Zusammenfassung
Die Präeklampsie zeichnet sich durch eine hohe fetale und maternale Morbidität und
Mortalität aus und ist in hohem Maße für die Frühgeburtlichkeit verantwortlich. Trotz
der klinischen Bedeutung konnten die pathophysiologischen Mechanismen bis heute nicht
abschließend geklärt werden. Demzufolge sind auch kausale bzw. präventive Therapiestrategien
nicht ausreichend bekannt. Eine zufriedenstellende Erfahrung in der Prävention einer
Präeklampsie liegt bisher nur für die Anwendung von Acetylsalicylsäure (ASS) in Risikokollektiven
vor. ASS greift direkt in die Dysbalance des vasodilatierenden Prostazyklins und des
vasokonstringierenden Thromboxans ein. Erste Studien beweisen darüber hinaus auch
einen präventiven Effekt der Antioxidanzien Vitamin C und E. Eine frühzeitige antihypertensive
Therapie kann dagegen eine spätere Progression der Erkrankung nicht positiv beeinflussen.
Eine Natriumrestriktion, eine Kalzium- und Magnesiumsubstitution, die Gabe von Fischöl
oder eine Steroidtherapie sind in der Prävention einer Präeklampsie unwirksam. Die
zukünftige Klärung der pathophysiologischen Zusammenhänge der Präeklampsie könnte
helfen, die Akuttherapie zu verbessern und gleichzeitig wirksame präventive Strategien
zu entwickeln.
Abstract
Preeclampsia is accompanied by high fetal and maternal morbidity and mortality and
to a high degree responsible for preterm delivery. The pathophysiologic mechanisms
underlying this disease remain poorly understood. Accordingly, only few causative
or preventive therapeutical strategies are known. One such example for a preventive
strategy is the use of aspirin (ASA) which directly affects the imbalance of vasodilative
prostacycline and vasoconstrictive thromboxane. Recently, some studies are indicating
a preventive effect of vitamin C and E substitution. In contrast, early antihypertensive
therapy did not prevent later progression of the disease. Furthermore, sodium restriction,
calcium and magnesium substitution, fish oil substitution, or steroid therapy are
without any effect regarding the later development of preeclampsia. It is of utmost
importance to further elucidate underlying pathophysiological mechanisms to improve
therapeutical and preventive strategies.
Schlüsselwörter
Präeklampsie - HELLP-Syndrom - Prävention - pathophysiologische Mechanismen - Acetylsalicylsäure
- Heparin
Key words
Preeclampsia - HELLP syndrome - prevention - pathophysiology - acetyl salicylic acid
- heparin
Literatur
1
Alfirevic Z, Roberts D, Martlew V.
How strong is the association between maternal thrombophilia and adverse pregnancy
outcome? A systemic review.
Eur J Obstet Gynecol Reprod Biol.
2002;
101
6-14
2
Bates S M, Greer I A, Hirsh J, Ginsberg J S.
Use of antithrombotic agents during pregnancy.
Chest.
2004;
126 (3 Suppl)
627S-644S
3
Baylis C, Beinder E, Suto T, August P.
Recent insights into the roles of nitric oxide and renin-angiotensin in the pathophysiology
of preeclamptic pregnancy.
Semin Nephrol.
1998;
18
208-230
4
Beinder E, Mohaupt M.
NO-Donatoren zur Verhütung und Behandlung präeklamptischer Erkrankungen.
Gynakologe.
1999;
32
768-775
5
Beinder E, Mohaupt M, Schlembach D, Fischer T, Sterzel R B, Lang N, Baylis C.
Nitric oxide synthase activity and doppler parameters in the fetoplacental and uteroplacental
circulation in preeclampsia.
Hypertens Pregnancy.
1999;
18
115-127
6
Belfort M A, Moise K J.
Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomized,
placebo-controlled study.
Am J Obstet Gynecol.
1992;
167
661-666
7
Bootstaylor B S, Roman C, Parer J T, Heymann M A.
Fetal and maternal hemodynamic and matabolic effects of maternal nitroglycerin infusions
in sheep.
Am J Obstet Gynecol.
1997;
176
644-650
8
Boulanger C, Luscher T F.
Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric
oxide.
J Clin Invest.
1990;
85
587-590
9
Boy K, Zimmermann U, Wildt L.
Enhanced tumor necrosis factor alpha (TNF alpha) secretion by stimulated mononuclear
leucocytes in gestosis (abstract).
Exp Clin Endocinol Diabetes.
