Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022)

Abstract

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols.

Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out.

Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

Key words

guideline - recurrent miscarriage - recurrent pregnancy loss - incidence - diagnosis - therapy

Publication History

Received: 28 June 2022

Accepted after revision: 05 July 2022

Article published online:
25 November 2022

• References

• 1 ESHRE Guideline Group on RPL. Bender Atik R, Christiansen OB. et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018: hoy004
• 2 RCOG. The investigation and treatment of Couples with recurrent first-trimester and second-trimester miscarriage. RCOG Green-top Guideline No 17: Royal College of Obstetricians & Gynaecologists; 2011. Accessed August 08, 2022 at: https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/the-investigation-and-treatment-of-couples-with-recurrent-miscarriage-green-top-guideline-no-17
• 3 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
• 4 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98: 1103-1111
• 5 Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597
• 6 WHO. 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
• 7 Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90 (5 Suppl): S60
• 8 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611
• 9 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: 356-367
• 10 Kolte AM, Westergaard D, Lidegaard O. et al. Chance of live birth: a nationwide, registry-based cohort study. Hum Reprod 2021; 36: 1065-1073
• 11 Ng KYB, Cherian G, Kermack AJ. et al. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Sci Rep 2021; 11: 7081
• 12 Rooney KL, Domar A. The relationship between stress and infertility. Dialogues Clin Neurosci 2018; 20: 41-47
• 13 Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract 2018; 47: 432-436
• 14 Leung LW, Davies GA. Smoking Cessation Strategies in Pregnancy. J Obstet Gynaecol Can 2015; 37: 791-797
• 15 Balsells M, Garcia-Patterson A, Corcoy R. Systematic review and meta-analysis on the association of prepregnancy underweight and miscarriage. Eur J Obstet Gynecol Reprod Biol 2016; 207: 73-79
• 16 Boedt T, Vanhove AC, Vercoe MA. et al. Preconception lifestyle advice for people with infertility. Cochrane Database Syst Rev 2021; (04) CD008189
• 17 Best D, Avenell A, Bhattacharya S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Hum Reprod Update 2017; 23: 681-705
• 18 van den Berg MM, van Maarle MC, van Wely M. et al. Genetics of early miscarriage. Biochim Biophys Acta 2012; 1822: 1951-1959
• 19 Zhang T, Sun Y, Chen Z. et al. Traditional and molecular chromosomal abnormality analysis of products of conception in spontaneous and recurrent miscarriage. BJOG 2018; 125: 414-420
• 20 De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519-528
• 21 du Fosse NA, van der Hoorn MP, van Lith JMM. et al. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update 2020; 26: 650-669
• 22 Pereza N, Ostojic S, Kapovic M. et al. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017; 107: 150-159.e2
• 23 Kähler C, Gembruch U, Heling KS. et al. DEGUM. [DEGUM guidelines for amniocentesis and chorionic villus sampling]. Ultraschall Med 2013; 34: 435-440
• 24 Kozlowski P, Burkhardt T, Gembruch U. et al. DEGUM, OGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures. Ultraschall Med 2019; 40: 176-193
• 25 Salomon LJ, Sotiriadis A, Wulff CB. et al. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound Obstet Gynecol 2019; 54: 442-451
• 26 Iews M, Tan J, Taskin O. et al. Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review. Reprod Biomed Online 2018; 36: 677-685
• 27 Franssen MT, Musters AM, van der Veen F. et al. Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review. Hum Reprod Update 2011; 17: 467-475
• 28 Ikuma S, Sato T, Sugiura-Ogasawara M. et al. Preimplantation Genetic Diagnosis and Natural Conception: A Comparison of Live Birth Rates in Patients with Recurrent Pregnancy Loss Associated with Translocation. PLoS One 2015; 10: e0129958
• 29 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
