Ätiologie und modernes Management der Gestose C Tempfer Universitätsklinik für Frauenheilkunde Medizinische Universität Wien

Definition - Präeklampsie Proteinurie + Hypertonie (140/90+3g/24hrs) ACOG 2001 - ‘HIP’ - end organ involvement renal - preeclampsia hepatic - HELLP central - eclampsia systemic disease placenta, endothelium 140/90 nach 20. SSW elevation of >30mm Hg systolic or >15mm Hg diastolic above baseline - wurde verlassen, weil v.a. junge Frauen das öfter haben 0.3 g protein in 24 hrs severe 160/110, 5g proteinuria, Oligurie <500 ml/24 hrs, thrombocytopenia, impaired liver function, pulmonary edema, central disturbance, e.g. visual

Morbidität HIP: 12-22%; PE: 3-5% of pregnancies (Roberts et al. 2001) 17,6% of maternal deaths (Koonin et al. 1997) n=588; severe maternal morbidity (Waterstone et al. 2001) 12/1000 total 6.7/1000 hemorrhage 3.9/1000 severe PE 0.2/1000 eclampsia 0.5/1000 HELLP Maternal deaths 1987-1990

Morbidität Intensive Care Unit (ICU) admissions 1987-1998 (Loverro et al. 2001) 75.6% worsening of preeclampsia 14,7% severe bleeding 4.9% mat. cardiac disease (stage III AHA) 2.4% pulmonary embolism/edema Loverro: Frauenklinik Bari Waterstone: Maternal deaths 1987-1990 andere Länder: Frankreich Bouvier-Colle 1996: 26.2% worsening hypertension 20% severe hemorrhage

Fetale Morbidität 40% of premature deliveries (Meis et al. 1998) mild preeclampsia: preterm del...............13-54% abrupt. plac..............1% IUGR........................5-13% fetal death................<1% (Dekker et al. 2001) Maternal deaths 1987-1990

Ätiologie - Genetik Elliot 1873, Scanzoni 1867, Hinselmann 1924 Chesley et al. 1961 - systemat. Analyse Risiko für Verwandte: Schwestern - 37%, Töchter - 25% Schwiegertöchter - 6% OR 2.1 Väter mit PE-Mutter (Esplin et al. 2001) Vererbungsmodus single gene model; polygenetic model; non-mendelian inheritance (Folgero et al.) Daß PE familiär gehäuft auftritt ist seit über 200 a bekannt frühe geburtshilfl. Lit. Beschreibt Fälle von PE in Müttern und Schwestern von betroff. Frauen Erst Leon Chesley (Gynäkologe and der State Univ. of NY) und Desmond Cooper (Biologe, NSW, Australien) haben in den 60er Jahren systematische Analysen non-mendelian inheritance: Folgero and colleagues demonstrated mitochondrial DNA mutations, mainly single base substitutions, among preeclampsia families

Ätiologie - Tiermodelle Renin - fetal contribution (Takimoto et al. 1996) transgenic mice - hREN, hAGT Hypertonie, Proteinurie 15% Konvulsionen Modell f. genet. ind. Präeklampsie Takimoto et al. 1996 Science human and murine RAS do not interfere, single transgenics are normotensive wenn pregnant, dann PIH in third trimestedurch Interaktion von matern. hAGT mit plazentarem hREN, + Proteinurie, + 15% convulsions Mechanismus: Renin cleaves AGT into ANG I, ANG II Nachweis einer genetisch induzierten Präeklampsie Analoge Ergebnisse im Rattenmodell (Bohlender et al. 2000) X hAGT - TGM hREN - TGM PIH - 3. Trimester

Ätiologie - Tiermodelle Knock-out Mausmodell Angiotensinogen (Agt) Agt 0/0, Agt 1/0, Agt 1/1, Agt 2/1, Agt 2/2 Endotheliale NO-Synthase (Nos3) Nos3 0/0, Nos3 1/0, Nos3 1/1

