Antithrombotic therapy in idiopathic infertility

Submitted: 6 March 2024
Accepted: 24 July 2024
Published: 3 October 2024
Abstract Views: 75
PDF: 60
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Idiopathic infertility is an emerging condition among couples, who face difficulties in accomplishing their family plan, in which no organic cause of reproductive failure can be found. Since 1978 the role of assisted reproductive techniques (ARTs) has been established as the best treatment option with increasing success rate in all-cause infertility couples, but still with some limitations and unfavorable outcomes including idiopathic infertility. Aspirin and heparin are commonly used as adjuvant therapy in women with idiopathic infertility undergoing ARTs, however robust evidence proving the efficacy of this therapeutic approach from purposely designed controlled clinical trials is still lacking. A systematic literature search on the use of antiplatelet and/or antithrombotic therapy in idiopathic infertility was performed in PubMed using infertility, heparin and aspirin as search terms, focusing our attention on clinical trials. Despite some trials had shown a benefit of the administration of heparin or aspirin, in terms of increasing pregnancy and live birth rate in women undergoing ARTs, no routine use of these drugs is recommended as adjuvant therapy for unselected women with idiopathic infertility. Routine use of low dose aspirin and heparin in women undergoing ARTs should be discouraged giving the lack of high-quality evidence and potential harm compared to marginal benefits. Their use can be considered after a comprehensive evaluation of risk-benefit ratio of single individual, deriving from a multidisciplinary approach involving experts in hemostasis. However, large multicenter randomized clinical trials are warranted to validate efficacy and safety of such approach in reproductive medicine

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Vander Borght M, Wyns C. Fertility and infertility: definition and epidemiology. Clin Biochem 2018;62:2-10. DOI: https://doi.org/10.1016/j.clinbiochem.2018.03.012
Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2020;113:533-5. DOI: https://doi.org/10.1016/j.fertnstert.2019.11.025
Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. American Society for Reproductive Medicine. Fertil Steril 2020;113:305-22.
Wyns CDG, Calhaz-Jorge C, Kupka MS, et al. ART in Europe, 2018: results generated from European registries by ESHRE. Hum Reprod Open 2022;1-20.
Szamatowicz M. Assisted reproductive technology in reproductive medicine - Possibilities and limitations. Ginekol Pol 2016;87:820-3. DOI: https://doi.org/10.5603/GP.2016.0095
Griesinger G. Conventional outcome reporting per IVF cycle/embryo transfer may systematically underestimate chances of success for women undergoing ART: relevant biases in registries, epidemiological studies, and guidelines. Hum Reprod Open 2023;2023:hoad018. DOI: https://doi.org/10.1093/hropen/hoad018
Ku DHW, Arkel YS, Paidas MP, Lockwood CJ. Circulating levels of inflammatory cytokines (IL-Iβ and TNF-α), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies. Thromb Haemost 2003;90: 1074-9. DOI: https://doi.org/10.1160/TH03-02-0119
Rajat K. Goswamy, Gillian Williams PCS. Decreased uterine perfusion: a cause of infertility. Hum Reprod 1988;3:955-9. DOI: https://doi.org/10.1093/oxfordjournals.humrep.a136825
Azem F, Many A, Ben Ami I, et al. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod 2004;19:368-70. DOI: https://doi.org/10.1093/humrep/deh069
Behjati R, Modarressi MH, Jeddi-Tehrani M, et al. Thrombophilic mutations in Iranian patients with infertility and recurrent spontaneous abortion. Ann Hematol 2006;85:268-71. DOI: https://doi.org/10.1007/s00277-005-0021-0
Bianca S, Barrano B, Cutuli N, et al. Unexplained infertility and inherited thrombophilia. Fertil Steril 2009;92:e4. DOI: https://doi.org/10.1016/j.fertnstert.2009.02.007