• 30 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
• 31 Sugiura-Ogasawara M, Ozaki Y, Katano K. et al. Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med 2011; 29: 514-521
• 32 Venetis CA, Papadopoulos SP, Campo R. et al. Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies. Reprod Biomed Online 2014; 29: 665-683
• 33 Oppelt P, Binder H, Birraux J. et al. Diagnosis and Therapy of Female Genital Malformations (Part 1). Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/052, May 2019). Geburtshilfe Frauenheilkd 2021; 81: 1307-1328 DOI: 10.1055/a-1471-4781.
• 34 Turocy JM, Rackow BW. Uterine factor in recurrent pregnancy loss. Semin Perinatol 2019; 43: 74-79
• 35 Hooker AB, Lemmers M, Thurkow AL. et al. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update 2014; 20: 262-278
• 36 Hooker AB, Aydin H, Brolmann HA. et al. Long-term complications and reproductive outcome after the management of retained products of conception: a systematic review. Fertil Steril 2016; 105: 156-164.e1-2
• 37 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
• 38 Cicinelli E, Resta L, Nicoletti R. et al. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod 2005; 20: 1386-1389
• 39 Jaslow CR. Uterine factors. Obstet Gynecol Clin North Am 2014; 41: 57-86
• 40 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
• 41 Rikken JFW, Verhorstert KWJ, Emanuel MH. et al. Septum resection in women with a septate uterus: a cohort study. Hum Reprod 2020; 35: 1578-1588
• 42 Rikken JFW, Kowalik CR, Emanuel MH. et al. Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial. Hum Reprod 2021; 36: 1260-1267
• 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 Roy KK, Baruah J, Sharma JB. et al. Reproductive outcome following hysteroscopic adhesiolysis in patients with infertility due to Ashermanʼs syndrome. Arch Gynecol Obstet 2010; 281: 355-361
• 45 Chen L, Zhang H, Wang Q. et al. Reproductive Outcomes in Patients With Intrauterine Adhesions Following Hysteroscopic Adhesiolysis: Experience From the Largest Womenʼs Hospital in China. J Minim Invasive Gynecol 2017; 24: 299-304
• 46 Metwally M, Raybould G, Cheong YC. et al. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev 2020; (01) CD003857
• 47 Bosteels J, van Wessel S, Weyers S. et al. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev 2018; (12) CD009461
• 48 Bosteels J, Weyers S. Outpatient treatment for uterine polyps. BMJ 2015; 350: h1469
• 49 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
• 50 Zolghadri J, Momtahan M, Aminian 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
• 51 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
• 52 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
• 53 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
• 54 Pirtea P, Cicinelli E, De Nola R. et al. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis. Fertil Steril 2021; 115: 546-560
• 55 Haahr T, Jensen JS, Thomsen L. et al. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Hum Reprod 2016; 31: 795-803
• 56 Moreno I, Codoner FM, Vilella F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 2016; 215: 684-703
• 57 Fu M, Zhang X, Liang Y. et al. Alterations in Vaginal Microbiota and Associated Metabolome in Women with Recurrent Implantation Failure. mBio 2020; 11: e03242-19
• 58 Moreno I, Garcia-Grau I, Perez-Villaroya D. et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. medRxiv 2021; DOI: 10.1101/2021.02.05.21251207.
• 59 Kyono K, Hashimoto T, Kikuchi S. et al. A pilot study and case reports on endometrial microbiota and pregnancy outcome: An analysis using 16S rRNA gene sequencing among IVF patients, and trial therapeutic intervention for dysbiotic endometrium. Reprod Med Biol 2019; 18: 72-82
• 60 Cicinelli E, Resta L, Loizzi V. et al. Antibiotic therapy versus no treatment for chronic endometritis: a case-control study. Fertil Steril 2021; 115: 1541-1548
• 61 Song D, He Y, Wang Y. et al. Impact of antibiotic therapy on the rate of negative test results for chronic endometritis: a prospective randomized control trial. Fertil Steril 2021; 115: 1549-1556