Nos3 Nos3-defiziente Mäuse: Hypertonie, IUGR und Ödembildung in der Spätschwangerschaft (Tempfer 1999; Hefler 2001)

Nos3 und Agt Nos3-defiziente und Agt-überexprimierende Mäuse: erhöhten RR in der Schwangerschaft, “double mutants” den höchsten RR (Hefler, 2001)

Nos3 und Agt Nos3-defiziente, Agt-überexprimierende und “double mutants” zeigen im Gegensatz zu Kontrollen eine verstärkte Proteinurie in der Schwangerschaft (Hefler 2001)

Humanes NOS3-Gen US-Hispanische Population (n=131) Polymorphismus, 27 bp repeat region in intron 4 des Gens Odds Ratio: 7.2 (95% CI: 2.0 – 25.5) Assoziation mit Blutdruck OR bezieht sich auf hetero- und/oder homo-Trägerschaft des mutierten Allels (A) Genotypfrequenzen (A=mutant): A/B - 27% A/A - 12% +/+ m/+ m/m 420 bp 393 bp

Humanes IL-1 Gen System. Inflammationsreaktion (Redman 1999) IL-1: 2 Polymorphismen (Promoter, exon 5) IL-1 RA: 2 Polymorphismen (intron 2) IL-1 RA: 178 vs. 159 mmHg, P=0.03 3 polymorphe Allele 182 vs. 160 mmHg, P=0.009 Leberenzyme ALT: 67 vs. 20 IU/L, P=0.04 AST: 118 vs. 24 IU/L, P=0.002 Redman et al. 1999 excessive maternal inflammatory response to pregnancy erhöhte Expression von CD11b, CD 64 auf Granulozyten, erhöhte Produktion von Sauerstoffradikalen in Granulozyten, Monozyten und Lymphozyten also eine generalisierte Aktivierung zirkulierender Leukozyten, dieser Effekt ist bei Präeklampsie verstärkt IL-1 RA Allel 2 Allelfrequenz: 26% in Caucasians IL-1B exon 5 Allelfrequenz: 14% IL-1B promoter Allelfrequenz: 40% 500 bp 410 bp 240 bp

Ätiologie - Kandidatengene Angiotensinogen (M235T; Ward 1998) Factor V Leyden (G1691A; Dizon 1996) PAI I (4G/4G; Glueck 2001) HLA-DR4 (Kilpatrick 1989) TNF-alpha (-308; Chen 1996) MTHFR (C677T; Grandone 1997) MR (810leu-ser; Geller 2000) AGT: T235 mutation, Assoziation mit PE, reduziertem Plasmavolumen (nichtschwanger; Bernstein 1998) und Spiralarterienverengung (Morgan 1999) Allelfrequenz: T235 (=mutant): 0.65 (in PE-patients, caucasians) factor V Leyden: a substitution of a G with A at position 1691. This mutation results in the replacement of arginine with glutamine at the factor V CLEAVAGE site for APC (activated protein C), causing APC resistanc. Is an important cause of familial thrombophilia and venous thrombosis, 2-4% of caucasians HLA DR4: affected sib-pair analysis showed excessive haplotype sharing with respect to HLA DR4 among sisters and among spouses. This indicates fetomaternal sharing of a single recessive, HLA-linked gene; i.e. affected sisters showed HLA DR4 haplotype sharing with their husbands more often than unaffected sisters or the general population TNF alpha: polymorphism (NF 1 allele) is a 87 bp allele. Homozygosity for TNF 1 is associated with PE MTHFR: C to T missense mutation; Homozygous MTHFR mutations were found in 8 of 120 (6.67%) preeclamptic women neither sufficient nor necessary worauf wirken sie ein? -nächstes Dia

This failure of placentation leads to a situation of deficient local placental blood supply, hypoxia, and vasospasms. This is consistent with studies that have been done almost 20 years ago by radioisotope techniques (Lunell 1982) and Doppler studies (Trudinger 1985, Campbell 1986) that preeclampsia is characterised by decreased uteroplacental blood flow Also, we know that in situations of relative placental ischemia as for example in gestational trophoblastic disease or women with multiple gestations or underlying vascular disease we find a predisposition for preeclampsia Now the question is: if due to adhesion molecule mediated failure of endovascular invasion and consequently placentation there is local placental ischemia - WHAT transforms this local placental phenomenon in a systemic multiorgan and often life-threatening disease?

