Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050)

Abstract

Purpose Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (ÖGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members.

Methods Based on the current literature, the committee members developed the statements and recommendations of this guideline in a formalized process which included DELPHI rounds and a formal consensus meeting.

Recommendations Recommendations for the diagnosis and treatment of patients with RM were compiled based on the international literature. Specific established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders were taken into consideration.

Key words

recurrent miscarriage - incidence - diagnosis - therapy - recommendations

• References/Literatur

• 1 RCOG. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. In: RCOG Green-top Guideline No 17. Royal College of Obstetricians & Gynaecologists; 2011. Online: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf last access: 24.04.2018
• 2 American College of Obstetricians and Gynecologists. 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 2002; 78: 179-190
• 3 ASRM Practice Committee. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98: 1103-1111
• 4 Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597
• 5 WHO. Recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Modifications recommended by FIGO as amended October 14 1976. Acta Obstet Gynecol Scand 1977; 56: 247-253
• 6 Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90 (5 Suppl.): S60
• 7 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611
• 8 Li TC, Makris M, Tomsu M. et al. Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update 2002; 8: 463-481
• 9 Nybo Andersen AM, Wohlfahrt J, Christens P. et al. Maternal age and fetal loss: population based register linkage study. BMJ 2000; 320: 1708-1712
• 10 Li W, Newell-Price J, Jones GL. et al. Relationship between psychological stress and recurrent miscarriage. Reprod Biomed Online 2012; 25: 180-189
• 11 Kolte AM, Olsen LR, Mikkelsen EM. et al. Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Hum Reprod 2015; 30: 777-782
• 12 Greenwood DC, Alwan N, Boylan S. et al. Caffeine intake during pregnancy, late miscarriage and stillbirth. Eur J Epidemiol 2010; 25: 275-280
• 13 Maconochie N, Doyle P, Prior S. et al. Risk factors for first trimester miscarriage–results from a UK-population-based case-control study. BJOG 2007; 114: 170-186
• 14 Stefanidou EM, Caramellino L, Patriarca A. et al. Maternal caffeine consumption and sine causa recurrent miscarriage. Eur J Obstet Gynecol Reprod Biol 2011; 158: 220-224
• 15 Leung LW, Davies GA. Smoking cessation strategies in pregnancy. J Obstet Gynaecol Can 2015; 37: 791-797
• 16 Zhang BY, Wei YS, Niu JM. et al. Risk factors for unexplained recurrent spontaneous abortion in a population from southern China. Int J Gynaecol Obstet 2010; 108: 135-138
• 17 Wilcox AJ, Weinberg CR, Baird DD. Risk factors for early pregnancy loss. Epidemiology 1990; 1: 382-385
• 18 Venners SA, Wang X, Chen C. et al. Paternal smoking and pregnancy loss: a prospective study using a biomarker of pregnancy. Am J Epidemiol 2004; 159: 993-1001
• 19 Laurino MY, Bennett RL, Saraiya DS. et al. Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors. J Genet Couns 2005; 14: 165-181
• 20 Robberecht C, Pexsters A, Deprest J. et al. Cytogenetic and morphological analysis of early products of conception following hystero-embryoscopy from couples with recurrent pregnancy loss. Prenat Diagn 2012; 32: 933-942
• 21 Goddijn M, Leschot NJ. Genetic aspects of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14: 855-865
• 22 Philipp T, Philipp K, Reiner A. et al. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 2003; 18: 1724-1732
• 23 De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519-528
• 24 Franssen MT, Korevaar JC, Leschot NJ. et al. Selective chromosome analysis in couples with two or more miscarriages: case-control study. BMJ 2005; 331: 137-141
• 25 Franssen MT, Korevaar JC, van der Veen F. et al. Reproductive outcome after chromosome analysis in couples with two or more miscarriages: index [corrected]-control study. BMJ 2006; 332: 759-763
• 26 van den Berg MM, van Maarle MC, van Wely M. et al. Genetics of early miscarriage. Biochim Biophys Acta 2012; 1822: 1951-1959