Casadei L, Puca F, Privitera L, et al. Inherited thrombophilia in infertile women: implication in unexplained infertility. Fertil Steril 2010;94:755-7. DOI: https://doi.org/10.1016/j.fertnstert.2009.10.014
Fatini C, Conti L, Turillazzi V, et al. Unexplained infertility: association with inherited thrombophilia. Thromb Res 2012;129:e185-8. DOI: https://doi.org/10.1016/j.thromres.2012.02.012
Grandone E, Colaizzo D, Lo Bue A, et al. Inherited thrombophilia and in vitro fertilization implantation failure. Fertil Steril 2001;76:201-2. DOI: https://doi.org/10.1016/S0015-0282(01)01832-5
Güngör Y, Kayataş M, Yıldız G, et al. The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients. Ren Fail 2011;33:169-75. DOI: https://doi.org/10.3109/0886022X.2011.552151
Mary MJ, Saravanan L, Deecaraman M, et al. Polymorphism of the PAI-1gene (4G/5G) may be linked with Polycystic Ovary Syndrome and associated pregnancy disorders in South Indian Women. Bioinformation 2017;13:149-53. DOI: https://doi.org/10.6026/97320630013149
Qublan HS, Eid SS, Ababneh HA, et al. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 2006;21:2694-8. DOI: https://doi.org/10.1093/humrep/del203
Vaquero E, Lazzarin N, Caserta D, et al. Diagnostic evaluation of women experiencing repeated in vitro fertilization failure. Eur J Obstet Gynecol Reprod Biol 2006;125:79-84. DOI: https://doi.org/10.1016/j.ejogrb.2005.08.001
D’Elia PQ, dos Santos AA, Bianco B, et al. MTHFR polymorphisms C677T and A1298C and associations with IVF outcomes in Brazilian women. Reprod Biomed Online 2014;28:733-8. DOI: https://doi.org/10.1016/j.rbmo.2014.02.005
Deroux A, Dumestre-Perard C, Dunand-Faure C, et al. Female infertility and serum auto-antibodies: a systematic review. Clin Rev Allergy Immunol 2017;53:78-86. DOI: https://doi.org/10.1007/s12016-016-8586-z
Marci R, Lisi F, Soave I, et al. Impact of 677C>T mutation of the 5,10-methylenetetrahydrofolate reductase on IVF outcome: is screening necessary for all infertile women? Genet Test Mol Biomarkers 2012;16:1011-4. DOI: https://doi.org/10.1089/gtmb.2012.0087
Di Nisio M, Rutjes AWS, Ferrante N, et al. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. Blood 2011;118:2670-8. DOI: https://doi.org/10.1182/blood-2011-03-340216
Patounakis G, Bergh E, Forman EJ, et al. Multiple thrombophilic single nucleotide polymorphisms lack a significant effect on outcomes in fresh IVF cycles: an analysis of 1717 patients. J Assist Reprod Genet 2016;33:67-73. DOI: https://doi.org/10.1007/s10815-015-0606-z
Ricci G, Bogatti P, Fischer-Tamaro L, et al. Factor V Leiden and prothrombin gene G20210A mutation and in vitro fertilization: prospective cohort study. Hum Reprod 2011;26: 3068-77. DOI: https://doi.org/10.1093/humrep/der261
Rosen MP, Shen S, McCulloch CE, et al. Methylenetetrahydrofolate reductase (MTHFR) is associated with ovarian follicular activity. Fertil Steril 2007;88:632-8. DOI: https://doi.org/10.1016/j.fertnstert.2006.11.165
Rudick B, Su HI, Sammel MD, et al. Is factor V Leiden mutation a cause of in vitro fertilization failure? Fertil Steril 2009;92:1256-9. DOI: https://doi.org/10.1016/j.fertnstert.2009.03.089
Simopoulou M, Sfakianoudis K, Maziotis E, et al. The impact of autoantibodies on IVF treatment and outcome: a systematic review. Int J Mol Sci 2019;20. DOI: https://doi.org/10.3390/ijms20040892
Steinvil A, Raz R, Berliner S, et al. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Thromb Haemost 2012;108: 1192-7. DOI: https://doi.org/10.1160/TH12-06-0381
Tan X, Yu Z, Sao J, et al. Association between in vitro fertilization outcomes and inherited thrombophilias: a meta-analysis. J Assist Reprod Genet 2016;33:1093-8. DOI: https://doi.org/10.1007/s10815-016-0726-0
ESHRE. Recurrent pregnancy loss. Guideline of the European Society of Human Reproduction and Embryology. European Society of Human Reproduction and Embryology 2022;20:1-153.