31 Studien; 1966-2002 7 522 Schwangere F5 Leiden: Präeklampsie OR 1.81 (1.14-2.87) Schwere Präeklampsie OR 2.24 (1.28-3.94) AGT: T235 mutation, Assoziation mit PE, reduziertem Plasmavolumen (nichtschwanger; Bernstein 1998) und Spiralarterienverengung (Morgan 1999) Allelfrequenz: T235 (=mutant): 0.65 (in PE-patients, caucasians) factor V Leyden: a substitution of a G with A at position 1691. This mutation results in the replacement of arginine with glutamine at the factor V CLEAVAGE site for APC (activated protein C), causing APC resistanc. Is an important cause of familial thrombophilia and venous thrombosis, 2-4% of caucasians HLA DR4: affected sib-pair analysis showed excessive haplotype sharing with respect to HLA DR4 among sisters and among spouses. This indicates fetomaternal sharing of a single recessive, HLA-linked gene; i.e. affected sisters showed HLA DR4 haplotype sharing with their husbands more often than unaffected sisters or the general population TNF alpha: polymorphism (NF 1 allele) is a 87 bp allele. Homozygosity for TNF 1 is associated with PE MTHFR: C to T missense mutation; Homozygous MTHFR mutations were found in 8 of 120 (6.67%) preeclamptic women neither sufficient nor necessary worauf wirken sie ein? -nächstes Dia

neither sufficient nor necessary worauf wirken sie ein? -nächstes Dia AGT: T235 mutation, Assoziation mit PE, reduziertem Plasmavolumen (nichtschwanger; Bernstein 1998) und Spiralarterienverengung (Morgan 1999) Allelfrequenz: T235 (=mutant): 0.65 (in PE-patients, caucasians) factor V Leyden: a substitution of a G with A at position 1691. This mutation results in the replacement of arginine with glutamine at the factor V CLEAVAGE site for APC (activated protein C), causing APC resistanc. Is an important cause of familial thrombophilia and venous thrombosis, 2-4% of caucasians HLA DR4: affected sib-pair analysis showed excessive haplotype sharing with respect to HLA DR4 among sisters and among spouses. This indicates fetomaternal sharing of a single recessive, HLA-linked gene; i.e. affected sisters showed HLA DR4 haplotype sharing with their husbands more often than unaffected sisters or the general population TNF alpha: polymorphism (NF 1 allele) is a 87 bp allele. Homozygosity for TNF 1 is associated with PE MTHFR: C to T missense mutation; Homozygous MTHFR mutations were found in 8 of 120 (6.67%) preeclamptic women neither sufficient nor necessary worauf wirken sie ein? -nächstes Dia

Ätiologie - Plazentation 1st wave - 10.-16. week of gestation 2nd wave - 16.-22. week of gestation dilated vessels, incapable of vasoconstriction hemodynamic shift shallow placentation no dilation of spiral arteries The first candidate for this common pathway is early placentation Many lines of evidence indicate that the causative agent of PE is the placenta, among them: delivery is sufficient to relieve PE, it’s cause must be related to the feto-plac. Unit. PE reporte in abdominal pregnancy-rules out uterus; Fetus also not necessary: molar pregnancies, where there is NO fetus, carry a significantly elevated risk for PE. This points to the placenta as source of the disease…..and many studies on functional aspects of this disease clearly point to the placenta as organ of origin of whatever ultimately causes this disease. In normal pregnancy spiral arteries reach 30 times their diameter first wave of trophoblastic invasion occurs and the muscular walls and the endothelium of the decidual portions of the spiral arteries are replaced by trophoblast 2nd wave trophoblast invasion extends to the myometrial portions of the spiral arteries Result: vessels that are dilated, incapable of vasoconstriction, and lined by trophoblast in direct contact with maternal blood dramatic hemodynamic shift : the situation is one of high volume, high flow, and low peripheral resistance in PE: 2nd wave failure (Robertson and Brosens in the 70’s) shallow placentation highly muscular and contractable spiral arteries in contrast to normal pregnancy we find a situation of low volume, high pressure, and high resistance

