren, Entbindungsmodalität und maternaler und neonataler Morbiditäten und Mortalitäten zu charakterisieren und zusätzlich mit denen der Gestationshypertonie und chronischen Hypertonie zu vergleichen. In einem retrospektiven Studienaufbau wurden 1089 Einlingsschwangerschaften mit hypertensiver Schwangerschaftserkrankung, deren Entbindung in einem Zeitraum von 10 Jahren (2003-2012) erfolgte, analysiert. Die maternalen und neonatalen Charakteristika der verschiedenen Gruppen hypertensiver Schwangerschaftserkrankungen wurden miteinander verglichen. Es wurden deskriptive und analytische (Chi-quadrat-Test und U-Test) statistische Methoden verwendet. Es zeigten sich signifikant unterschiedliche maternale Komorbiditäten und Risikofaktoren in den untersuchten Gruppen hypertensiver Schwangerschaftserkrankungen. Für die Mehrzahl der untersuchten Parameter waren Fälle mit Präeklampsie häufiger durch Morbidität und Mortalität betroffen waren. Patientinnen mit früher Präeklampsie fielen durch einen signifikant höheren mittleren arteriellen Druck vor Entbindung, eine erhöhte Kaiserschnittrate, eine ausgeprägtere Proteinurie und eine häufigere Korrelation zu HELLP-Syndrom, Eklampsie und vorzeitige Plazentalösung auf. Die Häufigkeit pathologischer Doppleruntersuchungen in den Arteriae uterinae und der Arteria umbilicalis verhielt sich umgekehrt proportional zur Schwangerschaftswoche zum Zeitpunkt der Entbindung. Ein nachteiliges fetales Outcome bezogen auf die perinatale und neonatale Mortalität, Beatmung über einen längeren Zeitraum als 24 Stunden, RDS-Syndrom, fetale Wachstumsrestriktion und Verlegung auf eine neonatologische Intensivstation trat unter früher Präeklampsie häufiger als unter mittlerer und bei mittlerer häufiger als unter später Präeklampsie auf. Das neonatale Outcome von Feten unter der 33. SSW war nicht vom Ausmaß der mütterlichen hypertensiven Erkrankung abhängig. Die späte Präeklampsie viel durch günstigere Outcomes als die Gestationshypertonie und chronische Hypertonie auf. Die Ergebnisse der Studie unterstützen die These, dass unterschiedliche pathophysiologische Mechanismen Präeklampsie bedingen können und dass frühe, mittlere und späte Präeklampsie entweder verschiedene Erkrankungen sind, oder die Präeklampsie eine Erkrankung darstellt, die durch verschiedene Einflussfaktoren ein unterschiedlich starkes Ausmaß annimmt. Das Gestationsalter ist demnach das entscheidende Kriterium für die klinische Ausprägung. Die unterschiedlichen Risikoprofile der einzelnen Formen hypertensiver Schwangerschaftserkrankungen fordern ein angepasstes klinisches Management.:I. Inhaltsverzeichnis II. Abkürzungsverzeichnis 1 Einleitung 1 2 Grundlagen 3 2.1 Hypertensive Schwangerschaftserkrankungen 3 2.1.1 Begriffe und Definitionen 3 2.1.2 Chronische Hypertonie 4 2.1.3 Gestationshypertonie 5 2.1.4 Präeklampsie 5 2.1.4.1 Epidemiologie 5 2.1.4.2 Pathogenese 6 2.1.4.3 Prädisposition und Risikofaktoren 7 2.1.4.4 Maternale Morbidität und Mortalität 8 2.1.4.5 Screening 9 2.1.4.6 Prävention 10 2.1.4.7 Management 11 2.2 Aspekte des fetalen Outcomes 12 2.2.1 Frühgeburtlichkeit 13 2.2.2 Fetale Wachstumsrestriktion 14 2.2.3 Totgeburt, neonatale und perinatale Mortalität 15 2.2.4 Fetale Komplikationen 15 2.3 Dopplersonographie in der Schwangerschaft 18 2.3.1 Aa. uterinae 19 2.3.2 Arteria umbilicalis 20 2.3.3 Arteria cerebri media 20 2.3.4 Ductus venosus 20 3 Material und Methoden 22 3.1 Maternale Variablen 22 3.2 Fetale und neonatale Variablen 24 3.3 Statistische Auswertung 25 3.3.1 Deskriptive Statistik 25 3.3.2 Analytische Statistik 25 4 Ergebnisse 27 4.1 Demographische Daten 28 4.2 Maternale Risikofaktoren 28 4.2.1 Body-Mass-Index 30 4.2.2 Alter 30 4.2.3 Parität 31 4.2.4 Diabetes 31 4.2.5 Nikotinabusus 32 4.3 Maternale Vorerkrankungen und Komorbiditäten 32 4.3.1 Depression, Asthma und chronisch entzündliche Darmerkrankungen 32 4.3.2 Thrombembolische Ereignisse 32 4.3.3 Nierenerkrankungen 33 4.3.4 Chronische Hypertonie 33 4.4 Schwangerschaftsbezogene Risikofaktoren 33 4.4.1 Pulsatilitätsindex der Arteria uterina 33 4.4.2 Konzeption 35 4.5 Kindliches Geschlecht 35 4.6 Entbindung – Geburtsmodus und Indikation 35 4.7 Maternale Komplikationen 37 4.7.1 HELLP-Syndrom 38 4.7.2 Eklampsie 41 4.7.3 Schwere Präeklampsie 41 4.7.4 Proteinurie 41 4.8 Maternale Mortalität 42 4.9 Das fetale Outcome 43 4.9.1 Wachstumsrestriktion und small for gestational age 45 4.9.1.1 Distribution 45 4.9.1.2 Outcome 47 4.9.2 Frühgeborene vor der vollendeten 33. SSW 49 4.9.2.1 Maternale Aspekte 50 4.9.2.2 Doppleruntersuchungen und Lungenreifeinduktion 50 4.9.2.3 Geburtsparameter 51 4.9.2.4 Geburtsgewicht und intrauterine Wachstumsrestriktion 53 5 Diskussion 55 5.1 Analyse der maternalen Faktoren 55 5.1.1 Analyse der Risikofaktoren und anderer Anamneseparameter 55 5.1.2 Analyse des Geburtsmodus oder der -indikation 57 5.1.3 Analyse der Patientinnen mit chronischer Hypertonie 58 5.1.4 Analyse der Patientinnen mit Gestationshypertonie 59 5.1.5 Analyse der prädiktiven Aussagekraft der Dopplersonographie der Aa uterinae für die Entwicklung einer Präeklampsie 60 5.1.6 Analyse der Komplikationen der Präeklampsie 61 5.2 Analyse des fetalen Outcomes 63 5.2.1 Analyse des fetalen Outcomes unter Gestationshypertonie 63 5.2.2 Analyse des fetalen Outcomes unter chronischer Hypertonie 64 5.2.3 Analyse des fetalen Outcomes unter Präeklampsie 66 5.2.4 Fetale Wachstumsrestriktion und Präeklampsie 67 5.2.5 Subanalyse der Feten mit Geburt vor der 33. SSW 69 5.3 Limitierung und Einordnung der Ergebnisse 71 6 Zusammenfassung 74 7 Literaturverzeichnis 77 8 Anhang 95 8.1 Tabellenverzeichnis 95 8.2 Abbildungsverzeichnis 97 III. Danksagung

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Clinical observations of individual patients are the cornerstones for furthering our understanding of the human body, diseases, and therapeutics. Traditionally, clinical observations were communicated through publishing case reports and case series. The effort of identifying and investigating unusual clinical observations has always rested on the shoulders of busy clinicians. To date, there has been little effort dedicated to increasing the efficiency of identifying unique and uncommon patient observations that may lead to valuable discoveries. In this thesis, we propose and implement an augmented intelligence framework to identify potential novel clinical observations by combining machine analytics through outlier analysis with the judgment of subject-matter experts. Preeclampsia is a significant cause of maternal and perinatal mortality and morbidity, and advances in its management have been slow. Considering the complex etiological nature of preeclampsia, clinical observations are essential in advancing our understanding of the disease and therapeutic approaches. Thus, the objectives and studies in this thesis aim to answer the hypothesis that using outlier analysis in preeclampsia-related medical data would lead to identifying previously uninvestigated clinical cases with new clinical insight. This thesis combines three articles published or submitted for publication in peer-reviewed journals. The first article (published) is a systematic review examining the extent to which case reports and case series in preeclampsia have contributed new knowledge or discoveries. We report that under one-third of the identified case reports and case series presented new knowledge. In our second article (submitted for publication), we provide an overview of outlier analysis and introduce the framework of augmented intelligence using our proposed extreme misclassification contextual outlier analysis approach. Furthermore, we conduct a systematic review of obstetrics-related research that used outlier analysis to answer scientific questions. Our systematic review findings indicate that such use is in its infancy. In our third article (published), we implement the proposed augmented intelligence framework using two different outlier analysis methods on two independent datasets from separate studies in preeclampsia and hypertensive disorders of pregnancy. We identify several clinical observations as potential novelties, thus supporting the feasibility and applicability of outlier analysis to accelerate clinical discovery.