1995;
103 (Suppl 1)
42
10
Bucher H C, Guyatt G H, Cook R J, Hatala R, Cook D J, Lang J D, Hunt D.
Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia:
a metaanalysis of rendomized controlled trials.
JAMA.
1996;
275
1113-1117
11
Bussolino F, Camussi G.
Effect of prostacyclin on platelet-activating factor induced rabbit and platelet aggregation.
Prostaglandins.
1980;
20
781-791
12
Carbonne B, Jannet D, Touboul C, Khelifati Y, Milliez J.
Nicardipine treatment of hypertension during pregnancy.
Obstet Gynecol.
1993;
81
908-914
13
Carp H, Dolitzky M, Inbal A.
Thromboprophylaxis improves the live birth rate in women with consecutive recurrent
miscarriages and hereditary thrombophilia.
J Thromb Haemost.
2003;
1
433-438
14
Chappell L C, Seed P T, Briley A L, Kelly F J, Lee R, Hunt B J, Parmar K, Bewley S J,
Shennan A H, Steer P J, Poston L.
Effect of antioxidants on the occurrence of pre-eclampsia in women at incresaed risk:
a randomised trial.
Lancet.
1999;
354
810-816
15
CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group .
CLASP: a randomized trial of low-dose aspirin for the prevention and treatment of
pre-eclampsia among 9 364 pregnant women.
Lancet.
1994;
343
619-629
16
Coomarasamy A, Papaioannou S, Gee H, Khan K S.
Aspririn for the prevention of preeclampsia in women with abnormal uterine artery
Doppler: a meta-analysis.
Obstet Gynecol.
2001;
98
861-866
17
Cotton D B, Hallak M, Janusz C, Irtenkauf S M, Berman R F.
Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced
seizures.
Am J Obstet Gynecol.
1993;
168
974-978
18
Cruickshank D J, Robertson A A, Campbell D M, MacGillivray I.
Does labetalol influence the development of proteinuria in pregnancy hypertension?
A randomised controlled study.
Eur J Obstet Gynecol Reprod Biol.
1992;
45
47-51
19
Dekker G, Sibai B.
Primary, secondary, and tertiary prevention of preeclampsia.
Lancet.
2001;
357
209-215
20
Del Rio G, Velardo A, Zizzo G, Avogaro A, Cipolli C, Della Casa L, Marrama P, MacDonald I A.
Effect of estradiol on the sympathoadrenal response to mental stress in normal men.
J Clin Endocrinol Metab.
1994;
79
836-840
21
DiSessa T G, Moretti M L, Khoury A, Pulliam D A, Arheart K L, Sibai B M.
Cardiac function in fetuses and newborns exposed to low-dose aspirin during pregnancy.
Am J Obstet Gynecol.
1994;
171
892-900
22
Duggan P M, McCowan L M, Stewart A W.
Antihypertensive drug effects on placental flow velocity waveforms in pregnant women
with severe hypertension.
Aust N Z J Obstet Gynaecol.
1992;
32
335-338
23
Duley L, Henderson-Smart D, Knight M, King J.
Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic
review.
BMJ.
2001;
322
329-333
24
Ettinger S M, Silber D H, Gray K S, Smith M B, Yang Q X, Kunselman A R, Sinoway L I.
Effects of the ovarian cycle on sympathetic neural outflow during static exercise.
J Appl Physiol.
1998;
85
2075-2081
25
England L J, Levine R J, Qian C, Morris C D, Sibai B M, Catalano P M, Curet L B, Klebanoff M A.
Smoking before pregnancy and risk of gestational hypertension and preeclampsia.
Am J Obstet Gynecol.
2002;
186
1035-1040
26
Fischer T, Krause M, Beinder E, Schlembach D, Rabenbauer B, Wildt L, Lang N.
Schwangerschaftsverlängerung bei Patientinnen mit HELLP-Syndrom.
Geburtshilfe Frauenheilkd.
1999;
59
335-345
27
Fischer T, Schneider M P, Schobel H P, Heusser K, Langenfeld M, Schmieder R E.
Vascular reactivity in patients with preeclampsia and HELLP syndrome.
Am J Obstet Gynecol.
2000;
183
1489-1494
28
Fischer T, Schobel H P, Frank H, Andreae M, Schneider K T, Heusser K.
Pregnancy-induced sympathetic overactivity: a precursor of preeclampsia.
Eur J Clin Invest.
2004;
34
443-448
29
Fischer T, Heusser K, Schobel H.
Autonomes Nervensystem und Präeklampsie.
Zentrlbl Gynäkol.
1999;
121
603-607
30
Fischer T, Wildt L.