Adhäsionsmoleküle cell surface glycoproteins 4 families (Ig’s, integrins, selectins, cadherins) cell-cell and cell-matrix interactions promote tumor invasion in: Cervical cancer (Kainz et al., Gynecol Oncol 1995, 1996) Endometrial cancer (Tempfer et al., Brit J Cancer 1998) Vulvar cancer (Tempfer et al., Cancer 1995, 1998) In a series of studies that we have done in Dr. Kainz’s lab in Vienna we could show that adhesion molecules such as CD44 are intricately involved in tumor cell dedifferentiation, invasion potential, and metastatic spread beyond regional borders Bearing in mind the striking similarities between tumor cell invasion and the behavior of syncytiotrophoblast and endovascular trophoblast cells during placentation it comes as no surprise that adhesion molecules in fact play a crucial role in both processes.

Plazentation - ‘integrin-switch’ EVT acquires an invasive phenotype changing the extracellular matrix receptor ECM receptors are adhesion molecules Balance (Zhou et al., 1997; Burrows et al., 1994) up: VE-cadherin, alpha1/beta1, alphaV/beta3 down: alpha6/beta4,alpha5/beta1, E-cadherin Susan Fisher’s lab, published in a landmark paper in JCI 1997 others Pijnenborg et al. , Burrows et al.

Plazentation - LFA-3 adhesion molecule - expression lymphocyte adhesion, cytokine release upregulation in normal pregnancy failure of upregulation in preeclampsia regression model: 0.1 (95% CI, 0.006 to 0.7) r=-0.26 (systolic RR; P =0.02) r=-0.22 (diastolic RR; P =0.04) (Tempfer et al. 1998) Heavily glycosylated adhesion molecule, MW of about 50 kDa Expressed by endothelia, epithelia, and various hematopoetic cells in a study that was done in cooperation with Prof. Hussleins department in Vienna, and that was published two months ago, we were able to demonstrate Healthy pregnant women showed significantly elevated serum levels of LFA-3 compared to healthy, non-pregnant female controls. Among preeclamptic women a failure of LFA-3 upregulation resulted in a significantly higher risk of developing severe disease and ultimately premature termination of pregnancy due to exacerbation of preeclamptic symptoms. In accordance with these findings, LFA-3 serum levels were inversely associated with BP-characteristics These data support the assumption that a failure of LFA-3 upregulation in preeclampsia influences the course of the disease and ultimately the clinical outcome.71

‘shallow placentation’ - Ursache Twins, GTD, vascular disease Doppler-studies, radioisotope studies Lunell et al. 1982; Trudinger et al., 1985 deficient blood supply - hypoxia This failure of placentation leads to a situation of deficient local placental blood supply, hypoxia, and vasospasms. This is consistent with studies that have been done almost 20 years ago by radioisotope techniques (Lunell 1982) and Doppler studies (Trudinger 1985, Campbell 1986) that preeclampsia is characterised by decreased uteroplacental blood flow Also, we know that in situations of relative placental ischemia as for example in gestational trophoblastic disease or women with multiple gestations or underlying vascular disease we find a predisposition for preeclampsia Now the question is: if due to adhesion molecule mediated failure of endovascular invasion and consequently placentation there is local placental ischemia - WHAT transforms this local placental phenomenon in a systemic multiorgan and often life-threatening disease?

genetic conflict theory (Haig 1993) fetal/maternal genes selected: increase/decrease nutrient transfer to fetus genomic imprinting: maternally/paternally derived genes in fetal cells maternal blood pressure continuum position on this continuum: net result of fetal factors vs. maternal factors gestational hypertension: good prognosis hypoxic placenta: fetal high-risk strategy Hypoxia regulates adhesion molecule expression