Guideline Group on Unexplained Infertility, Romualdi D, Ata B, et al. Evidence-based guideline: unexplained infertility. Hum Reprod 2023;38:1881-90. DOI: https://doi.org/10.1093/humrep/dead150
Grandone E, Tomaiuolo M, Colaizzo D, et al. Role of thrombophilia in adverse obstetric outcomes and their prevention using antithrombotic therapy. Semin Thromb Hemost 2009;35: 630-43. DOI: https://doi.org/10.1055/s-0029-1242717
Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018;2:3317-59. DOI: https://doi.org/10.1182/bloodadvances.2018024802
Martinelli I, Battaglioli T, De Stefano V, et al. The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost 2008;6:494-8. DOI: https://doi.org/10.1111/j.1538-7836.2007.02880.x
Luxembourg B, Henke F, Kirsch-Altena A, et al. Impact of double heterozygosity for Factor V Leiden and prothrombin G20210A on the thrombotic phenotype. Thromb Res 2021; 200:121-7. DOI: https://doi.org/10.1016/j.thromres.2021.01.022
Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342:374-80. DOI: https://doi.org/10.1056/NEJM200002103420602
Biron-Andréani C, Bauters A, Le Cam-Duchez V, et al. Factor V Leiden homozygous genotype and pregnancy outcomes. Obstet Gynecol 2009;114:1249-53. DOI: https://doi.org/10.1097/AOG.0b013e3181c2243d
Kujovich JL. Factor V Leiden thrombophilia. Genet Med 2011;13:1-16. DOI: https://doi.org/10.1097/GIM.0b013e3181faa0f2
Bates SM, Greer A, Middeldorp S, et al. 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 2012;141:e691S-736S. DOI: https://doi.org/10.1378/chest.11-2300
D’Ippolito S, Barbaro G, Paciullo C, et al. Antiphospholipid syndrome in pregnancy: new and old pathogenetic mechanisms. Int J Mol Sci 2023;24. DOI: https://doi.org/10.3390/ijms24043195
ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018;2018:hoy004. DOI: https://doi.org/10.1093/hropen/hoy004
Qublan H, Amarin Z, Dabbas M, et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil 2008;11:246-53. DOI: https://doi.org/10.1080/14647270801995431
Urman B, Ata B, Yakin K, et al. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum Reprod 2009;24:1640-7. DOI: https://doi.org/10.1093/humrep/dep086
Berker B, Taşkin S, Kahraman K, et al. The role of low-molecular-weight heparin in recurrent implantation failure: A prospective, quasi-randomized, controlled study. Fertil Steril 2011;95:2499-502. DOI: https://doi.org/10.1016/j.fertnstert.2010.12.033
Lodigiani C, Dentali F, Banfi E, et al. The effect of parnaparin sodium on in vitro fertilization outcome: A prospective randomized controlled trial. Thromb Res 2017;159:116-21. DOI: https://doi.org/10.1016/j.thromres.2017.08.006
Siristatidis C, Dafopoulos K, Salamalekis G, et al. Administration of low-molecular-weight heparin in patients with two or more unsuccessful IVF/ICSI cycles: a multicenter cohort study. Gynecol Endocrinol 2018;34:747-51. DOI: https://doi.org/10.1080/09513590.2018.1442426
Siristatidis C, Dafopoulos K, El-Khayat W, et al. Administration of prednisolone and low molecular weight heparin in patients with repeated implantation failures: a cohort study. Gynecol Endocrinol 2018;34:136-9. DOI: https://doi.org/10.1080/09513590.2017.1380182
Quenby S, Booth K, Hiller L, et al. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet 2023;6736:1-8. DOI: https://doi.org/10.1097/01.ogx.0001006880.59476.45