Glukokortikoide und HELLP-Syndrom - Eine Standortbestimmung.
Gynakologe.
1999;
32
783-790
31
Fischer T, Wallukat G, Schneider M P, Schlembach D, Munz W, Homuth V.
HELLP syndrome in the 18th week of gestation in association with elevated angiotensin AT(1)-receptor autoantibodies.
Eur J Obstet Gynecol Reprod Biol.
2001;
97
255-257
32
Goldman R S, Finkbeiner S M.
Therapeutic use of magnesium sulfate in selected cases of cerebral ischemia and seizure.
N Engl J Med.
1988;
319
1224-1225
33
Gris J C, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S,
Tailland M L, Dauzat M, Mares P.
Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss
and a constitutional thrombophilic disorder.
Blood.
2004;
103
3695-3699
34
Gruppo di Studio Ipertensione in Gravidanza .
Nifedipine versus expectant management in mild to moderate hypertension in pregnancy.
Br J Obstet Gynaecol.
1998;
105
718-722
35
Harper A, Murnaghan G A.
Maternal and fetal haemodynamics in hypertensive pregnancies during maternal treatment
with intravenous hydralazine or labetalol.
Br J Obstet Gynaecol.
1991;
98
453-459
36
Hasbargen U, Hasler M, Sattler C, Kolben M.
Low incidence of HELLP syndrome before 32nd week of pregnancy: discontinuation of the Munich study.
Z Geburtshilfe Neonatol.
2000;
204
78-79
37
He X R, Wang W, Crofton J T, Share L.
Effects of 17beta-estradiol on sympathetic activity and pressor response to phenylephrine
in ovariectomized rats.
Am J Physiol.
1998;
275
1202-1208
38
Heilmann L, Hojnacki E, Spanuth E.
Hämostase und Präeklampsie.
Geburtshilfe Frauenheilkd.
1991;
51
223-227
39
Hjertberg R, Belfrage P, Hanson U.
Conservative treatment of mild and moderate hypertension in pregnancy.
Acta Obstet Gynecol Scand.
1992;
71
439-446
40
Holzgreve W, Li J J, Steinborn A, Kulz T, Sohn C, Hodel M, Hahn S.
Elevation in erythroblast count in maternal blood before the onset of preeclampsia.
Am J Obstet Gynecol.
2001;
184
165-168
41
Imperiale T F, Petrulis A S.
A meta-analysis of low dose aspirin for the prevention of pregnancy-induced hypertensive
disease.
JAMA.
1991;
266
260-264
42
Janes S L, Kyle P M, Redman C, Goodall A H.
Flow cytometric detection of activated platelets in pregnant women prior to the development
of pre-eclampsia.
Thromb Haemost.
1995;
74
1059-63
43 Klockenbusch W, Löbbecke K. Präventiv-therapeutische Möglichkeiten. In: Klockenbusch
W, Fischer T (Hrsg). Präeklampsie. Uni-Med Verlag, Bremen, London, Boston 2004; 70-76
44
Klockenbusch W, Rath W.
Prävention der Präeklampsie mit Acetylsalicylsäure - eine kritische Analyse.
Z Geburtshilfe Neonatol.
2002;
206
125-130
45
Kupferminc M J, Fait G, Many A, Lessing J B, Yair D, Bar-Am A, Eldor A.
Low-molecular-weight heparin for the prevention of obstetric complications in women
with thrombophilias.
Hypertens Pregnancy.
2001;
20
25-44
46
Lachmeijer A M, Dekker G A, Pals G, Aarnoudse J G, ten Kate L P, Arngrimsson R.
Searching for preeclampsia genes: the current position.
Eur J Obstet Gynecol Reprod Biol.
2002;
105
94-113
47
Lees C, Valensise H, Black R, Harrington K, Byiers S, Romanini C, Campbell S.
The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate
in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind
placebo-controlled trial.
Ultrasound Obstet Gynecol.
1998;
12
334-338
48
Leitich H, Egarter C, Husslein P, Kaider A, Schemper M.
A meta-analysis of low dose aspirin for the prevention of intrauterine growth retardation.
Br J Obstet Gynaecol.
1997;
104
450-459
49
Levine R J, Hauth J C, Curet L B, Sibai B M, Catalano P M, Morris C D, DerSimonian R,
Esterlitz J R, Raymond E G, Bild D E, Clemens J D, Cutler J A.
Trial of calcium to prevent preeclampsia.
N Engl J Med.
1997;
337
69-76
50
Lydakis C, Lip G Y, Beevers M, Beevers D G.