• 27 Pereza N, Ostojić S, Kapović M. et al. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017; 107: 150-159.e2
• 28 Seckin B, Sarikaya E, Oruc AS. et al. Office hysteroscopic findings in patients with two, three, and four or more, consecutive miscarriages. Eur J Contracept Reprod Health Care 2012; 17: 393-398
• 29 Raga F, Casañ EM, Bonilla-Musoles F. Expression of vascular endothelial growth factor receptors in the endometrium of septate uterus. Fertil Steril 2009; 92: 1085-1090
• 30 Ludwin A, Ludwin I, Banas T. et al. Diagnostic accuracy of sonohysterography, hysterosalpingography and diagnostic hysteroscopy in diagnosis of arcuate, septate and bicornuate uterus. J Obstet Gynaecol Res 2011; 37: 178-186
• 31 Smit JG, Kasius JC, Eijkemans MJ. et al. The international agreement study on the diagnosis of the septate uterus at office hysteroscopy in infertile patients. Fertil Steril 2013; 99: 2108-2113.e2
• 32 Salim R, Regan L, Woelfer B. et al. A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod 2003; 18: 162-166
• 33 Grimbizis GF, Di Spiezio Sardo A, Saravelos SH. et al. The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. Hum Reprod 2016; 31: 2-7
• 34 Sunkara SK, Khairy M, El-Toukhy T. et al. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum Reprod 2010; 25: 418-429
• 35 Saravelos SH, Yan J, Rehmani H. et al. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod 2011; 26: 3274-3279
• 36 Metwally M, Cheong YC, Horne AW. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev 2012; (11) CD003857
• 37 Valle RF, Ekpo GE. Hysteroscopic metroplasty for the septate uterus: review and meta-analysis. J Minim Invasive Gynecol 2013; 20: 22-42
• 38 Rikken JF, Kowalik CR, Emanuel MH. et al. Septum resection for women of reproductive age with a septate uterus. Cochrane Database Syst Rev 2017; (01) CD008576
• 39 Yang JH, Chen MJ, Chen CD. et al. Optimal waiting period for subsequent fertility treatment after various hysteroscopic surgeries. Fertil Steril 2013; 99: 2092-2096.e3
• 40 Sugiura-Ogasawara M, Ozaki Y, Katano K. et al. Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med 2011; 29: 514-521
• 41 Jaslow CR. Uterine factors. Obstet Gynecol Clin North Am 2014; 41: 57-86
• 42 Bailey AP, Jaslow CR, Kutteh WH. Minimally invasive surgical options for congenital and acquired uterine factors associated with recurrent pregnancy loss. Womens Health (Lond) 2015; 11: 161-167
• 43 Conforti A, Alviggi C, Mollo A. et al. The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol 2013; 11: 118
• 44 Bosteels J, Weyers S. Outpatient treatment for uterine polyps. BMJ 2015; 350: h1469
• 45 Johnston-MacAnanny EB, Hartnett J, Engmann LL. et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril 2010; 93: 437-441
• 46 Zolghadri J, Momtahan M, Aminiam K. et al. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 2011; 155: 217-220
• 47 Cicinelli E, Matteo M, Tinelli R. et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci 2014; 21: 640-647
• 48 McQueen DB, Bernardi LA, Stephenson MD. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril 2014; 101: 1026-1030
• 49 Yang R, Du X, Wang Y. et al. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients. Arch Gynecol Obstet 2014; 289: 1363-1369
• 50 Nigro G, Mazzocco M, Mattia E. et al. Role of the infections in recurrent spontaneous abortion. J Matern Fetal Neonatal Med 2011; 24: 983-989
• 51 Ng SC, Gilman-Sachs A, Thaker P. et al. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 2002; 48: 77-86
• 52 Anselmo J, Cao D, Karrison T. et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292: 691-695
• 53 van Dijk MM, Vissenberg R, Bisschop PH. et al. Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?. Reprod Biomed Online 2016; 33: 745-751
• 54 Thangaratinam S, Tan A, Knox E. et al. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 2011; 342: d2616
• 55 Cocksedge KA, Saravelos SH, Wang Q. et al. Does free androgen index predict subsequent pregnancy outcome in women with recurrent miscarriage?. Hum Reprod 2008; 23: 797-802
• 56 Craig LB, Ke RW, Kutteh WH. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril 2002; 78: 487-490
• 57 Tian L, Shen H, Lu Q. et al. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J Clin Endocrinol Metab 2007; 92: 1430-1433
• 58 Melamed N, Hod M. Perinatal mortality in pregestational diabetes. Int J Gynaecol Obstet 2009; 104 (Suppl. 01) S20-S24