• 62 Practice Committee of the American Society for Reproductive Medicine. Current clinical irrelevance of luteal phase deficiency: a committee opinion. Fertil Steril 2015; 103: e27-e32
• 63 DeVilbiss EA, Sjaarda LA, Mumford SL. Routine assessment of ovulation is unlikely to be medically necessary among eumenorrheic women. Fertil Steril 2020; 114: 1187-1188
• 64 Chinta P, Rebekah G, Kunjummen AT. et al. Revisiting the role of serum progesterone as a test of ovulation in eumenorrheic subfertile women: a prospective diagnostic accuracy study. Fertil Steril 2020; 114: 1315-1321
• 65 Akhtar MA, Agrawal R, Brown J. et al. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev 2019; (06) CD011009
• 66 Dhillon-Smith RK, Middleton LJ, Sunner KK. et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med 2019; 380: 1316-1325
• 67 Sarne DH. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med 2019; 381: 190-191
• 68 Schafer-Graf UM, Gembruch U, Kainer F. et al. Gestational Diabetes Mellitus (GDM) – Diagnosis, Treatment and Follow-Up. Guideline of the DDG and DGGG (S3 Level, AWMF Registry Number 057/008, February 2018). Geburtshilfe Frauenheilkd 2018; 78: 1219-1231
• 69 Kentenich H, Wischmann T, Stöbel-Richter Y. Hrsg. Fertilitätsstörungen – psychosomatisch orientierte Diagnostik und Therapie. Leitlinie und Quellentext (Revision). Gießen: Psychosozial-Verlag; 2013
• 70 Catherino WH. Stress relief to augment fertility: the pressure mounts. Fertil Steril 2011; 95: 2462-2463
• 71 Li W, Newell-Price J, Jones GL. et al. Relationship between psychological stress and recurrent miscarriage. Reprod Biomed Online 2012; 25: 180-189
• 72 Schilling K, Toth B, Rosner S. et al. Prevalence of behaviour-related fertility disorders in a clinical sample: results of a pilot study. Arch Gynecol Obstet 2012; 286: 1307-1314
• 73 Läpple M. Streß als Erklärungsmodell für Spontanaborte (SA) und rezidivierende Spontanaborte (RSA). Zentralblatt für Gynäkologie 1988; 110: 325-335
• 74 Rohde A, Dorn A. Gynäkologische Psychosomatik und Gynäkopsychiatrie. Stuttgart: Schattauer; 2007
• 75 El Hachem H, Crepaux V, May-Panloup P. et al. Recurrent pregnancy loss: current perspectives. Int J Womens Health 2017; 9: 331-345
• 76 Farren J, Mitchell-Jones N, Verbakel JY. et al. The psychological impact of early pregnancy loss. Hum Reprod Update 2018; 24: 731-749
• 77 Koert E, Malling GMH, Sylvest R. et al. Recurrent pregnancy loss: couplesʼ perspectives on their need for treatment, support and follow up. Hum Reprod 2019; 34: 291-296
• 78 Musters AM, Koot YE, van den Boogaard NM. et al. Supportive care for women with recurrent miscarriage: a survey to quantify womenʼs preferences. Hum Reprod 2013; 28: 398-405
• 79 Newbatt E, Beckles Z, Ullman R. Guideline Development Group. Ectopic pregnancy and miscarriage: summary of NICE guidance. BMJ 2012; 345: e8136
• 80 Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol 2019; 59: 36-44
• 81 Dimitriadis E, Menkhorst E, Saito S. et al. Recurrent pregnancy loss. Nat Rev Dis Primers 2020; 6: 98
• 82 Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2014; (2014): CD000112
• 83 Odendaal J, Quenby S, Sammaritano L. et al. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?. Fertil Steril 2019; 112: 1002-1012
• 84 Carp H. Immunotherapy for recurrent pregnancy loss. Best Pract Res Clin Obstet Gynaecol 2019; 60: 77-86
• 85 Achilli C, Duran-Retamal M, Saab W. et al. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril 2018; 110: 1089-1100
• 86 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010; 363: 1740-1747
• 87 Vomstein K, Voss P, Molnar K. et al. Two of a kind? Immunological and clinical risk factors differ between recurrent implantation failure and recurrent miscarriage. J Reprod Immunol 2020; 141: 103166
• 88 Branch DW. Whatʼs new in obstetric antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 2019; 2019: 421-425
• 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 Toth B, Baston-Bust DM, Behre HM. et al. Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015–085, February 2019) – Part 1, Basic Assessment of the Woman. Geburtshilfe Frauenheilkd 2019; 79: 1278-1292