Atenolol and fetal growth in pregnancies complicated by hypertension.
Am J Hypertens.
1999;
12
541-547
51
Magee L A, Schick B, Donnenfeld A E, Sage S R, Conover B, Cook L, McElhatton P R,
Schmidt M A, Koren G.
The safety of calcium channel blockers in human pregnancy: a prospective, multicenter
cohort study.
Am J Obstet Gynecol.
1996;
174
823-828
52
Mahmoud T Z, Bjornsson S, Calder A A.
Labetalol therapy in pregnancy induced hypertension: the effects on fetoplacental
circulation and fetal outcome.
Eur J Obstet Gynecol Reprod Biol.
1993;
50
109-113
53
Martin J N, Perry K G, Miles J F, Blake P G, Magann E F, Roberts W E, Martin R W.
The interrelationship of eclampsia, HELLP syndrome, and prematurity: cofactors for
significant and perinatal risk.
Br J Obstet Gynaecol.
1993;
100
1095-1100
54
Montan S, Anandakumar C, Arulkumaran S, Ingemarsson I, Ratnam S S.
Effects of methyldopa on uteroplacental and fetal hemodynamics in pregnancy-induced
hypertension.
Am J Obstet Gynecol.
1993;
168
152-156
55
Moretti M M, Fairlie F M, Akl S, Khoury A D, Sibai B M.
The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia
remote from term.
Am J Obstet Gynecol.
1990;
163
1844-1848
56
Morrison E R, Miedzybrodzka Z H, Campbell D M, Haites N E, Wilson B J, Watson M S,
Greaves M, Vickers M A.
Prothrombic genotypes are not associated with pre-eclampsia and gestational hypertension:
results from a large poulation-based study and systematic review.
Thromb Haemost.
2002;
87
779-785
57
Nakaki T, Nakayama M, Kato R.
Inhibition by nitric oxide and nitric oxide-producing vasodilators of DNA synthesis
in vascular smooth muscle cells.
Eur J Pharmacol.
1990;
189
347-353
58
Olsen S F, Secher N J, Tabor A, Weber T, Walker J J, Gluud C.
Randomised clinical trials of fish oil supplementation in high risk pregnancies. Fish Oil
Trials In Pregnancy (FOTIP) Team.
BJOG.
2000;
107
382-395
59
Pickles C J, Symonds E M, Broughton Pipkin F.
The fetal outcome in a randomized double-blind controlled trial of labetalol versus
placebo in pregnancy-induced hypertension.
Br J Obstet Gynaecol.
1989;
96
38-43
60
Pirhonen J P, Erkkola R U, Ekblad U U.
Uterine and fetal flow velocity waveforms in hypertensive pregnancy: the effect of
a single dose of nifedipine.
Obstet Gynecol.
1990;
76
37-41
61
Plouin P F, Breart G, Llado J, Dalle M, Keller M E, Goujon H, Berchel C.
A randomized comparison of early with conservative use of antihypertensive drugs in
the management of pregnancy-induced hypertension.
Br J Obstet Gynaecol.
1990;
97
134-141
62
Rey E.
Effects of methyldopa on umbilical and placental artery blood flow velocity waveforms.
Obstet Gynecol.
1992;
80
783-787
63
Redman C W.
Immunological aspects of pre-eclampsia.
Baillieres Clin Obstet Gynaecol.
1992;
6
601-615
64
Redman C W, Roberts J M.
Management of pre-eclampsia.
Lancet.
1993;
341
1451-1454
65
Reubinoff B E, Schenker J G.
HELLP-Syndrome - a syndrome of hemolysis, elevated liver enzymes and low platelet
count - complicating preeclampsia-eclampsia.
Int J Gynaecol Obstet.
1991;
36
95-102
66
Richichi J, Vasilenko P.
The effects of nifedipine on pregnancy outcome and morphology of the placenta, uterus,
and cervix during late pregnancy in the rat.
Am J Obstet Gynecol.
1992;
167
797-803
67
Schlembach D, Beinder E, Zingsem J, Wunsiedler U, Beckmann M W, Fischer T.
Association of maternal and/or fetal factor V Leiden and G20210A prothrombin mutation
with HELLP syndrome and intrauterine growth retardation.
Clin Sci.
2003;
105
279-285
68
Schobel H P, Fischer T, Heuszer K, Geiger H, Schmieder R E.
Preeclampsia - A state of sympathetic overactivity.
N Engl J Med.