• 59 Christiansen OB. Evidence-based investigations and treatments of recurrent pregnancy loss. Curr Opin Obstet Gynecol 2006; 18: 304-312
• 60 Negro R, Schwartz A, Stagnaro-Green A. Impact of levothyroxine in miscarriage and preterm delivery rates in first trimester thyroid antibody-positive women with TSH less than 2.5 mIU/L. J Clin Endocrinol Metab 2016; 101: 3685-3690
• 61 Palomba S, Falbo A, Orio jr. F. et al. Effect of preconceptional metformin on abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2009; 92: 1646-1658
• 62 Hahn KA, Hatch EE, Rothman KJ. et al. Body size and risk of spontaneous abortion among danish pregnancy planners. Paediatr Perinat Epidemiol 2014; 28: 412-423
• 63 Kentenich H, Wischmann T, Stöbel-Richter Y. Hrsg. Fertilitätsstörungen – psychosomatisch orientierte Diagnostik und Therapie. Leitlinie und Quellentext (Revision). Gießen: Psychosozial-Verlag; 2013
• 64 Catherino WH. Stress relief to augment fertility: the pressure mounts. Fertil Steril 2011; 95: 2462-2463
• 65 Kwak-Kim J, Lee SK, Gilman-Sachs A. Elevated Th1/Th2 cell ratios in a pregnant woman with a history of RSA, secondary Sjogrenʼs syndrome and rheumatoid arthritis complicated with one fetal demise of twin pregnancy. Am J Reprod Immunol 2007; 58: 325-329
• 66 Kwak-Kim JY, Chung-Bang HS, Ng SC. et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod 2003; 18: 767-773
• 67 Romagnani P, Annunziato F, Piccinni MP. et al. Th1/Th2 cells, their associated molecules and role in pathophysiology. Eur Cytokine Netw 2000; 11: 510-511
• 68 Piccinni MP, Scaletti G, Vultaggio A. et al. Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. J Reprod Immunol 2001; 52: 35-43
• 69 Yuan J, Li J, Huang SY. et al. Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol 2015; 110: 81-88
• 70 Raghupathy R, Makhseed M, Azizieh F. et al. Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum Reprod 2000; 15: 713-718
• 71 Lee SK, Na BJ, Kim JY. et al. Determination of clinical cellular immune markers in women with recurrent pregnancy loss. Am J Reprod Immunol 2013; 70: 398-411
• 72 Makhseed M, Raghupathy R, Azizieh F. et al. Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod 2001; 16: 2219-2226
• 73 Shimada S, Iwabuchi K, Kato EH. et al. No difference in natural-killer-T cell population, but Th2/Tc2 predominance in peripheral blood of recurrent aborters. Am J Reprod Immunol 2003; 50: 334-339
• 74 Kuon RJ, Müller F, Vomstein K. et al. Pre-pregnancy levels of peripheral natural killer cells as markers for immunomodulatory treatment in patients with recurrent miscarriage. Arch Immunol Ther Exp (Warsz) 2017; 65: 339-346
• 75 Kwak JY, Beaman KD, Gilman-Sachs A. et al. Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol 1995; 34: 93-99
• 76 King K, Smith S, Chapman M. et al. Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage. Hum Reprod 2010; 25: 52-58
• 77 Karami N, Boroujerdnia MG, Nikbakht R. et al. Enhancement of peripheral blood CD56(dim) cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J Reprod Immunol 2012; 95: 87-92
• 78 Kuon RJ, Weber M, Heger J. et al. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol 2017; DOI: 10.1111/aji.12721.
• 79 Gao Y, Wang PL. Increased CD56(+) NK cells and enhanced Th1 responses in human unexplained recurrent spontaneous abortion. Genet Mol Res 2015; 14: 18103-18109
• 80 Kaider AS, Kaider BD, Janowicz PB. et al. Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 1999; 42: 335-346
• 81 Matsubayashi H, Sugi T, Arai T. et al. Different antiphospholipid antibody specificities are found in association with early repeated pregnancy loss versus recurrent IVF-failure patients. Am J Reprod Immunol 2001; 46: 323-329
• 82 Giasuddin AS, Mazhar I, Haq AM. Prevalence of anticardiolipin antibody in Bangladeshi patients with recurrent pregnancy loss. Bangladesh Med Res Counc Bull 2010; 36: 10-13
• 83 Ticconi C, Rotondi F, Veglia M. et al. Antinuclear autoantibodies in women with recurrent pregnancy loss. Am J Reprod Immunol 2010; 64: 384-392
• 84 Molazadeh M, Karimzadeh H, Azizi MR. Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. Iran J Reprod Med 2014; 12: 221-226
• 85 Hefler-Frischmuth K, Walch K, Hefler L. et al. Serologic markers of autoimmunity in women with recurrent pregnancy loss. Am J Reprod Immunol 2017; DOI: 10.1111/aji.12635.
