Thrombophilia, Inflammation, and Recurrent Pregnancy Loss: A Case-Based Review

Abstract

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies and is often multifactorial with the majority of miscarriages being due to aneuploidy and anatomic or physiological abnormalities. However, inherited or acquired thrombophilias have also been associated with RPL, albeit inconsistently. While inherited thrombophilias, such as factor V Leiden and prothrombin gene mutation, are relatively prevalent in women with RPL compared with the general population, a causal link has yet to be definitively established. Recently, systemic inflammation, as measured by high-sensitivity C-reactive protein, has also been hypothesized to play a role in infertility. Based on limited prospective trial data, antithrombotic therapy and antiplatelet agents have been proposed as possible tools for the prevention of RPL. Because of the multifactorial nature of RPL and infertility, various clinicians, as obstetricians and gynecologists, endocrinologists, hematologists, or vascular medicine specialists, may be requested to counsel these women. This, together with evidence gaps, frequently leads to distinctly different diagnostic and therapeutic recommendations, especially regarding thrombophilia testing and treatment. Using four case vignettes in this review, we critically appraise the literature and highlight how two clinicians from different subspecialties approach the relationship between RPL, inflammation, and thrombophilia.

Keywords

antithrombotic therapy - anticoagulation - recurrent pregnancy loss - thrombophilia - thrombosis

Support

None.

Publikationsverlauf

Artikel online veröffentlicht:
02. Juli 2021

• References

• 1 van Dijk MM, Kolte AM, Limpens J. et al. Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update 2020; 26 (03) 356-367
• 2 Carroll BJ, Piazza G. Hypercoagulable states in arterial and venous thrombosis: When, how, and who to test?. Vasc Med 2018; 23 (04) 388-399
• 3 Piazza G. Thrombophilia testing, recurrent thrombosis, and women's health. Circulation 2014; 130 (03) 283-287
• 4 Lussana F, Dentali F, Abbate R. et al; Italian Society for Haemostasis and Thrombosis. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009; 124 (05) e19-e25
• 5 Schisterman EF, Silver RM, Lesher LL. et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet 2014; 384 (9937): 29-36
• 6 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 (05) 1495-1504
• 7 Korteweg FJ, Bouman K, Erwich JJ. et al. Cytogenetic analysis after evaluation of 750 fetal deaths: proposal for diagnostic workup. Obstet Gynecol 2008; 111 (04) 865-874
• 8 Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 2004; 164 (05) 558-563
• 9 Robertson L, Wu O, Langhorne P. et al; Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132 (02) 171-196
• 10 Arachchillage DRJ, Makris M. Inherited thrombophilia and pregnancy complications: should we test?. Semin Thromb Hemost 2019; 45 (01) 50-60
• 11 de Ziegler D, Frydman RF. Recurrent pregnancy losses, a lasting cause of infertility. Fertil Steril 2021; 115 (03) 531-532
• 12 Baglin T, Gray E, Greaves M. et al; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149 (02) 209-220
• 13 The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green-Top Guideline 2011; 17: 1-18
• 14 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 2011; 13 (01) 67-76
• 15 Bates SM, Greer IA, 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-e736S
• 16 Bender Atik R, Christiansen OB, Elson J. et al; ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018 (02) hoy004
• 17 Villani M, Baldini D, Totaro P. et al. Rationale and design of two prospective, multicenter, observational studies on reproductive outcome in women with recurrent failures after spontaneous or assisted conception: OTTILIA and FIRST registries. BMC Pregnancy Childbirth 2019; 19 (01) 292
• 18 de Jong PG, Quenby S, Bloemenkamp KW. et al. ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia–study protocol for a randomized controlled trial. Trials 2015; 16: 208
• 19 Vomstein K, Herzog A, Voss P. et al. Recurrent miscarriage is not associated with a higher prevalence of inherited and acquired thrombophilia. Am J Reprod Immunol 2021; 85 (01) e13327
• 20 Chan WS. The ‘ART’ of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol 2009; 21 (03) 207-218
• 21 Grandone E, Di Micco PP, Villani M. et al; RIETE Investigators. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE Registry. Thromb Haemost 2018; 118 (11) 1962-1968
• 22 Piazza G. Oh heavy burden: recognizing the risk of venous thromboembolism in women undergoing assisted reproduction. Thromb Haemost 2018; 118 (12) 2011-2013
• 23 Petrilli CM, Heidemann L, Mack M, Durance P, Chopra V. Inpatient inherited thrombophilia testing. J Hosp Med 2016; 11 (11) 801-804
• 24 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
• 25 Hamulyák EN, Scheres LJJ, Goddijn M, Middeldorp S. Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome - What is the evidence?. J Thromb Haemost 2021; 19 (05) 1174-1185
• 26 Lodigiani C, Di Micco P, Ferrazzi P. et al. Low-molecular-weight heparin in women with repeated implantation failure. Womens Health (Lond) 2011; 7 (04) 425-431
• 27 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 (Camb) 2008; 11 (04) 246-253
• 28 Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev 2021; 3: CD001689
• 29 Harlin J, Aanesen A, Csemiczky G, Wramsby H, Fried G. Delivery rates following IVF treatment, using two recombinant FSH preparations for ovarian stimulation. Hum Reprod 2002; 17 (02) 304-309
• 30 Dentali F, Grandone E, Rezoagli E, Ageno W. Efficacy of low molecular weight heparin in patients undergoing in vitro fertilization or intracytoplasmic sperm injection. J Thromb Haemost 2011; 9 (12) 2503-2506
• 31 Akhtar MA, Sur S, Raine-Fenning N, Jayaprakasan K, Thornton JG, Quenby S. Heparin for assisted reproduction. Cochrane Database Syst Rev 2013; (08) CD009452
• 32 Dentali F, Ageno W, Rezoagli E. et al. Low-dose aspirin for in vitro fertilization or intracytoplasmic sperm injection: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2012; 10 (10) 2075-2085
• 33 Grandone E, Villani M, Tiscia GL. et al. Clinical utility of antithrombotic prophylaxis in ART procedures: an Italian experience. PLoS One 2014; 9 (05) e97604
• 34 Fukui A, Funamizu A, Fukuhara R, Shibahara H. Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss. J Obstet Gynaecol Res 2017; 43 (11) 1678-1686
• 35 Brouillet S, Boursier G, Anav M. et al. C-reactive protein and ART outcomes: a systematic review. Hum Reprod Update 2020; 26 (05) 753-773
• 36 Jauniaux E, Gulbis B, Jamil A, Jurkovic D. Evaluation of the role of maternal serum high-sensitivity C-reactive protein in predicting early pregnancy failure. Reprod Biomed Online 2015; 30 (03) 268-274
• 37 Memtsa M, Jurkovic D, Jauniaux E. Royal College of Obstetricians and Gynaecologists. Diagnostic biomarkers for predicting adverse early pregnancy outcomes: scientific impact paper no. 58. BJOG 2019; 126 (03) e107-e113
• 38 Ivanov P, Tsvyatkovska T, Konova E, Komsa-Penkova R. Inherited thrombophilia and IVF failure: the impact of coagulation disorders on implantation process. Am J Reprod Immunol 2012; 68 (03) 189-198
• 39 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98 (05) 1103-1111