? Plazentation localized placental disease systemic vascular disorder This failure of placentation leads to a situation of deficient local placental blood supply, hypoxia, and vasospasms. This is consistent with studies that have been done almost 20 years ago by radioisotope techniques (Lunell 1982) and Doppler studies (Trudinger 1985, Campbell 1986) that preeclampsia is characterised by decreased uteroplacental blood flow Also, we know that in situations of relative placental ischemia as for example in gestational trophoblastic disease or women with multiple gestations or underlying vascular disease we find a predisposition for preeclampsia Now the question is: if due to adhesion molecule mediated failure of endovascular invasion and consequently placentation there is local placental ischemia - WHAT transforms this local placental phenomenon in a systemic multiorgan and often life-threatening disease?

aspects of preeclampsia Increased TXA2 /PGI2 ratio increased serum factor VIII antigen increased sensitivity to vasopressors increased production of vasopressors increased vascular permeability glomerular fibrin deposits TXA2 geht hoch durch mehr Produktion in Thrombos Over the last three decades a multitude of features have been described, that are characteristically disrupted or unbalanced in women with preeclampsia. The most important changes are: increased TXA2 /PGI2 ratio increased production of vasopressors: vasopressors: norepinephrine, aniotensin II glomerular capillary damage characteristic for renal disease observed in preeclampsia Every factor that is supposed to explain the systemic aspect of preeclampsia must be able to cover these numerous pathophysiological changes. Today most researchers agree that most likely there is one organ that is not only able to bring about all these disturbances, but that is also directly connected to the organs that are typically affected among preeclamptic women, namely the liver, kidney, and the brain:

Endothelium 3 Hauptfunktionen 1) Integrität des Gefäßsystems 2) Modulation des Gefäßtonus 3) Modulation der intravask. Gerinnungsfaktoren Endothelschädigung = gemeinsame Endstrecke; Summeneffekt + endothelin, PDGF, factor XII activator, fibronectin, factor VIII - prostacyclin, vascular resistance, sensitivity to vasopressors glomerular capillary endotheliosis The endothelium is a remarkable organ 3 functions all of these functions are characteristically disrupted in preeclampsia and characteristically damaged endothelial cells produce vasopressors (endothelin - Gryglewski et al. , PDGF), procoagulants (factor XII activator) and fail to produce vasodilating agents (prostacyclin) all of these features are found in PE factors that are elevated in PE are located on the endothelial cell membrane (fibronectin, factor VII antigen) In vitro studies demonstrate damaged endothelial cells show increased vascular resistance, sensitivty to vasopressors morphologic changes in the kidney are compatible with endothelial damage

Endothelial activation markers Matched-pair study (Tempfer 1999) 86 women ELAM-1/E-selectin/CD62E elevated (P =0.01) stepwise log. regression We have shown in a study that has been published earlier this year regression model also showed that there was a direct correlation between ELAM-1 levels and the clinical outcome, in this case premature delivery of the baby due to exacerbation of preeclamptic symptoms. This figure shows a ROC curve which essentially plots sensitivity versus 1- specificity. Ideally this curve should stay leftbound as long as possible. ‘cause that would mean that the particular marker identifies a lot of women with the condition tsted for, without having many false positive results, represented by the curve turning to the right. Now for ELAM-1 this ROC curve shows clearly that there is a functional correlation between preeclampsia and elevated third trimester ELAM-1 expression.

