Skip to main content
SpringerLink
Log in

Gerinnungsabklärung und Therapie bei habituellen Aborten und wiederholtem Implantationsversagen

Coagulation diagnostics and treatment for recurrent pregnancy loss and implantation failure

  • Leitthema
  • Published:
Gynäkologische Endokrinologie Aims and scope

Zusammenfassung

Rezidivierende habituelle Spontanaborte betreffen etwa 1–3 % aller Partnerschaften. Neben genetischen, endokrinen, anatomischen, autoimmunen und infektiösen Ursachen wurden in der Vergangenheit auch thrombophile Faktoren im Kontext der Pathogenese dieses Krankheitsbilds diskutiert. In Analogie hierzu wird unter dem Begriff des rezidivierenden Implantationsversagens die Konstellation verstanden, dass es im Rahmen einer Behandlung mit In-vitro-Fertilisation bzw. intrazytoplasmatischer Spermieninjektion nach mehreren Embryonentransfers zu keinem Schwangerschaftseintritt gekommen ist. Auch für diese Konstellation wurden mütterliche Thrombophilien verantwortlich gemacht. Die vorliegende Übersichtsarbeit stellt die aktuelle Datenlage zur Diagnostik und Therapie beider Entitäten dar.

Abstract

Recurrent spontaneous abortions (RSA) affect 1%–3% of all couples. In addition to genetic, endocrine, anatomical, autoimmune and infectious causes, maternal thrombophilia has been discussed as a risk factor for this disease. Like RSA, recurrent implantation failure (RIF) is understood as a constellation in which no pregnancy occurs after several embryo transfers in the course of multiple in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) cycles. RIF has also been attributed to maternal thrombophilia. This review article summarizes the current data on diagnosis and treatment of both diseases with regard to maternal thrombophilia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. ESHRE Early Pregnancy Guideline Development Group (2017) Recurrent pregnancy loss

    Google Scholar 

  2. Royal College of Obstetricians and Gynaecologists (2011) The investigation and treatment of couples with recurrent first-trimester ans second-trimester miscarriage. Green-top guideline No. 17

    Google Scholar 

  3. American College of Obestetricians and Gynecologists (2002) ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin Number 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 78:179–190

    Article  Google Scholar 

  4. Toth B, Jeschke U, Rogenhofer N, Scholz C, Wurfel W, Thaler CJ, Makrigiannakis A (2010) Recurrent miscarriage: Current concepts in diagnosis and treatment. J Reprod Immunol 85:25–32

    Article  CAS  PubMed  Google Scholar 

  5. Roberts LN, Patel RK, Arya R (2009) Venous thromboembolism and ethnicity. Br J Haematol 146:369–383

    Article  PubMed  Google Scholar 

  6. Bates SM et al (2012) VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(Suppl 2):e691S–e736S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Markoff A, Bogdanova N, Samama MM (2011) Hereditary thrombophilic risk factors for recurrent pregnancy loss. Hereditary Genet 1:103

    Google Scholar 

  8. Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ (2003) Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod 18:2473–2477

    Article  CAS  PubMed  Google Scholar 

  9. College of American Pathologists Consensus Conference XXXVI (2002) Diagnostic Issues in Thrombophilia. Arch Pathol Lab Med 126(11):1277–433

    Google Scholar 

  10. Rey E et al (2003) Thrombophilic disorders and fetal loss: A meta-analysis. Lancet 361:901–908

    Article  PubMed  Google Scholar 

  11. Rodger MA, Betancourt MT, Clark P, Lindqvist PG, Dizon-Townson D, Said J, Seligsohn U, Carrier M, Salomon O, Greer IA (2010) The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: A systematic review and meta-analysis of prospective cohort studies. PLoS Med 7:e1000292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Silver RM et al (2010) Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 115:14–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pihusch R, Buchholz T, Lohse P, Rübsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ (2001) Thrombophilic gene mutations and recurrent spontaneous abortion: Prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 46:124–131

    Article  CAS  PubMed  Google Scholar 

  14. Bouter A, Gounou C, Bérat R, Tan S, Gallois B, Granier T, d’Estaintot BL, Pöschl E, Brachvogel B, Brisson AR (2011) Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair. Nat Commun 2:270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chinni E, Tiscia GL, Colaizzo D, Vergura P, Margaglione M, Grandone E (2010) Annexin V expression in human placenta is influenced by the carriage of the common haplotype M2. Fertil Steril 91:940–942

