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

Preeclampsia (PE) is a multisystem disorder that contributes to maternal and fetal mortality and morbidity worldwide. It is characterized by de-novo hypertension and proteinuria or other maternal organ damage after 20 weeks of gestation. Evidence suggested that endogenous digitalis-like factor (EDLF) contributes to the pathogenesis of PE, and that the potential source of EDLF is the placenta. EDLF can inhibit the sodium pump (SP) specifically and may lead to hypertension, it has also been associated with hypoxia, oxidative stress and other abnormalitites present in PE.We studied whether normal human placenta responded to SP inhibition casued by EDLF with a change in abundance of lipids in the placental cytosol, and whether there was a characteristic set of lipid changes that could serve as a signature for EDLF exposure if there were such changes. Placenta tissues from 20 normal pregnancies were incubated for 48 hr in the presence and absence of ouabain, a widely studied EDLF, followed by tissue homogenization, lipid extraction, and the study of lipids using a mass spectrometery (MS) based lipidomics approach. 1207 lipidomic markers were surveyed by paired Student t-test, among which 26 markers had significantly different abundances between cases and control at the FDR=0.05 level. A set of 8 lipidomic markers were selected by a statistical model built with a sparse partial least squares discriminant analysis method (sPLS-DA) and a bootstrap procedure. All eight markers were then chemically characterized and partially identified using tandem MS. These markers might be used to identify placentas that have been previously exposed to EDLF in return.Endogenous peptides and small proteins might contribute to the pathophysiology of various diseases. Therefore, we investigated the potential peptidomic profile of placenta tissues in response to EDLF exposure as well. Placenta tissues from 20 normal pregnancies were incubated for 25 hr with and without the addition of ouabain, followed by homogenization, protein depletion, and the study of the peptides by a LC-MS based peptidomics approach. 275 peptidomic markers were evaluated by Student t-test. A set of 8 markers was chosen using a logistic regression model build with the Akaike information criterion (AIC). However, no peptidomics markers or set of markers showed specific, statististically significantly different changes in abundances between cases and controls after applying a false discovery rate (FDR) correction or using more conservative methods to overcome over-fitting. Using an optimal sPLS- DA, cross-validation studies and logistic regression models, we also found that the addition of any peptidomic marker to the previously selected lipidomic profile was unlikely to help identify placentas that had been exposed to EDLF.Alzheimer's disease (AD) is the most common form of dementia and the number of AD cases worldwide is currently estimated to be 36 million. The exact pathogenesis of AD remainsiielusive and available therapeutic strategies can only delay its progession temporarily. Several hypotheses have been proposed regarding the pathophysiology of AD and the beta-amyloid (Aβ) hypothesis is considered the core mechanism. However, the majority of studies concerning AD, or AD biomarkers specifically, have ignored a potentially important variable that is gender, despite reported gender differences in the risk of developing AD, the risk factors, clinical symptoms and CSF biomarkers of the disease, among many other aspects.We analyzed data obtained from a previous study of diagnostic serum lipid biomarkers for AD with the consideration of potential gender difference. Firstly, we studied the interaction between gender and disease stage using analysis of variance (ANOVA) and analysis of covariance (ANCOVA). Lipid markers that showed statistically significant interaction were selected after applying a FDR correction. Secondly, using a lasso logistic regression model with binary classification (control vs. all AD stages), we identified gender-specific markers and found different coefficient estimates for different genders as well. Lastly, we build a new ordinal model with the addition of a gender-specific marker using a Bayesian lasso probit ordinal regression model. The predictive performance of the new model was found to be statistically significantly better than the previous model which was built without the consideration of gender.In conclusion, we successfully discovered, chemically characterized lipidomic markers indicative of EDLF exposure in placenta and detected gender-specific lipid markers for AD.