• 86 Bustos D, Moret A, Tambutti M. et al. Autoantibodies in Argentine women with recurrent pregnancy loss. Am J Reprod Immunol 2006; 55: 201-207
• 87 Kumar A, Meena M, Begum N. et al. Latent celiac disease in reproductive performance of women. Fertil Steril 2011; 95: 922-927
• 88 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010; 363: 1740-1747
• 89 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: 295-306
• 90 Gomaa MF, Elkholy AG, El-Said MM. et al. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet 2014; 290: 757-762
• 91 Fawzy M, Shokeir T, El-Tatongy M. et al. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 2008; 278: 33-38
• 92 Tempfer CB, Kurz C, Bentz EK. et al. A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril 2006; 86: 145-148
• 93 Tang AW, Alfirevic Z, Turner MA. et al. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum Reprod 2013; 28: 1743-1752
• 94 Hasbargen U, Reber D, Versmold H. et al. Growth and development of children to 4 years of age after repeated antenatal steroid administration. Eur J Pediatr 2001; 160: 552-555
• 95 Laskin CA, Bombardier C, Hannah ME. et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337: 148-153
• 96 Gur C, Diav-Citrin O, Shechtman S. et al. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004; 18: 93-101
• 97 Stephenson MD, Kutteh WH, Purkiss S. et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 2010; 25: 2203-2209
• 98 Ata B, Tan SL, Shehata F. et al. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril 2011; 95: 1080-5.e1-1080-5.e2
• 99 Ensom MH, Stephenson MD. A two-center study on the pharmacokinetics of intravenous immunoglobulin before and during pregnancy in healthy women with poor obstetrical histories. Hum Reprod 2011; 26: 2283-2288
• 100 Winger EE, Reed JL. Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves live birth rates in women with recurrent spontaneous abortion. Am J Reprod Immunol 2008; 60: 8-16
• 101 Egerup P, Lindschou J, Gluud C. et al. The effects of intravenous immunoglobulins in women with recurrent miscarriages: a systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data. PLoS One 2015; 10: e0141588
• 102 Granato D, Blum S, Rössle C. et al. Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. JPEN J Parenter Enteral Nutr 2000; 24: 113-118
• 103 Roussev RG, Ng SC, Coulam CB. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol 2007; 57: 262-269
• 104 Roussev RG, Acacio B, Ng SC. et al. Duration of intralipidʼs suppressive effect on NK cellʼs functional activity. Am J Reprod Immunol 2008; 60: 258-263
• 105 Roussev RG, Donsʼkoi BV, Stamatkin C. et al. Preimplantation factor inhibits circulating natural killer cell cytotoxicity and reduces CD69 expression: implications for recurrent pregnancy loss therapy. Reprod Biomed Online 2013; 26: 79-87
• 106 Mayer K, Meyer S, Reinholz-Muhly M. et al. Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. J Immunol 2003; 171: 4837-4843
• 107 Coulam CB, Acacio B. Does immunotherapy for treatment of reproductive failure enhance live births?. Am J Reprod Immunol 2012; 67: 296-304
• 108 Moraru M, Carbone J, Alecsandru D. et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol 2012; 68: 75-84
• 109 Meng L, Lin J, Chen L. et al. Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch Gynecol Obstet 2016; 294: 29-39
• 110 Dakhly DM, Bayoumi YA, Sharkawy M. et al. Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels of natural killer cells. Int J Gynaecol Obstet 2016; 135: 324-327
• 111 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006; (02) CD000112
• 112 Cavalcante MB, Sarno M, Araujo Júnior E. et al. Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. Arch Gynecol Obstet 2017; 295: 511-518
• 113 Liu Z, Xu H, Kang X. et al. Allogenic lymphocyte immunotherapy for unexplained recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 2016; 76: 443-453
• 114 Christiansen OB, Mathiesen O, Husth M. et al. Placebo-controlled trial of active immunization with third party leukocytes in recurrent miscarriage. Acta Obstet Gynecol Scand 1994; 73: 261-268
• 115 Illeni MT, Marelli G, Parazzini F. et al. Immunotherapy and recurrent abortion: a randomized clinical trial. Hum Reprod 1994; 9: 1247-1249
• 116 Cauchi MN, Lim D, Young DE. et al. Treatment of recurrent aborters by immunization with paternal cells–controlled trial. Am J Reprod Immunol 1991; 25: 16-17
• 117 Lee BE, Jeon YJ, Shin JE. et al. Tumor necrosis factor-α gene polymorphisms in Korean patients with recurrent spontaneous abortion. Reprod Sci 2013; 20: 408-413