    Article  CAS  Google Scholar 

  16. Shu F, Sugimura M, Kanayama N, Kobayashi H, Kobayashi T, Terao T (2000) Immunohistochemical study of annexin V expression in placentae of preeclampsia. Gynecol Obstet Invest 49:17–23

    Article  CAS  PubMed  Google Scholar 

  17. Sifakis S, Soufla G, Koukoura O et al (2010) Decreased annexin A5 mRNA placental expression in pregnancies complicated by fetal growth restriction. Thromb Res 125:326–331

    Article  CAS  PubMed  Google Scholar 

  18. Bogdanova N, Horst J, Chlystun M, Croucher PJ, Nebel A, Bohring A, Todorova A, Schreiber S, Gerke V, Krawczak M, Markoff A (2007) A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet 16:573–578

    Article  CAS  PubMed  Google Scholar 

  19. Rogenhofer N, Engels L, Bogdanova N, Tüttelmann F, Markoff A, Thaler C (2012) Paternal and maternal carriage of the annexin A5 M2 haplotype are equal risk factors for recurrent pregnancy loss: A pilot study. Fertil Steril 98:383–388

    Article  CAS  PubMed  Google Scholar 

  20. Baumann K, Beuter-Winkler P, Hackethal A, Strowitzki T, Toth B, Bohlmann MK (2013) Maternal factor V Leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in Caucasian patients. Am J Reprod Immunol 70:518–521

    Article  CAS  PubMed  Google Scholar 

  21. Practice Committee of the American Society for Reproductive Medicine (2008) Definitions of infertility and recurrent pregnancy loss. Fertil Steril 89:1603

    Article  Google Scholar 

  22. Toth B, Würfel W, Bohlmann M, Zschocke J, Rudnik-Schöneborn S, Nawroth F, Schleußner E, Rogenhofer N, Wischmann T, von Wolff M, Hancke K, von Otte S, Kuon R, Feil K, Tempfer C (2018) Recurrent miscarriage: Diagnostic and therapeutic procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-level, AWMF registry number 015/050). Geburtshilfe Frauenheilkd 78:364–381

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sarig G et al (2005) Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss. Thromb Haemost 94:980–985

    Article  CAS  PubMed  Google Scholar 

  24. Clark P et al (2010) SPIN (Scottish Pregnancy Intervention) study: A multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 115:4162–4167

    Article  CAS  PubMed  Google Scholar 

  25. Kaandorp SP et al (2010) Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 362:1586–1596

    Article  CAS  PubMed  Google Scholar 

  26. Rogenhofer N, Schleussner E, Kamin G, Seeliger G, Toth B (2013) No benefit of low molecular weight heparin in recurrent pregnancy loss—Results of the ETHIG II study. Hum Reprod 28(Suppl 1):i4–i6

    Article  Google Scholar 

  27. Schleussner E, Kamin G, Seliger G, Rogenhofer N, Ebner S, Toth B, Schenk M, Henes M, Bohlmann MK, Fischer T, Brosteanu O, Bauersachs R, Petroff D (2015) Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: A multicenter trial with a minimization randomization scheme. Ann Intern Med 162:601–609

    Article  PubMed  Google Scholar 

  28. Tan WK et al (2012) Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. Singapore Med J 53:659–663

    PubMed  Google Scholar 

  29. Visser J et al (2011) Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: A randomised multicentre trial. Thromb Haemost 105:295–301

    Article  CAS  PubMed  Google Scholar 

  30. Mantha S, Bauer KA, Zwicker JI (2010) Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review. J Thromb Haemost 8(2):263–8

    Article  CAS  PubMed  Google Scholar 

  31. Bohlmann MK (2011) Effects and effectiveness of heparin in assisted reproduction. J Reprod Immunol 90:82–90

    Article  CAS  PubMed  Google Scholar 

  32. American College of Obstetricians and Gynecologists (2013) ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol 122:706–717

    Article  Google Scholar 

  33. Rogenhofer N, Bohlmann MK, Beuter-Winkler P, Würfel W, Rank A, Thaler CJ, Toth B (2014) Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol 93:385–392

    Article  CAS  PubMed  Google Scholar 

  34. Bauersachs RM et al (2007) Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 98:1237–1245

    Article  CAS  PubMed  Google Scholar 

  35. Gris JC (2011) LMWH have no place in recurrent pregnancy loss: Debate – Against the motion. Thromb Res 127(Suppl 3):S110–S112

    Article  CAS  PubMed  Google Scholar 

  36. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S (2014) Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev 7:CD4734