soluble factors free radicals (Cheeseman et al. 1993) from activated leukocytes produce lipid peroxides, e.g oxidized LDL cytokines: IL-10, TNF-alpha (Rinehart et al. 1999) free fatty acids (FFA): endothelial tox. cGMP, PGI2, platelet activation syncytiotrophoblast deportation cytokeratin 18, 19 expression (Tempfer et al. 2000) Many papers have been written in the last years trying to close the gap between placental ischemia and endothelial cell damage A study has been presented at this year’s SGI meeting VEGF We thought about that question and took a slightly different approach based on work that we have done 2 years ago on ovarian cancer and that has been published this year in the BJC: Both damage and increased cell turnover of epithelia and epithelia-derived tissues leads to the release of tiny parts of the cytoskeleton, so called CK’s. And these CK’s are also known, and this has been shown by in-vitro studies to be toxic to endothelial cells. (Bjorklund) We hypothesized that if syncytiotrophoblast deportation plays a role in this respect we should find cytokeratins in these women and if the whole story is hypoxia driven we may find correlations with other features that are affected by adequate blood supply, for example fetal growth. in a study that will be published in the green journal later this year we propose increased syncytiotrophoblast deportation as a possible causative agent

Cytokeratin 19 - preeclampsia

Cytokeratin 19 - birth weight Scattergramm I believe that within the next years we should be able to zero in on one factor or factors that are responsible for transforming preeclampsia from a limited placental phenomenon into a systemic disease. This is important because here is where most likely therapy - by blocking such factors - could be very effective. Dr. Gregg and I have crafted a 10 Mio S project that is currently reviewed by the European Union’s Human F S Commission, and with this funding we may be able to find new and even better answers in order to ultimately improve the outcome of affected women.

Summary predisposing factors genetic, immunologic common pathway - early placentation failure dependent on adhesion molecule expression generalized endothelial cell damage Most likely dependent on adhesion molecule expression patterns among others adhesion molecules reflect endothelial cell activation and damage resulting in a positive feedback loop and aggravation of the endothelial damage by recruiting leucocytes adding further to ednothelail damage

Primärprävention I Paternität Primipaternität (Robillard 1999) sperm exposure donor insemination, Eizellspende (Dekker 1998) Dauer Kohabitation (Robillard 1994) Oralverkehr - HLA-Exposition (Koelman 2000) teenage pregnancies (Marti 1977) paternaler Faktor OR 1.8 f. PE mit 2. Partnerin (Lie 1998) Dass Langzeitexposition mit paternalen HLA-Antigenen einen Schutzfaktor darstellt, ist eventuell eine der Erklärungen für die erhöhte Frequenz an PE unter Teenagern. Dauer Kohabitation: 0-4 Monate: OR 11.6 5-8 Monate: OR 5.9 9-12 Monate: OR 4.2 Konkrete Bedeutung für Beratung: Familienplanung >1a Kenntnis der Primipaternität: die Multipara mit neuem Partner ist bzgl. PE gleich zu behnadeln wie die Nullipara Männer, die einmal eine Schwangerschaft mit PE hatten - höheres risk Paternaler Faktor: auch heuer NEJM

Primärprävention II Alter Rauchen Risiko OR 1.3 per 5a (Lie 1998) Intervall OR 1.5 per 5a (Lie 1998) Rauchen 30%-40% reduziertes Risiko (Conde-Agudelo 2000) IUGR, Plazentalösung Nikotin reduziert IL-2, TNF: Therapieansätze D.h. es ist besser, eine Schwangerschaft in einem Alter zu haben, in dem das Endothelium noch eher den inflammatorischen Stress einer Schwangerschaft kompensieren kann. Problem: Industirestaaten delayed pregnancy

Primärprävention III Körpergewicht OR 3 (Stone 1994) n=878 680 2.6% bei BMI <19.8 10.1% bei BMI >29 (Conde-Agudelo 2000) Ursache unbekannt - Lipidstoffwechsel Potential zur Primärprävention Ursache: 3 Theorien: obesity hyperdynamische Zirkulation: erhöhte Scherkräfte am Endothel Dyslipidämie erhöht oxidativen Stress increased sympathetic activity in hyperinsulinemic state Frühgeburtlichkeit beeinflussen durch Fitnessprogramme

Sekundärprävention Sekundärprävention vor allem 4 Interventionen Kalzium Aspirin Fischöl Vitamin C, Vitamin E Keine effektive Methode der Früherkennung, daher Sek.-präv. In populationsbasierten Studien