Die Bedeutung der angiogenen Faktoren „soluble fms-like tyrosine kinase-1“ (sFlt-1) und „placental growth factor“ (PIGF) in der Pathogenese der Präeklampsie (PE) ist in den letzten Jahren hinreichend belegt worden. Bei Patienten mit manifester PE lassen sich dramatisch hohe sFlt-1- bzw. sehr niedrige PlGF-Werte nachweisen. Mittlerweile konnte in Studien die sFlt-1/PlGF-Ratio als sensitiver Parameter ermittelt werden. Ziel der vorliegenden Arbeit ist es, die Zusammenhänge zwischen klinischen Parametern der manifesten Präeklampsie und der sFlt-1/PlGF-Ratio zu spezifizieren. Dabei soll geprüft werden, ob bei manifester PE die Höhe der sFlt-1/PlGF-Ratio vor Entbindung klinische Bedeutung hat und mit Parametern des Schwangerschaftsausgangs in Beziehung steht.

Die Präeklampsie ist eine schwangerschaftsspezifische Erkrankung, deren klinische Zeichen in der Regel erst nach der 20. Schwangerschaftswoche auftreten. Behandlungsmöglichkeiten zur Verminderung von Komplikationen, wie der uterinen Wachstumsretardierung, sind durch ein spätes Erkennen des Krankheitsbildes limitiert. Ziel der Studie war es zu prüfen, ob die parallele Messung von uteriner Perfusion und der maternalen Blutplasmakonzentration der anti-/angiogenen Faktoren PlGF, sFlt-1 und sEndoglin im 2. Trimenon die prädiktive Wertigkeit der Dopplersonographie hinsichtlich der Entwicklung einer Präeklampsie erhöhen kann. Anhand der Ergebnisse weisen Frauen mit gestörter uteroplazentarer Perfusion und einem anschließend komplikationsreichen Verlauf erhöhte Werte an sFlt-1 und sEndoglin sowie erniedrigte Werte an PlGF im Vergleich zu Frauen mit normalem Schwangerschaftsausgang auf. Die zusätzliche Analyse dieser Faktoren konnte die prädiktive Fähigkeit der Dopplersonographie bezüglich einer Präeklampsie erhöhen, insbesondere bei der frühen Form mit Entbindung vor der 34. SSW. Somit können Hochrisikopatientinnen für die Entwicklung einer Präeklampsie durch die Messung von PlGF, sFlt-1 und sEndoglin frühzeitiger erfasst werden. Weitere Studien sind zur Bestimmung eines idealen Messungszeitpunktes, der optimalen Kombination der Faktoren und endgültiger Cutoffwerte notwendig.:Bibliographische Beschreibung Abkürzungsverzeichnis 1. Einleitung 1 2. Grundlagen 3 2.1 Anatomische und physiologische Grundlagen 3 2.1.1 Die menschliche Plazenta 3 2.1.2 Vaskuläre Veränderung während der Schwangerschaft 3 2.2 Hypertensive Schwangerschaftserkrankungen 4 2.3 Präeklampsie 8 2.3.1 Pathogenese 8 2.3.2 Erklärungsmodelle der Ätiologie 10 2.3.3 Aspekte zum 2-Phasenmodell 14 2.4 anti-/angiogene Faktoren PlGF, sFlt-1 und sEndoglin 15 2.4.1. Zusammenhang mit Präeklampsie 15 2.4.2 PlGF 15 2.4.3 sFlt-1 17 2.4.4 sEndoglin 19 2.5 Intrauterine Wachstumsretardierung 22 2.6 Dopplersonographie 23 3. Zielsetzung der Arbeit 24 4. Methoden und Material 25 4.1 Studiendesign 25 4.2 Patientinnengut 26 4.3 Dopplersonographie 27 4.3.1 Widerstandindizes zur Perfusionsdiagnostik uteroplazentarer Gefäße 27 4.3.2 Ultraschallgerät 29 4.3.3 Durchführung 29 4.4 ELISA 29 4.4.1 Allgemeine Funktionsweise 29 4.4.2 Probengewinnung 30 4.4.3 Materialliste 31 4.4.4 Durchführung 33 4.5 Statistik 35 5. Ergebnisse 37 5.1 Patientinnencharakteristika 37 5.2 Messung der anti-/angiogenen Faktoren 38 5.2.1. Messung von PlGF 38 5.2.2 Messung von sFlt-1 39 5.2.3. Messung von sEndoglin 40 5.2.4 Korrelation der einzelnen Parameter 41 5.2.5 Analyse der sFlt-1/PlGF-Ratio 43 5.3 Prädiktive Wertigkeit der anti-/angiogenen Faktoren 44 6. Diskussion 50 6.1 Analyse der gemessenen PlGF-, sFlt-1- und sEndoglinkonzentrationen 50 6.1.1 Analyse von PlGF 50 6.1.2 Analyse von sFlt-1 51 6.1.3 Analyse von sEndoglin 55 6.1.4 Korrelation und sFlt-1/PlGF-Ratio 56 6.2 Prädiktive Wertigkeit von Doppler und der anti-/angiogenen Faktoren PlGF, sFlt-1 und sEndoglin für die Entwicklung einer Präeklampsie 58 6.2.1. Analyse der prädiktiven Fähigkeit 58 6.2.2 Veränderungen der anti-/angiogenen Faktoren bei früher Präeklampsie 60 6.2.3 Veränderte Faktorenkonzentration als Hinweis auf PE oder IUGR? 61 6.2.4 Frühe Vorhersage der Präeklampsie 63 6.3 Klinischer Nutzen der Ergebnisse 65 7. Zusammenfassung der Arbeit 69 8. Literaturverzeichnis 72 9. Verzeichnis der Tabellen und Abbildungen 95 Publikation Danksagung