1996;
335
1480-1485
69 Schobel H P, Fischer T. The autonomic nervous system in normal and hypertensive
pregnancy. In: Rubin C (Ed). Handbook of Hypertension. Vol. 21. Hypertension in Pregnancy.
2nd ed. 2000; 76-90
70
Sibai B M, Gonzalez A R, Mabie W C, Morretti M.
A comparison of labetalol plus hospitilization versus hospitilization alone in the
management of preeclampsia remote from term.
Obstet Gynecol.
1987;
70
323-327
71
Sibai B M, Mabie W C, Shamsa F, Villar M A, Anderson G D.
A comparison of no medication versus methydopa or labetalol in chronic hypertension
during pregnancy.
Am J Obstet Gynecol.
1990;
162
960-967
72
Sibai B M, Barton J R, Akl S, Sarinoglu C, Mercer B M.
A randomized prospective comparison of nifedipine and bed rest versus bed rest alone
in the management of preeclampsia remote from term.
Am J Obstet Gynecol.
1992;
167
879-884
73 Skrabal F, Kotanko P, Lueger A Goedde B, Balmes R, Barenbrock M, Fischer T. Augmented
reciprocal α-2 and β-2 adrenoceptor changes and rise of total peripheral resistance
during increase of salt intake in salt-sensitive humans. In: Rettig R, Ganten D, Luft
FC (Hrsg). Salt and Hypertension. Springer, Berlin, New York 1989; 128-138
74
Spätling L, Spätling G.
Magnesium supplementation in pregnancy. A double-blind study.
Br J Obstet Gynaecol.
1988;
95
120-125
75
Thaler I, Amit A, Jakobi P, Itskovitz-Eldor J.
The effect of isosorbide dinitrate on uterine artery and umbilical artery flow velocity
waveforms at mid-pregnancy.
Obstet Gynecol.
1996;
88
838-843
76
The Eclampsia Trial Collaborative Group .
Which anticonvulsant for woman with eclampsia? Evidence from the collaborative eclampsia
trial.
Lancet.
1995;
345
1455-1463
77
Altmany D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, Smith D. The Magpie
Trial Collaborative Group .
Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The
Magpie Trial: a randomised placebo-controlled trial.
Lancet.
2002;
359
1877-1890
78
Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J.
Low dose acetylsalicylic acid in prevention of pregnany-induced hypertension and intrauterine
growth retardation in women with bilateral uterine artery notches.
BJOG.
2002;
109
161-167
79
Vetter K, Kilavuz Ö.
Dopplersonographie und Präeklampsie.
Gynakologe.
1999;
32
761-767
80
Dadelszen P von, Ornstein M P, Bull S B, Logan A G, Koren G, Magee L A.
Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension:
a meta-analysis.
Lancet.
2000;
355
87-92
81
Wagner P M, Heyl W, Rath W.
Die Bedeutung von Stickstoffmonoxid in der Pathophysiologie und Therapie der Präeklampsie.
Geburtshilfe Frauenheilkd.
2000;
60
1-10
82
Waismann G D, Mayorga L M, Camera M I, Vignolo C A, Martinotti A.
Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia?.
Am J Obstet Gynecol.
1988;
159
308-309
83
Wallenburg H C.
Prevention of preeclampsia: status and perspectives 2000.
Eur J Obstet Gynecol Reprod Biol.
2001;
94
13-22
84
Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jüpner A, Baur E, Nissen E,
Vetter K, Neichel D, Dudenhausen J W, Haller H, Luft F C.
Patients with preeclampsia develop agonistic autoantibodies against the angiotensin
AT1-receptor.
J Clin Invest.
1999;
103
945-952
85
Wide-Swensson D H, Ingemarsson I, Lunell N O, Forman A, Skajaa K, Lindberg B, Lindeberg S,
Marsal K, Andersson K E.
Calcium channel blockade (isradipine) in treatment of hypertension in pregnancy: a
randomized placebo-controlled study.
Am J Obstet Gynecol.
1995;
173
872-878
86
Zhang J, Klebanoff M A, Levine R J, Puri M, Moyer P.
The puzzling association between smoking and hypertension during pregnancy.
Am J Obstet Gynecol.
1999;
181
1407-1413
Für die Autoren der Projektgruppe Präeklampsie der Technischen Universität München:
Priv.-Doz. Dr. med. Thorsten FischerLtd. Oberarzt und stellvertretender Abteilungsleiter
Perinatalmedizin
Frauenklinik der Technischen Universität München · Klinikum rechts der Isar
Ismaninger Str. 22
81675 München
Telefon: 0 89/41 40/24 30
Fax: 0 89/41 40/24 47