Sekundärprävention I Kalzium Cochrane 2006 n>15 000, 12 Studien reduziertes Risiko OR 0.78 (0.68-0.89) v.a. Frauen mit low baseline intake + high risk (RR 0.36; 0.18-0.70) 1.5 – 2 g/d Ca-Carbonat Keine effektive Methode der Früherkennung, daher Sek.-präv. In populationsbasierten Studien

Sekundärprävention II Aspirin azetyliert Cyclooxygenase Plättchen können keine COX nachsynthetisieren, Reduktion v. COX-abh. AS-Der., v.a. TXA2 Cochrane 2004 51 Studien, n>36 000 Präeklampsie RR 0.81 (0.75-0.88) Frühgeburt RR 0.93 (0.89-0.98) 16% red.Risiko perinatal death Erhöht Prostazyklin/TXA2-ratio

Sekundärprävention II Empfehlungen ACOG Low risk: nein; high risk: möglich Cochrane Moderate/high risk: NNT 59-167 Risiko? St. p. Präeklampsie, IDDM, APS, Hypertonus SSW 12-14, min. 81mg Bis 5-10 d vor Geburt Erhöht Prostazyklin/TXA2-ratio

Sekundärprävention II UA-Doppler N=1253; Nullipara; UAD SSW 23-24 – pathologisch: ASS 100 vs. no UAD + Plazebo 20% patholog. UAD – Prädiktor: Präeklampsie: 6% vs. 1% IUGR: 18% vs. 8% ASS in UAD patholg. nicht effektiver Erhöht Prostazyklin/TXA2-ratio

Sekundärprävention III Fischöl Fettsäuren konkurrieren mit Arachidonsäure reduzieren TXA2 Cochrane 2006; 4 RCTs, v.a. FOTIP trial (Olsen 2000) kein Effekt Erhöht Prostazyklin/TXA2-ratio

Sekundärprävention IV Vitamine Vitamin C (1000 mg/d), Vitamin E (400 IE/d) 4 RCTs; High risk; n=3609: 15 vs. 16% Low risk; n=1877: 6 vs. 5% Keine Empfehlung Ev. Risiko (SIH; IUFT) Erhöht Prostazyklin/TXA2-ratio

Sekundärprävention V Cinzia et al. 2006 n=305; St. p. preeclampsia or FGR + F5 Leiden or F2 G20210A 151 (Dalteparin) vs. 154 (no treatment) preeclampsia: 44 (28%) vs. 10 (6%) preeclampsia <30 SSW: 27 (17%) vs. 2 (1%) higher gestational age (p<0.01) higher birth weight (p<0.002) higher placental weight (p<0.01) Erhöht Prostazyklin/TXA2-ratio

Tertiärprävention - Therapie Vorbeugung von Komplikationen 45 random. Studien (Dadelszen 2000) n=3773, mild-to-moderate hypertension orale Antihypertensiva mean arterial pressure - Unterschied IUGR höher bei Behandlung maternaler benefit: keiner Twins: normotensive = higher rate of preterm delivery, lower BW

Therapie II severe preeclampsia prevent cerebral complications hemorrhage, encephalopathy >10 rand. trials: hydralazine, labetalol, nifedipine, ketanserin hydralazine most side effects beta blockers less effective than calcium channel blockers (Magee et al. 1999) Nifedipine: calcium channel blocker ketanserin: serotonin 2 receptor blocker labetalol =trandate

Therapie II konservativ – severe early onset Neue Daten 3 rand. trials (Sibai et al. 1994, Fenakel et al. 1991, Odendaal et al. 1990) conservative approach better perinatal outcome, no increased mat. Risk Neue Daten 50% Remission; IUFT + perinatal death häufiger Dass Langzeitexposition mit paternalen HLA-Antigenen einen Schutzfaktor darstellt, ist eventuell eine der Erklärungen für die erhöhte Frequenz an PE unter Teenagern. Dauer Kohabitation: 0-4 Monate: OR 11.6 5-8 Monate: OR 5.9 9-12 Monate: OR 4.2 Konkrete Bedeutung für Beratung: Familienplanung >1a Kenntnis der Primipaternität: die Multipara mit neuem Partner ist bzgl. PE gleich zu behnadeln wie die Nullipara Männer, die einmal eine Schwangerschaft mit PE hatten - höheres risk Paternaler Faktor: auch heuer NEJM