<p>Preeclampsia and other hypertensive disorders of pregnancy impact 2-8% of pregnancies with often devastating results. Current treatment methods resort to birth, which forces the fetus into the world before they are fully developed but can save the mother’s life. Preeclampsia is broadly considered to be of placental origin and current etiologic understanding focuses on systemic endothelial dysfunction triggered by an imbalance of vasoregulatory factors released by this maternal/fetal organ. This imbalance explains many early-term cases but fails to adequately address later cases where this imbalance is not always seen. Conversely, ischemia-reperfusion of the kidney is known to correlate with endothelial dysfunction, and preeclamptic women are known to have a stenosis in their left renal vein (LRV) in the supine position (on their back). Herein, we suggest that extrinsic compression of the LRV by the gravid uterus, without collaterals, produces a renal injury which can induce systemic endothelial cell dysfunction. We theorize this compression is position dependent and produces renal ischemia through an unchecked cycle of increased intrarenal pressure, subsequent afferent arteriole constriction and decreased glomerular perfusion, and activation of the renin-angiotensin-aldosterone system. We aim to elucidate this through murine studies of a surgically induced LRV stenosis and a retrospective clinical study where the maternal renal veins are measured from magnetic resonance images. Findings from this work suggest partial renal venous outflow obstruction leads to renal injury but could be moderated through alternative maternal resting positions. This potential alternative pathologic mechanism has significant clinical implications for future therapies targeting this condition.</p>

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

In recent times the potential impact of preeclampsia on the cardiovascular health of offspring has been identified. This thesis explores the relationship between preeclampsia and offspring cardiovascular phenotype during the first three decades of life. A systematic review and meta-analysis provided evidence that there was increased blood pressure and BMI in the offspring of preeclamptic pregnancies (n = 45,249). There was however limited data on metabolic features and inadequate characterisation of the degree of prematurity or growth restriction in existing literature. I therefore studied data on two birth cohorts with up to 28 years of detailed prospective follow up (n = 2868 and n = 926). Those born very preterm to preeclamptic pregnancies had transient perinatal reductions in insulin and cholesterol, although extreme prematurity was the only determinant of variation in cardiovascular risk in later life, with changes in both metabolism and blood pressure. In those born closer to, or at term, gestation was no longer relevant and an independent impact of preeclampsia on blood pressure was evident, so that by age 20, those born at term to preeclamptic pregnancies were four and a half times more likely to demonstrate clinically-apparent hypertension. I then investigated whether there were changes in other features of cardiovascular phenotype, independent of blood pressure, in preterm neonates born following preeclampsia (n = 46). At 3 months of age preterm infants born to hypertensive pregnancies had subclinical alterations in cardiac strain, independent of gestation or birth weight but not differences in blood pressure, or microvascular structure. These findings highlight preeclampsia and prematurity as key, independent perinatal factors, important in determining cardiovascular phenotype and risk during early life. Preeclampsia is associated with a specific lean, hypertensive phenotype, associated with cardiac functional alterations; these findings begin to define a distinct at risk population who may require targeted preventative interventions.

