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Karoline Mayer-Pickel, MD:

Novel strategies for prevention and therapy of high-risk pregnancies

Department of Obstetrics, Medical University of Graz, Auenbruggerplatz 14, A-8036 Graz;
phone: +43-316-385 83698, fax: +43-316-385 14197, ✉ e-mail
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Keywords:

Inflammation, placenta, pre-eclampsia, autoimmune diseases, antiphospholipid syndrome, systemic lupus erythematosus, management of high-risk pregnancies, anti-inflammatory therapy

Research interest:

Preeclampsia is a leading cause of mortality and morbidity during pregnancy in developed countries and complicates 1 % to 7 % of pregnancies. Different mechanisms have been suggested to explain pre-eclampsia, including thrombosis, vascular and endothelial inflammation, or an imbalance of angiogenic and antiangiogenic placental factors, such as endoglin and soluble fms-like tyrosine kinase 1 (sFlt-1) (1, 2). Even though significant improvement of prevention and management in pregnancy has been achieved, there is still a substantial amount of feto-maternal morbidity and mortality.

Antiphospholipid syndrome (APS) is an autoimmune disease and is characterized by the presence of antiphospholipid antibodies (anticardiolipin antibodie, ACLA; lupus antikoagulans, LA; and anti-β2-glycoprotein) in the maternal circulation.

These antibodies are associated with arterial and / or venous thromboses and with adverse obstetric outcomes such as recurrent fetal loss, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD) and pre-eclampsia (PE) (3). Antiphospholipid antibodies (aPL) activate platelets and endothelial cells, inhibit fibrinolysis and interfere with the protein C pathway in patients with APS. Platelet activation leads to the clinical manifestations of thrombocytopenia and thrombosis (4, 5). In APS, aPL impair placentation, decreases trophoblast proliferation and invasion. Generally, involvement of inflammatory mediators is part of both the etiology and pathophysiology in APS. Activation of the complement system and leucocyte activation are i. a. considered important in the pathophysiology of APS (6, 7, 8).

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease of unknown aetiology with a polymorphic clinical picture characterized by the presence of autoantibodies against a large number of tissue components. Women with SLE are at high risk for complications in pregnancy such as miscarriages, preterm delivery, IUGR, pre-eclampsia and HELLP-syndrome (9, 10, 11). Despite the advances in obstetric and neonatal management, APS and SLE remain associated with significant maternal and fetal morbidity and mortality. In up to 20–30 % of cases, poor obstetric outcomes happen despite treatment (12).

It is known fact that women with APS and SLE are at increased risk of developing pre-eclampsia and / or HELLP-Syndrome. In these pregnancies pre-eclampsia is often severe and might develop very early, even in the second trimester (13).

One of the main problems in pregnancies complicated by pre-eclampsia, especially at early gestation is the lack of effective, especially causative therapeutic options (14). Plasmapheresis has been used successfully in pregnancy for pre-eclampsia, HELLP-syndrome (15, 16) and has been reported being safe during pregnancy (17). The therapeutical background of plasmapheresis in pregnancies with APS is the removal of aPl, as well as the simultaneous removal of pro-inflammatory and pro-coagulatory markers, adhesion molecules, vasopressive factors and atherogenic lipoproteins in order to improve maternal endothelial function, to prevent thrombosis and to increase the placental perfusion with consecutive impaired trophoblast invasiveness and placentation. Plasmapheresis or immunoadsorption as treatment for refractory and high-risk-APS in pregnancy has been described by several authors (18–25).

Statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors) are effective in the long-term prevention of cardiovascular morbidities and mortality, due to their lipid lowering effect, as well as through pleiotropic abilities, such as immune-modulation, anti-inflammation and anti-thrombosis (26). In APS, statins have effects on monocytes, lymphoctes , and endothelial cell activities; all of these might prevent thrombosis in patients with APS: Currently, the use of statins is contraindicated in pregnancy due to putative teratogenic effects, especially when administered in first trimester. However, the majority of fetal malformations are in children exposed to lipophilic statins (simvastatin or fluvastatin) compared to hydrophilic statins, such as pravastatin (27). A review from Morton et. al. could not reveal an increased risk of congenital malformations in fetuses of mothers, who where treated with statins (28).

