Preeclampsia – Aetiology, Current Diagnostics and Clinical Management, New Therapy Options and Future Perspectives

 

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Abstract

Preeclampsia is a multisystem disease for which the exact causes have not yet been sufficiently clarified. However, in the past few years it has become clear that a placental imbalance between angiogenic and anti-angiogenic proteins is the decisive pathogenetic factor for the occurrence of preeclampsia. With the possibility to measure these angiogenic factors (sFlt-1/PlGF ratio) in maternal blood full new diagnostic possibilities have been opened that enable the certain diagnosis or exclusion of the diseases as well as a short-term prognosis to be made. In secondary prevention the current data situation for ASA confirms a moderate but measurable utility. The management concept depends on gestational age. In the case of early clinical manifestations (< 34th week of pregnancy) the clinical management in a perinatal centre remains unchanged with foeto-maternal monitoring and induction of pulmonary maturation, symptomatic therapy under careful blood pressure lowering and determination of the optimal delivery time. A balance must be made here between foetal immaturity and maternal risks upon prolongations. The pathomechanism of anti-angiogenic overload with sFlt-1 provides a starting point for first therapeutic interventions. The present article gives an overview of current diagnostic options and presents possible future therapeutic perspectives for discussion.

Zusammenfassung

Die Präeklampsie ist eine Multisystemerkrankung, deren genaue Ursache noch nicht hinreichend geklärt ist. Allerdings ist in den letzten Jahren klar geworden, dass ein plazentares Ungleichgewicht zwischen angiogenen und antiangiogenen Proteinen der entscheidende pathogenetische Faktor für die Entstehung der Präeklampsie ist. Mit der Möglichkeit der Messung dieser angiogenen Faktoren (sFlt-1/PlGF-Quotient) im maternalen Blut ergeben sich völlig neue diagnostische Möglichkeiten, die die sichere Diagnose bzw. den Ausschluss der Erkrankung und darüber hinaus eine Kurzzeitprognose ermöglichen. In der Sekundärprävention belegt die Datenlage für ASS einen moderaten, aber doch messbaren Nutzen. Das Betreuungskonzept ist abhängig vom Gestationsalter. Bei früher klinischer Manifestation (< 34. SSW) ist das klinische Management im Perinatalzentrum unverändert die fetomaternale Überwachung mit Induktion der Lungenreife, symptomatischer Therapie unter vorsichtiger Blutdrucksenkung und Festlegung des optimalen Entbindungszeitpunkts. Abgewogen werden muss hierbei die fetale Unreife gegen die fetalen und maternalen Risiken bei Prolongation. Der Pathomechanismus des antiangiogenen Overloads mit sFlt-1 liefert einen Ansatz für erste therapeutische Interventionen. Der vorliegende Beitrag gibt einen Überblick in die aktuellen diagnostischen Möglichkeiten und stellt eventuelle Therapieaussichten in der Zukunft zur Diskussion.