• 118 Rychly DJ, DiPiro JT. Infections associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy 2005; 25: 1181-1192
• 119 Fellermann K. Adverse events of tumor necrosis factor inhibitors. Dig Dis 2013; 31: 374-378
• 120 Tursi A, Giorgetti G, Brandimarte G. et al. Effect of gluten-free diet on pregnancy outcome in celiac disease patients with recurrent miscarriages. Dig Dis Sci 2008; 53: 2925-2928
• 121 Empson M, Lassere M, Craig J. et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; (02) CD002859
• 122 Empson M, Lassere M, Craig JC. et al. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol 2002; 99: 135-144
• 123 Mak A, Cheung MW, Cheak AA. et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 2010; 49: 281-288
• 124 Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol 2010; 115: 1256-1262
• 125 American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 118: antiphospholipid syndrome. Obstet Gynecol 2011; 117: 192-199
• 126 Gardiner C, Hills J, Machin SJ. et al. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 2013; 22: 18-25
• 127 Cohn DM, Goddijn M, Middeldorp S. et al. Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 2010; 8: 2208-2213
• 128 Alijotas-Reig J, Ferrer-Oliveras R. EUROAPS Study Group. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary first year report. Lupus 2012; 21: 766-768
• 129 Mekinian A, Loire-Berson P, Nicaise-Roland P. et al. Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol 2012; 94: 222-226
• 130 Arachchillage DR, Machin SJ, Mackie IJ. et al. Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost 2015; 113: 13-19
• 131 Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009; 146: 369-383
• 132 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 (2 Suppl.): e691S-e736S
• 133 Jauniaux E, Farquharson RG, Christiansen OB. et al. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006; 21: 2216-2222
• 134 Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89: 1603
• 135 Bohlmann MK. Effects and effectiveness of heparin in assisted reproduction. J Reprod Immunol 2011; 90: 82-90
• 136 Bauersachs RM, Dudenhausen J, Faridi A. et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007; 98: 1237-1245
• 137 Clark P, Walker ID, Langhorne P. et al. Scottish Pregnancy Intervention Study (SPIN) collaborators. 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 2010; 115: 4162-4167
• 138 Kaandorp SP, Goddijn M, van der Post JA. et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362: 1586-1596
• 139 Schleussner E, Petroff D. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss. Ann Intern Med 2015; 163: 485
• 140 Rodger MA, Gris JC, de Vries JIP. et al. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 2016; 388: 2629-2641
• 141 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. Hum Reprod Update 2013; 19: 656-673
• 142 Check JH. The use of heparin for preventing miscarriage. Am J Reprod Immunol 2012; 67: 326-333
• 143 Gris JC. LMWH have no place in recurrent pregnancy loss: debate-against the motion. Thromb Res 2011; 127 (Suppl. 03) S110-S112
• 144 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
• 145 Tan WK, Lim SK, Tan LK. et al. Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. Singapore Med J 2012; 53: 659-663
• 146 Rolnik DL, Wright D, Poon LC. et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377: 613-622
• 147 de Jong PG, Kaandorp S, Di Nisio M. et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev 2014; (07) CD004734
• 148 Schisterman EF, Silver RM, Lesher LL. et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet 2014; 384: 29-36
• 149 Liddell HS, Pattison NS, Zanderigo A. Recurrent miscarriage–outcome after supportive care in early pregnancy. Aust N Z J Obstet Gynaecol 1991; 31: 320-322
• 150 Saccone G, Schoen C, Franasiak JM. et al. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials. Fertil Steril 2017; 107: 430-438.e3
• 151 Coomarasamy A, Williams H, Truchanowicz E. et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med 2015; 373: 2141-2148
• 152 Ismail AM, Abbas AM, Ali MK. et al. Peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial. J Matern Fetal Neonatal Med 2018; 31: 388-394
• 153 Scott JR, Pattison N. Human chorionic gonadotrophin for recurrent miscarriage. Cochrane Database Syst Rev 2000; (02) CD000101
• 154 Scarpellini F, Sbracia M. Use of granulocyte colony-stimulating factor for the treatment of unexplained recurrent miscarriage: a randomised controlled trial. Hum Reprod 2009; 24: 2703-2708
• 155 Santjohanser C, Knieper C, Franz C. et al. Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. Arch Immunol Ther Exp (Warsz) 2013; 61: 159-164