Thesis (MPhil)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Pre-eclampsia is a common and dangerous condition of pregnancy. During clinical care the sensitive obstetrician will frequently recognise moral ambiguity and ethical conflicts. It is important to understand the pertinent issues and find ways of resolving them. Counselling is an important element of modern medicine. In deciding which counselling model to apply, clinicians must consider many variables including the particular clinical scenario, strength of evidence, and the justifiable limits of paternalism and autonomy in a position of shared responsibility. Couples have a moral right to procreate even when the pursuit of pregnancy involves significant risks. However, with their understanding of care ethics as well as rights ethics, informed women are well placed to negotiate the extremes of these positions when deciding whether to risk a pregnancy or not. The concept of the “fetal patient” is a helpful one. An autonomous woman may choose to confer or deny this status to her previable fetus, while obstetricians must balance autonomy- and beneficence-based obligations to the pregnant woman with beneficence-based obligations to her fetus. Maternal behaviour that harms the fetus and future child is categorised as maternal-fetal conflict. However, any pregnant woman is morally required to avoid harming the fetus, if this can be done without sacrificing her own important interests. The term non-compliance implies a hierarchical nature in the doctor-patient relationship. This reduces patient agency, erodes trust and conflicts with informed choice. Although sometimes justified, this “label” generally does more harm than good. Expectant management of early pre-eclampsia recognises that neonatal intensive care is an expensive and limited resource. The ultimate goal of expectant management remains the safety of the mother and the delivery of a live infant who will not require intensive and prolonged neonatal care. This judicious use of neonatal intensive care improves distributive justice but by consenting to expectant management as an inpatient, the pregnant woman voluntarily restricts her freedom. The decision is morally undergirded by the value accorded to the viable fetus and the scientific evidence informing the decision. When an extremely preterm, growth restricted fetus requires delivery, resuscitation may become an issue for consideration. The distinction between withholding resuscitation in such cases, or initiating but later withdrawing care is morally irrelevant. Categories of optional and obligatory treatments are more helpful, but perinatologists must determine treatment thresholds through understanding the relevant data and ethics issues. Finally, women do not lose their rights when they become terminally ill. When an undelivered woman is declared brain dead following complications of pre-eclampsia, her doctors and family must formulate clear plans for her and her living fetus. She must still be treated with respect and her right to die with dignity not forgotten. Extension of somatic support to optimise the outcome of her fetus can be supported ethically provided that the fetus is at the threshold of viability, the support is not prolonged (distributive justice), advanced level support is available with a successful outcome likely, and that doctors and family are in clear agreement. / AFRIKAANSE OPSOMMING: Pre-eklampsie is ‘n algemene en gevaarlike toestand van swangerskap. Die verloskundige met ‘n fyn waarnemingsvermoë sal dikwels morele dubbelsinnigheid en etiese konflik tydens kliniese sorg erken. Dit