    Google Scholar 

  37. Check JH (2012) The use of heparin for preventing miscarriage. Am J Reprod Immunol 67:326–333

    Article  CAS  PubMed  Google Scholar 

  38. Bashiri A, Halper KI, Orvieto R (2018) Recurrent implantation failure-update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol 16:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeyneloglu HB, Onalan G (2014) Remedies for recurrent implantation failure. Semin Reprod Med 32:297–305

    Article  PubMed  Google Scholar 

  40. Nelson SM, Greer IA (2008) The potential role of heparin in assisted conception. Hum Reprod Update 14:623–645

    Article  CAS  PubMed  Google Scholar 

  41. Sharif KW, Ghunaim S (2010) Management of 273 cases of recurrent implantation failure: Results of a combined evidence-based protocol. Reprod Biomed Online 21:373–380

    Article  CAS  PubMed  Google Scholar 

  42. Coulam CB, Jeyendran RS, Fishel LA, Roussev R (2006) Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online 12:322–327

    Article  PubMed  Google Scholar 

  43. Ata B, Urman B (2016) Thrombophilia and assisted reproduction technology-any detrimental impact or unnecessary overuse? J Assist Reprod Genet 33:1305–1310

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lodigiani C, di Micco P, Ferrazzi P, Libre L, Arfuso V, Polatti F, Benigna M, Rossini R, Morenghi E, Rota L, Brenner B, Setti PE (2011) Low-molecular-weight heparin in women with repeated implantation failure. Womens Health 7:425–431

    CAS  Google Scholar 

  45. Potdar N, Gelbaya TA, Konje JC, Nardo LG (2013) Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: A systematic review and meta-analysis. Hum Reprod Update 19:674–684

    Article  CAS  PubMed  Google Scholar 

  46. Qublan H, Amarin Z, Dabbas M, Farraj AE, Beni-Merei Z, Al-Akash H, Bdoor AN, Nawasreh M, Malkawi S, Diab F et al (2008) Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: A prospective randomized placebo-controlled trial. Hum Fertil 11:246–253

    Article  CAS  Google Scholar 

  47. Berker B, Taskin S, Kahraman K, Taskin EA, Atabekoglu C, Sonmezer M (2011) The role of low-molecular-weight heparin in recurrent implantation failure: A prospective, quasi-randomized, controlled study. Fertil Steril 95:2499–2502

    Article  CAS  PubMed  Google Scholar 

  48. Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R, Balaban B (2009) Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: A randomized open-labeled pilot trial. Hum Reprod 24:1640–1647

    Article  CAS  PubMed  Google Scholar 

  49. Nardo LG, El-Toukhy T, Stewart J, Balen AH, Potdar N (2015) British Fertility Society Policy and Practice Committee: Adjuvants in IVF: Evidence for good clinical practice. Hum Fertil (Camb) 18:2–15

    Article  CAS  Google Scholar 

  50. Simcox LE, Ormesher L, Tower C, Greer IA (2015) Thrombophilia and pregnancy complications. Int J Mol Sci 16:28418–28428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Siristatidis C, Dafopoulos K, El-Khayat W, Salamalekis G, Anifandis G, Vrantza T, Elsadek M, Papantoniou N (2018) Administration of prednisolone and low molecular weight heparin in patients with repeated implantation failures: A cohort study. Gynecol Endocrinol 34:136–139

    Article  CAS  PubMed  Google Scholar 

  52. Hamdi K, Danaii S, Farzadi L, Abdollahi S, Chalabizadeh A, Abdollahi Sabet S (2015) The role of heparin in embryo implantation in women with recurrent implantation failure in the cycles of assisted reproductive techniques (without history of thrombophilia). J Family Reprod Health 9:59–64

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, LMU München, München, Deutschland

    Nina Rogenhofer

  2. Frauenklinik, St. Elisabethen-Krankenhaus Lörrach, Feldbergstraße 15, 79539, Lörrach, Deutschland

    Michael K. Bohlmann

Authors
  1. Nina Rogenhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael K. Bohlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael K. Bohlmann.

Ethics declarations

Interessenkonflikt

N. Rogenhofer und M.K. Bohlmann geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

B. Imthurn, Zürich

B. Toth, Innsbruck

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rogenhofer, N., Bohlmann, M.K. Gerinnungsabklärung und Therapie bei habituellen Aborten und wiederholtem Implantationsversagen. Gynäkologische Endokrinologie 17, 148–153 (2019). https://doi.org/10.1007/s10304-019-0261-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10304-019-0261-z

Schlüsselwörter

Keywords

Search

Navigation