Schisterman EF, Silver RM, Perkins NJ, et al. A randomised trial to evaluate the effects of low-dose aspirin in gestation and reproduction: design and baseline characteristics. Paediatr Perinat Epidemiol 2013;598-609. DOI: https://doi.org/10.1111/ppe.12088
Radin RG, Sjaarda LA, Perkins NJ, et al. Low-dose aspirin and sporadic anovulation in the EAGeR randomized trial. J Clin Endocrinol Metab 2017;102:86-92. DOI: https://doi.org/10.1210/jc.2016-2095
Sjaarda LA, Radin RG, Silver RM, et al. Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low-grade inflammation: a secondary analysis of a randomized trial. J Clin Endocrinol Metab 2017;102: 1495-504. DOI: https://doi.org/10.1210/jc.2016-2917
Lok IH, Yip SK, Cheung LP, et al. Adjuvant low-dose aspirin therapy in poor responders undergoing in vitro fertilization: a prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril 2004;81:556-61. DOI: https://doi.org/10.1016/j.fertnstert.2003.07.033
Päkkilä M, Räsänen J, Heinonen S, et al. Low-dose aspirin does not improve ovarian responsiveness or pregnancy rate in IVF and ICSI patients: a randomized, placebo-controlled double-blind study. Hum Reprod 2005;20:2211-4. DOI: https://doi.org/10.1093/humrep/dei020
Urman B, Mercan R, Alatas C, et al. Low-dose aspirin does not increase implantation rates in patients undergoing intracytoplasmic sperm injection: a prospective randomized study. J Assist Reprod Genet 2000;17:586-90. DOI: https://doi.org/10.1023/A:1026491426423
Dirckx K, Cabri P, Merien A, et al. Does low-dose aspirin improve pregnancy rate in IVF/ICSI? A randomized double-blind placebo controlled trial. Hum Reprod 2009;24:856-60. DOI: https://doi.org/10.1093/humrep/den476
Waldenström U, Hellberg D, Nilsson S. Low-dose aspirin in a short regimen as standard treatment in in vitro fertilization: a randomized, prospective study. Fertil Steril 2004;81: 1560-4. DOI: https://doi.org/10.1016/j.fertnstert.2004.02.082
Madani T, Ahmadi F, Jahangiri N, et al. Does low-dose aspirin improve pregnancy rate in women undergoing frozen-thawed embryo transfer cycle? A pilot double-blind, randomized placebo-controlled trial. J Obstet Gynaecol Res 2019;45:156-63. DOI: https://doi.org/10.1111/jog.13802
Weckstein LN, Jacobson A, Galen D, et al. Low-dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study. Fertil Steril 1997;68:927-30. DOI: https://doi.org/10.1016/S0015-0282(97)00330-0
Hsieh YY, Tsai HD, Chang CC, et al. Gynecology: low-dose aspirin for infertile women with thin endometrium receiving intraeuterine insemination: a prospective, randomized study. J Assist Reprod Genet 2000;17:174-7. DOI: https://doi.org/10.1023/A:1009474307376
Rubinstein M, Marazzi A, Polak de Fried E. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertil Steril 1999;71:825-9. DOI: https://doi.org/10.1016/S0015-0282(99)00088-6
Wada I, Hsu CC, Williams G, et al. Pregnancy: the benefits of low-dose aspirin therapy in women with impaired uterine perfusion during assisted conception. Hum Reprod 1994;9:1954-7. DOI: https://doi.org/10.1093/oxfordjournals.humrep.a138366
Davar R, Pourmasumi S, Mohammadi B, Lahijani MM. The effect of low-dose aspirin on the pregnancy rate in frozen-thawed embryo transfer cycles: a randomized clinical trial. Int J Reprod Biomed 2020;18:693-700 DOI: https://doi.org/10.18502/ijrm.v13i9.7664
Kuo HC, Hsu CC, Wang ST, Huang KE. Aspirin improves uterine blood flow in the peri-implantation period. J Formos Med Assoc 1997;96:253-7.