is belangrik om die kernaspekte te verstaan en maniere te vind om dit op te los. Berading is ‘n belangrike komponent van moderne geneeskunde. Tydens besluitneming oor watter model van berading toegepas moet word, moet klinici ‘n aantal veranderlikes teen mekaar opweeg insluitend die spesifieke kliniese senario, sterkte van die getuienis, die geregverdigde perke van paternalisme en outonomie in ‘n posisie van gedeelde verantwoordelikheid. Die egpare het ‘n morele reg om voort te plant selfs wanneer die verlange na swangerskap betekenisvolle risiko’s inhou. Vrouens wat goed ingelig is, het die vermoë om die uiterstes van etiek van sorg en regte teen mekaar op te weeg wanneer hulle besluit om die risiko van swangerskap te loop. Die konsep van “fetus as pasiënt” kan wel tot verdere besluitneming bydra. Die outonome vrou mag self besluit of die fetus daardie status het. Aan die ander kant moet die verloskundige outonomie en goedwilligheid- (“beneficence”) gebasseerde verpligtinge teenoor die swanger vrou opweeg teen die goedwilligheid-gebasseerde verpligting teenoor haar fetus. Moederlike gedrag wat die fetus en toekomstige kind skend, word as ‘n moeder-fetus konflik beskou. Enige swanger vrou is egter moreel verplig om nie die fetus skade te berokken nie, mits dit gedoen kan word sonder die prysgawe van haar eie noodsaaklike belange. Die term “nie-inskiklikheid” (“non-compliance”) impliseer hiërargie in die dokter-pasiëntverhouding. Hierdie hiërargie doen afbreuk aan die besluitneming van die pasiënt, ondermyn vertroue en bots met ingeligte keuses. Alhoewel besluitneming op grond van hiërargies-gebaseerde gesag soms geregverdig is, veroorsaak hierdie kategorisering gewoonlik meer kwaad as goed. Afwagtende hantering van vroeë pre-eklampsie gaan van die standpunt uit dat neonatale intensiewe sorg ‘n duur en skaars hulpbron is. Die uiteindelike doel van afwagtende hantering bly die veiligheid en gesondheid van die ma en die verlossing van ‘n lewendige baba wat nie verlengde intensiewe- en neonatale sorg benodig nie. Hierdie oordeelkundige gebruik van neonatale sorg bevorder distributiewe geregtigheid, maar wanneer sy toestemming gee tot afwagtende behandeling as binnepasiënt, beperk die swanger vrou vrywilliglik haar vryheid. Hierdie besluit word moreel ondersteun deur die waarde wat aan die lewensvatbare fetus toegevoeg word en die wetenskaplike gronde waarop die besluit berus. Wanneer ‘n erge voortydse, groeivertraagde fetus verlossing benodig, word ressussitasie soms iets wat oorweeg moet word. Die onderskeid tussen die weerhouding van ressussitasie in sulke gevalle en die onttrekking van sorg waar dit aanvanklik begin is, is moreel irrelevant. Kategorieë van opsionele en verpligte behandelings is meer behulpsaam, maar perinatoloë moet die behandelingsdrempels bepaal deur die relevante data en etiek te verstaan. Laastens, vroue verloor nie hul regte wanneer hulle terminaal siek word nie. Wanneer die komplikasies van pre-eklampsie breindood van die vrou veroorsaak voor die verlossing van haar baba, moet haar dokters en familie duidelike planne vir die hantering van haar en haar fetus ontwikkel. Sy moet nogsteeds met respek behandel word en haar reg om met waardigheid te sterf, mag nie uit die oog verloor word nie. Verlenging van die ondersteuning van lewensfunksies om die uitkoms van haar fetus te verbeter, kan eties ondersteun word, mits die fetus na aan lewensvatbaarheid is, die ondersteuning nie te lank duur nie (distributiewe geregtigheid), gevorderde ondersteuning beskikbaar is met ‘n goeie kans vir suksesvolle uitkoms en dat die dokters en familie ten volle saamstem.