Therapie II Magnesium - seizure prevention severe preeclampsia (Witlin et al. 1998) 19 rand. trials 1966-1998: magnesium sulfate 22/793 (2.8%) vs. 7/815 (0.9%): seizure 216/935 (23.1%) vs. 88/932 (9.4%): rec. seizure Dass Langzeitexposition mit paternalen HLA-Antigenen einen Schutzfaktor darstellt, ist eventuell eine der Erklärungen für die erhöhte Frequenz an PE unter Teenagern. Dauer Kohabitation: 0-4 Monate: OR 11.6 5-8 Monate: OR 5.9 9-12 Monate: OR 4.2 Konkrete Bedeutung für Beratung: Familienplanung >1a Kenntnis der Primipaternität: die Multipara mit neuem Partner ist bzgl. PE gleich zu behnadeln wie die Nullipara Männer, die einmal eine Schwangerschaft mit PE hatten - höheres risk Paternaler Faktor: auch heuer NEJM

Therapie II Magnesium – MAGPIE (2002) WHO, FIGO, ISSHP ACOG n>10 000; RCT; Mg 24 hrs (4g + 1g/h) Eclampsia 1.9 vs. 0.8% Morb., Mort. gleich WHO, FIGO, ISSHP Empfehlung seveer + mild ACOG Empfehlung severe Dass Langzeitexposition mit paternalen HLA-Antigenen einen Schutzfaktor darstellt, ist eventuell eine der Erklärungen für die erhöhte Frequenz an PE unter Teenagern. Dauer Kohabitation: 0-4 Monate: OR 11.6 5-8 Monate: OR 5.9 9-12 Monate: OR 4.2 Konkrete Bedeutung für Beratung: Familienplanung >1a Kenntnis der Primipaternität: die Multipara mit neuem Partner ist bzgl. PE gleich zu behnadeln wie die Nullipara Männer, die einmal eine Schwangerschaft mit PE hatten - höheres risk Paternaler Faktor: auch heuer NEJM

Therapie III HELLP stabilization by dexamethasone: case reports O’Boyle et al. 1999, Magann et al. 1995 1 prosp.-rand. Studie: n=25; dexam. 10 mg i.v. every 12 hrs vs. placebo thrombo, LDH, GOT, GPT, urinary output + 41 hrs to delivery 2 neue RCTs: kein Effekt keine Empfehlung Nifedipine: calcium channel blocker ketanserin: serotonin 2 receptor blocker labetalol =trandate

Therapie IV HELLP recovery p.p. 1 prosp.-rand. Studie: n=40 dexam. 10/10/5/5 mg i.v. every 12 hrs vs. placebo blood pressure thrombo, LDH, GOT, GPT, urinary output decreased platelet adhesion, endothelial protection Nifedipine: calcium channel blocker ketanserin: serotonin 2 receptor blocker labetalol =trandate

Therapie IV Entbindung Mild Severe SSW 37 Einleitung (HYPITAT; n=756, RCT) Maternal composite RR 0.71; -12% Severe LUREI + Entbindung: Einltg./Sectio <SSW 34 SSW 28-34 Erfolg Einleitung: 33% RCT n=278: Einltg. Vs. Sectio APGAR <3: 6 vs. 2% (Redman 1999) Nifedipine: calcium channel blocker ketanserin: serotonin 2 receptor blocker labetalol =trandate

Klinische Relevanz Primärprävention Sekundärprävention Beratung Risikoevaluierung Sekundärprävention Kalzium, Aspirin Risikopatientinnen (leicht/schwer) Thrombo, +5g, Krea, GOT/GPT, LDH, Hapto Tertiärprävention milde Hypertonie; Magnesium