• 91 Zhu H, Wang M, Dong Y. et al. Detection of non-criteria autoantibodies in women without apparent causes for pregnancy loss. J Clin Lab Anal 2019; 33: e22994
• 92 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; 2005 (02) CD002859 DOI: 10.1002/14651858.CD002859.pub2.
• 93 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
• 94 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
• 95 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
• 96 ACOG Practice Bulletin No. 118: antiphospholipid syndrome. Obstet Gynecol 2011; 117: 192-199
• 97 Derksen RH, de Groot PG. Clinical consequences of antiphospholipid antibodies. Neth J Med 2004; 62: 273-278
• 98 Gardiner C, Hills J, Machin SJ. et al. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 2013; 22: 18-25
• 99 Cohn DM, Goddijn M, Middeldorp S. et al. Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 2010; 8: 2208-2213
• 100 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
• 101 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
• 102 Arachchillage DR, Machin SJ, Mackie IJ. et al. Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost 2015; 113: 13-19
• 103 Lo HW, Chen CJ, Tsai EM. Pregnancy outcomes for women with non-criteria antiphospholipid syndrome after anticoagulant therapy. Eur J Obstet Gynecol Reprod Biol 2020; 244: 205-207
• 104 Toth B, Vocke F, Rogenhofer N. et al. Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am J Reprod Immunol 2008; 60: 325-332
• 105 Rogenhofer N, Engels L, Bogdanova N. et al. Paternal and maternal carriage of the annexin A5 M2 haplotype are equal risk factors for recurrent pregnancy loss: a pilot study. Fertil Steril 2012; 98: 383-388
• 106 Ormesher L, Simcox LE, Tower C. et al. ‘To test or not to test’, the arguments for and against thrombophilia testing in obstetrics. Obstet Med 2017; 10: 61-66
• 107 Joksic I, Mikovic Z, Filimonovic D. et al. Combined presence of coagulation factor XIII V34 L and plasminogen activator inhibitor 1 4 G/5 G gene polymorphisms significantly contribute to recurrent pregnancy loss in Serbian population. J Med Biochem 2020; 39: 199-207
• 108 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: e13327
• 109 Wang P, Yang H, Wang G. et al. Predictive value of thromboelastography parameters combined with antithrombin III and D-Dimer in patients with recurrent spontaneous abortion. Am J Reprod Immunol 2019; 82: e13165
• 110 Toth B, Jeschke U, Rogenhofer N. et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85: 25-32
• 111 Rodger MA, Betancourt MT, Clark P. et al. 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 2010; 7: e1000292
• 112 Bradley LA, Palomaki GE, Bienstock J. et al. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med 2012; 14: 39-50
• 113 Alecsandru D, Klimczak AM, Garcia Velasco JA. et al. Immunologic causes and thrombophilia in recurrent pregnancy loss. Fertil Steril 2021; 115: 561-566
• 114 Liu X, Chen Y, Ye C. et al. Hereditary thrombophilia and recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod 2021; 36: 1213-1229
• 115 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
• 116 Hamulyak EN, de Jong PG, Scheres LJJ. et al. Progress of the ALIFE2 study: A dynamic road towards more evidence. Thromb Res 2020; 190: 39-44
• 117 Skeith L, Carrier M, Kaaja R. et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127: 1650-1655
• 118 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
• 119 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
• 120 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
• 121 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
• 122 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
• 123 Jeng GT, Scott JR, Burmeister LF. A comparison of meta-analytic results using literature vs. individual patient data. Paternal cell immunization for recurrent miscarriage. JAMA 1995; 274: 830-836
• 124 Devall AJ, Papadopoulou A, Podesek M. et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev 2021; (04) CD013792
• 125 Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev 2019; 2019 (11) CD003511
• 126 Coomarasamy A, Devall AJ, Brosens JJ. et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol 2020; 223: 167-176