Preeclampsia is one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, women who have had preeclampsia have an increased risk of cardiovascular events over the next 10-15 years. Indeed, preeclampsia is associated with a four-fold increase in the risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. In addition, offspring born to preeclampsia are more likely to have higher blood pressure from childhood and stroke in later life. The risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery, the main interest of my research was to identify key phenotypic variations in mothers and children during the years between the episode of preeclampsia and emergence of established cardiovascular disease, which might explain the link between the two conditions. This information could then be used to devise ways to identify subjects at greatest risk of later cardiovascular disease and to establish intermediate endpoints for future preventative interventions. Therefore, in a case control study, women diagnosed with preeclampsia between 1998 and 2003 and their offspring were recruited and underwent comprehensive cardiovascular and metabolic phenotyping. Furthermore, young adults born preterm to hypertensive pregnancy were also investigated in their twenties. The research demonstrates that early-onset preeclampsia, diagnosed before 34 weeks gestation, is associated with blood pressure patterns in mothers 6-13 years after pregnancy that are distinct from those seen following later-onset disease. Furthermore, there is evidence of distinct differences in cardiac, vascular and metabolic profiles in these individuals with women having evidence of increased arterial stiffness, changes in cardiac function and reduced capillary density. Preterm offspring of hypertensive pregnancies similarly have higher blood pressure than seen in those born following late-onset disease and, in young adult life, have reduced endothelial function and changes in cardiac size proportional to this dysfunction. This research demonstrates adverse cardiac and vascular remodelling after preeclampsia in mothers and offspring that are evident before the development of clinical cardiovascular disease. The identified differences in cardiac and vascular function may be useful as surrogate endpoints in future preventive trials.

OBJECTIF: évaluer un modèle prédictif de prééclampsie associant des marqueurs cliniques, biologiques (Inhibine A, PP-13, hCG, ADAM12, PAPP-A et PlGF) et du Doppler des artères utérines (DAU) au 1er trimestre de la grossesse. METHODE : étude prospective de cohorte de 893 nullipares chez qui DAU et prélèvement sanguin étaient réalisés à 11-14 semaines. RESULTATS : 40 grossesses se sont compliquées de prééclampsie (4,5%) dont 9 de prééclampsie précoce (1,0%) et 16 de prééclampsie sévère (1,8%). Le meilleur modèle prédictif de la prééclampsie sévère associait les marqueurs cliniques, PAPP-A et PlGF (taux de détection 87,5% pour 10% de faux positif). Le DAU étant corrélé à la concentration de PAPP-A (r=-0,117 ; p<0,001), il n’améliorait pas la modélisation. CONCLUSION : la combinaison de marqueurs cliniques et biologiques (PlGF et PAPP-A) au 1er trimestre permet un dépistage performant de la prééclampsie sévère. Le DAU n’est pas un instrument efficace de dépistage au 1er trimestre dans cette population. / OBJECTIVE: To determine the value of combined screening for pregnancy hypertensive disorders by maternal characteristics, first trimester uterine artery Doppler (UAD) and serum biomarkers (Inhibine A, PP-13, hCG, ADAM12, PAPP-A et PlGF). STUDY DESIGN: In this prospective cohort study, 893 nulliparous women had UAD evaluation and collection of serum sample at 11-14 weeks. RESULTS: 40 women developed preeclampsia (4.5%) of which 9 early-onset preeclampsia (1.0%), and 16 severe preeclampsia (1.8%). The best model to predict preeclampsia associated maternal charateristics, PAPP-A and PlGF (detection rate 87.5% for 10% of false positive). UAD was correlated to PAPP-A concentration (r=-0.117 ; p<0.001), and so did not add to predictive accuracy. CONCLUSION: Combination of maternal characteristics and first trimester PlGF and PAPP-A provides a useful screening for severe preeclampsia. First trimester UAD was not an efficient screening tool in this population.