There is increasing knowledge, that statins might reduce the risk of pre-eclampsia; the beneficial effects seem to be due to vasoprotection; statins are able to reverse the angiogenic imbalance by increasing placental growth factor (PlGF) and decreasing fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) (29, 30). A recent study by Costantine et. al. demonstrated that the daily use of 10 mg pravastatin was not associated with any safety risks in a cohort of 10 women at high risk for pre-eclampsia. Additionally, the authors noted, although not statistically significant, a favorable pregnancy outcome including lower rates of pre-eclampsia, preterm delivery and neonatal admission to NICU as well as improved sFlt-1, PlGF and sEng levels in these women (31). Pravastatin as therapy for pre-eclampsia has also been described in literature. Lefkou et. al. report the successful therapy with pravastatin (20 mg/d) of 11 pregnant women with APS who developed PE despite therapy with heparin and aspirin. The authors noted shortly after beginning of additional therapy an improvement of uterine artery perfusion as well as a normalization of blood pressure and proteinuria (32).

Several other novel i. a. anti-inflammatory medications, such as metformin have been proposed in the management of early-onset pre-eclampsia, especially for prevention (33, 34). It seems that the placental secretion of various anti-angiogenic factors might be decreased and endothelial dysfunction therefore prevented (33, ).

Illustrations:

Fig. 1: Median endothelin-1, ADMA and SDMA levels throughout pregnancy in women with antiphospholipid syndrome, preclampsia, chronic hypertension and normal pregnancies.

References:

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  2. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA: Circulating angiogenic factors and the risk of pre-eclampsia. N Engl J Med, 2004; 350:​672–683.
  3. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost, 2006; 4(2):​295–306.
  4. Carrera-Marín A, Romay-Penabad Z, Papalardo E, Reyes-Maldonado E, García-Latorre E, Vargas G, Shilagard T, Pierangeli S: C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. Lupus, 2012; 21:​1497–505.
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  8. Cavazzana I, Manuela N, Irene C, Barbara A, Sara S, Orietta BM, Angela T, Francesco T, Luigi MP: Complement activation in anti-phospholipid syndrome: a clue for an inflammatory process?. J Autoimmun, 2007; 28:​160–164.
  9. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum, 1982; 25:​1271–1277.
  10. Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthitis Rheum, 1997; 40:​1725.
  11. Baer AN, Witter FR, Petri M: Lupus and pregnancy. Obstet Gynecol Survey, 2011; 66:​639–653.
  12. Alijotas-Reig J: Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus, 2013; 22:​6–17.
  13. Ornaghi S, Paidas MJ: Upcoming drugs for the treatment of pre-eclampsia in pregnant women. Expert Rev Clin Pharmacol, 2014; 7(5):​599&ndassp;603.
  14. Clark EA, Silver RM, Branch DW: Do antiphospholipid antibodies cause pre-eclampsia and HELLP syndrome?. Curr Rheumatol Rep, 2007; 9(3):​219–225.
  15. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC, Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA, Benzing T: Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in pre-eclampsia. Circulation, 2011; 124(8):​940–950.
  16. Wang Y, Walli AK, Schulze A, Blessing F, Fraunberger P, Thaler C, Seidel D, Hasbargen U: Heparin-mediated extracorporeal low density lipoprotein precipitation as a possible therapeutic approach in pre-eclampsia. Transfus Apher Sci, 2006; 35(2):​103–110.
  17. Bosch T: Therapeutic apheresis--state of the art in the year 2005. Ther Apher Dial, 2005; 9:​459–468.
  18. El-Haieg DO, Zanati MF, El-Foual FM: Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome. Int J Gynaecol Obstet, 2007; 99(3):​236–241.
  19. Frampton G, Cameron JS, Thom M, Jones S, Raftery M: Successful removal of anti-phospholipid antibody during pregnancy using plasma exchange and low-dose prednisolone. Lancet, 1987; 2(8566):​1023&ndasp;1024.
  20. Bontadi A, Ruffatti A, Marson P, Tison T, Tonello M, Hoxha A, De Silvestro G, Punzi L: Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome. J Clin Apher, 2012; 27:​200 204.
  21. Bortolati M, Marson P, Chiarelli S, Tison T, Facchinetti M, Gervasi MT, De Silvestro G, Ruffatti A: Case reports of the use of immunoadsorption or plasma exchange in high-risk pregnancies of women with antiphospholipid syndrome. Ther Apher Dial, 2009; 13:​157&ndasp;160.
  22. Ruffatti A, Marson P, Pengo V, Favaro M, Tonello M, Bortolati M, Minucci D, De  Silvestro G: Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature. Autoimmun Rev, 2007; 6(3):​196–202.
  23. Ruffatti A, Favaro M, Hoxha A, Zambon A, Marson P, Del Ross T, Calligaro A, Tonello M, Nardelli GB: Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study. J Reprod Immunol, 2016; 115:​14&ndasp;19.
  24. Ruffatti A, Favaro M, Brucato A, Ramoni V, Facchinetti M, Tonello M, Del͇Ross T, Calligaro A, Hoxha A, Grava C, De Silvestro G: Apheresis in high risk antiphospholipid syndrome pregnancy and autoimmune congenital heart block. Transfus Apher Sci, 2015; 53(3):​269–278.
  25. Bontadi A, Ruffatti A, Marson P, Tison T, Tonello M, Hoxha A, De Silvestro G, Punzi L: Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome. J Clin Apher, 2012; 27:​200‐;204.
  26. Danesh FR, Anel RL, Zeng L, Lomasney J, Sahai A, Kanwar YS: Immunomodulatory effects of HMG-CoA reductase inhibitors. Arch Immunol Ther Exp (Warsz), 2003; 51(3):​139–148 (PubMed).
  27. Lecarpentier E, Morel O, Fournier T, Elefant E, Chavatte-Palmer P, Tsatsaris V: Statins and pregnancy: between supposed risks and theoretical benefits. Drugs, 2012; 72(6):​773–788.
  28. Morton S, Thangaratinam S: Statins in pregnancy. Curr Opin Obstet Gynecol, 2013; 25(6):​433–440.
  29. Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C: Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm, 2012; 18(11):​)1519–1530.
  30. Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Kaitu'u-Lino TJ: Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta. BMC Pregnancy Childbirth, 2016; 16:117.
  31. Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D’Alton M, Hankins G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network: Safety and pharmacokinetics of pravastatin used for the prevention of pre-eclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol, 2016; 214(6):​720.e1–720.e17.
  32. Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G: Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest, 2016; 126(8):​2933–2940.
  33. Ilekis JV, Tsilou E, Fisher S, Abrahams VM, Soares MJ, Cross JC, Zamudio S, Illsley NP, Myatt L, Colvis C, Costantine MM, Haas DM, Sadovsky Y, Weiner C, Rytting E, Bidwell G: Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol, 2016; 215(1 Suppl):​S1–S46.
  34. Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S: Metformin as a prevention and treatment for pre-eclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol, 2016; 214(3):​356.e1–356.e15.

Know-how of the research group:

As one of Austria’s largest obstetric tertiary care centers, the Department of Obstetrics at the Medical University of Graz has a broad expertise for many years in the management of high risk pregnancies, such as pre-eclampsia and certain autoimmune diseases, such as antiphosphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The management contains of an extensive information about the disease and its propable complications during pregancy at early gestation as well a follow-up every 2 to 4 weeks during pregnancy in order to prevent, diagnose and treat certain complications such as pre-eclampsia. A collaboration with other departments (nephrologists, rheumatologists, neonatologists, hematologists etc.) for an additional improved obstetric outcome is an important part of our management.

Scientific concepts and techniques that students will learn in this laboratory:

DP-iDP students will be trained in the management of high-risk-pregnancies. Students will be involved in the research regarding novel strategies for prevention and treatment of several complications during pregnancy, especially anti-inflammatory therapy.

29.05.2018 DP-iDP Doctoral Programme “Inflammatory Disorders in Pregnancy”