• References

• 1 Walker JJ. Pre-eclampsia. Lancet 2000; 356: 1260-1265
  CrossrefPubMedGoogle Scholar
• 2 Bolte AC, van Geijn HP, Dekker GA. Management and monitoring of severe preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001; 96: 8-20
  CrossrefPubMedGoogle Scholar
• 3 Goldenberg RL, Culhane JF, Iams JD et al. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75-84
  CrossrefPubMedGoogle Scholar
• 4 Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001; 357: 2002-2006
  CrossrefPubMedGoogle Scholar
• 5 Garovic VD, Hayman SR. Hypertension in pregnancy: an emerging risk factor for cardiovascular disease. Nat Clin Pract Nephrol 2007; 3: 613-622
  CrossrefPubMedGoogle Scholar
• 6 Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 2008; 51: 970-975
  CrossrefPubMedGoogle Scholar
• 7 Huppertz B. Placental pathology in pregnancy complications. Thromb Res 2011; 127 (Suppl. 03) S96-S99
  CrossrefPubMedGoogle Scholar
• 8 Roberts JM, Taylor RN, Musci TJ et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161: 1200-1204
  CrossrefPubMedGoogle Scholar
• 9 Levine RJ, Maynard SE, Qian C et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672-683
  CrossrefPubMedGoogle Scholar
• 10 Staff AC, Braekke K, Harsem NK et al. Circulating concentrations of sFlt1/Soluble fms-like tyrosine kinase 1 in fetal and maternal serum during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2005; 122: 33-39
  CrossrefPubMedGoogle Scholar
• 11 Chaiworapongsa T, Romero R, Kim YM et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 2005; 17: 3-18
  CrossrefPubMedGoogle Scholar
• 12 Hladunewich M, Ananth Karumanchi S, Lafayette R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2007; 2: 543-549
  CrossrefPubMedGoogle Scholar
• 13 Osmanagaoglu MA, Karahan SC, Aran T et al. Predictive value of plasma total carnitine, arginine, asymmetric dimethylarginine and ischemia-modified albumin levels and their combined use in the early detection of preeclampsia. Geburtsh Frauenheilk 2011; 71: 773-778
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Milne F, Redman C, Walker J et al. PRECOG II Group. Assessing the onset of pre-eclampsia in the hospital day unit: summary of the pre-eclampsia guideline (PRECOG II). BMJ 2009; 339: b3129
  CrossrefPubMedGoogle Scholar
• 15 Stepan H, Schaarschmidt W, Jank A et al. Angiogene Faktoren zur Diagnosesicherung bei Präeklampsie in der klinischen Routine: erste Erfahrungen. Z Geb Neonatol 2010; 214: 234-238
  PubMedGoogle Scholar
• 16 Verlohren S, Herraiz I, Lapaire O et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2012; 206: 58.e1-58.e8
  CrossrefPubMedGoogle Scholar
• 17 Rana S, Hacker MR, Modest AM et al. Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia. Hypertension 2012; 60: 451-458
  CrossrefPubMedGoogle Scholar
• 18 Poon LC, Maiz N, Valencia C et al. First-trimester maternal serum pregnancy-associated plasma protein-A and pre-eclampsia. Ultrasound Obstet Gynecol 2009; 33: 23-33
  CrossrefPubMedGoogle Scholar
• 19 Lapaire O, Shennan A, Stepan H. The preeclampsia biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor: current knowledge, clinical implications and future application. Eur J Obstet Gynecol Reprod Biol 2010; 151: 122-129
  CrossrefPubMedGoogle Scholar
• 20 Akolekar R, Syngelaki A, Sarquis R et al. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11–13 weeks. Prenat Diagn 2011; 31: 66-74
  CrossrefPubMedGoogle Scholar
• 21 Rath W, Fischer T, Klockenbusch W. Diagnostik und Therapie hypertensiver Schwangerschaftserkrankungen. Leitlinie der Arbeitsgemeinschaft Schwangerschaftshochdruck/Gestose der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e.V. (DGGG), AWMF-Leitlinien-Register Nr. 015/018, letzte Aktualisierung 05/2008.
  PubMedGoogle Scholar
• 22 Panchal S, Arria AM, Harris AP. Intensive care utilization during hospital admission for delivery: prevalence, risk factors, and outcomes in a statewide population. Anesthesiology 2000; 92: 1537-1544
  CrossrefPubMedGoogle Scholar
• 23 Abalos E, Duley L, Steyn DW et al. Antihypertensive drug therapy for mild to moderate hypertension in pregnancy. Cochrane Database Syst Rev 2007; (1) CD002252
  PubMedGoogle Scholar
• 24 Ferrer RL, Sibai BM, Multrow CD et al. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000; 96: 849-860
  CrossrefPubMedGoogle Scholar
• 25 Helewa ME, Burrows RF, Smith J et al. Report of the Canadian Hypertension Society consensus conference: 1. Definitions, evaluations and classification of hypertensive disorders in pregnancy. CMAJ 1997; 157: 715
  PubMedGoogle Scholar
• 26 Lucas MJ, Leveno KJ, Cunnningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201
  CrossrefPubMedGoogle Scholar
• 27 Schott M, Henkelmann A, Meinkoehn Y et al. Postpartale Eklampsie und fulminantes HELLP-Syndrom. Anaesthesist 2011; 60: 343-351
  CrossrefPubMedGoogle Scholar
• 28 Woudstra DM, Chandra S, Hofmeyr GJ et al. Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database Syst Rev 2010; (9) CD008148
  PubMedGoogle Scholar
• 29 Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes and low platelet count. Obstet Gynecol 2004; 103: 981
  CrossrefPubMedGoogle Scholar
• 30 Klockenbusch W, Fischer T. Präeklampsie. Kapitel 8: Medikamentöse Therapie. Bremen: Uni-Med; 2005: 76-80
  Google Scholar
• 31 Duley L, Henderson-Smart DJ, Meher S et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007; (2) CD004659
  PubMedGoogle Scholar
• 32 Bujold E, Roberge S, Lacasse Y et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1) 402-414
  CrossrefPubMedGoogle Scholar
• 33 Rey E, Garneau P, David M et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 45: 86
  PubMedGoogle Scholar
• 34 Kupferminc MJ, Rimon E, Many A et al. Low molecular weight heparin treatment during subsequent pregnancies of women with inherited thrombophilia and previous severe pregnancy complications. J Matern Fetal Neonatal Med 2011; 24: 1042-1045
  CrossrefPubMedGoogle Scholar
• 35 Martinelli I, Ruggenenti P, Cetin I et al. HAPPY Study Group. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood 2012; 119: 3269-3275
  CrossrefPubMedGoogle Scholar
• 36 Thadhani R, Kisner T, Hagmann H et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011; 124: 940-950
  CrossrefPubMedGoogle Scholar
• 37 McCarthy FP, Drewlo S, English FA et al. Evidence implicating peroxisome proliferator-activated receptor-γ in the pathogenesis of preeclampsia. Hypertension 2011; 58: 882-887
  CrossrefPubMedGoogle Scholar
• 38 McCarthy FP, Drewlo S, Kingdom J et al. Peroxisome proliferator-activated receptor-γ as a potential therapeutic target in the treatment of preeclampsia. Hypertension 2011; 58: 280-286
  CrossrefPubMedGoogle Scholar
• 39 Elsen C, Rivas-Echeverría C, Sahland K et al. Vitamins E, A and B₂ as possible risk factors for preeclampsia – under consideration of the PROPER study (“Prevention of preeclampsia by high-dose riboflavin supplementation”). Geburtsh Frauenheilk 2012; 72: 846-852
  Article in Thieme ConnectPubMedGoogle Scholar

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