Muñoz EM, Linhardt RJ. Heparin-binding domains in vascular biology. Arterioscler Thromb Vasc Biol 2004;24:1549-57. DOI: https://doi.org/10.1161/01.ATV.0000137189.22999.3f
Akhtar MA, Sur S, Raine-Fenning N, et al. Heparin for assisted reproduction. Cochrane Datab Syst Rev 2013;2013:8. DOI: https://doi.org/10.1002/14651858.CD009452.pub2
Bates SM. Anticoagulation and in vitro fertilization and ovarian stimulation. Hematology (United States) 2014;2014:379-86. DOI: https://doi.org/10.1182/asheducation-2014.1.379
Carson DD, DeSouza MM, Regisford EGC. Mucin and proteoglycan functions in embryo implantation. BioEssays 1998;20:577-83. DOI: https://doi.org/10.1002/(SICI)1521-1878(199807)20:7<577::AID-BIES9>3.0.CO;2-H
Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401-7. DOI: https://doi.org/10.1182/blood-2005-02-0626
Grandone E, Di Micco PP, Villani M, et al. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE registry. Thromb Haemost 2018;118:1962-8. DOI: https://doi.org/10.1055/s-0038-1673402
Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update 2008;14:623-45. DOI: https://doi.org/10.1093/humupd/dmn031
Lodigiani C, Di Micco P, Ferrazzi P, et al. Low-molecular-weight heparin in women with repeated implantation failure. Women’s Health 2011;7:425-31. DOI: https://doi.org/10.2217/WHE.11.38
Siristatidis C, Chrelias C, Creatsa M, et al. Addition of prednisolone and heparin in patients with failed IVF/ICSI cycles: A preliminary report of a clinical trial. Hum Fertil 2013;16:207-10. DOI: https://doi.org/10.3109/14647273.2013.803608
Kaaja R, Julkunen H, Viinikka L, Ylikorkala O. Production of prostacyclin and thromboxane in lupus pregnancies: effect of small dose of aspirin. Obstet Gynecol 1993;81. DOI: https://doi.org/10.1016/0020-7292(93)90340-3
Abdalla HI, Brooks AA, Johnson MR, et al. Endometrial thickness: a predictor of implantation in ovum recipients? Hum Reprod 1994;9:363-5. DOI: https://doi.org/10.1093/oxfordjournals.humrep.a138509
Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791-8. DOI: https://doi.org/10.1016/S0140-6736(07)60712-0
Duley L, Henderson Smart DJ, Meher S KJ. Antiplatelet agents for preventing pre eclampsia and its complications. Cochrane Datab Syst Rev 2007;2. DOI: https://doi.org/10.1002/14651858.CD004659.pub2
Duvan CI, Ozmen B, Satıroglu H, et al. Does addition of low-dose aspirin and/or steroid as a standard treatment in nonselected intracytoplasmic sperm injection cycles improve in vitro fertilization success? A randomized, prospective, placebo-controlled study. J Assist Reprod Genet 2006;23:15-21. DOI: https://doi.org/10.1007/s10815-005-9003-3
Akhtar MA, Eljabu H, Hopkisson J, et al. Aspirin and heparin as adjuvants during IVF do not improve live birth rates in unexplained implantation failure. Reprod Biomed Online 2013;26:586-94. DOI: https://doi.org/10.1016/j.rbmo.2013.02.007
Kaandorp SP, Goddijn M, van der Post JAM, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. New Engl J Med 2010;362:1586-96. DOI: https://doi.org/10.1056/NEJMoa1000641

How to Cite

Tumminello, F., Cardi, S., Lodigiani, C., & Mancuso, M. E. (2024). Antithrombotic therapy in idiopathic infertility. Bleeding, Thrombosis and Vascular Biology, 3(3). https://doi.org/10.4081/btvb.2024.126