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DOI: 10.1055/s-0035-1558299
Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG (S1-Level, AWMF Registry No. 015/050, December 2013)
Diagnostik und Therapie beim wiederholten Spontanabort. Leitlinie der DGGG (S1-Level, AWMF-Registernummer 015/050, Dezember 2013)Publication History
Publication Date:
14 December 2015 (online)
![](https://www.thieme-connect.de/media/gebfra/201511/lookinside/thumbnails/10-1055-s-0035-1558299_gf984-1.jpg)
Abstract
Purpose: Official guideline coordinated and published by the German Society of Gynecology and Obstetrics (DGGG). Aim of the guideline was to standardize the diagnosis and treatment of patients with recurrent miscarriage (RM). Recommendations were proposed, based on the current national and international literature and the experience of the involved physicians. Consistent definitions, objective assessments and standardized therapy were applied. Methods: Members of the different involved societies developed a consensus in an informal process based on the current literature. The consensus was subsequently approved by the heads of the scientific societies. Recommendations: Recommendations for the diagnosis and treatment of patients with RM were compiled which took the importance of established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders into consideration.
Zusammenfassung
Ziel: Offizielle Leitlinie, koordiniert und publiziert von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG). Ziel der Leitlinie war es, die Diagnostik und Therapie des wiederholten Spontanaborts (WSA) anhand der aktuellen (inter-)nationalen Literatur sowie der Erfahrung der beteiligten Kolleginnen und Kollegen evidenzbasiert zu standardisieren. Dies erfolgte unter Verwendung einheitlicher Definitionen, objektiver Bewertungsmöglichkeiten und standardisierter Therapieprotokolle. Methoden: Anhand der internationalen Literatur entwickelten die Mitglieder der beteiligten Fachgesellschaften in einem informellen Prozess einen Konsensus. Anschließend wurde dieser durch die Vorsitzenden der Fachgesellschaften bestätigt. Empfehlungen: Es wurden Empfehlungen zur Diagnostik und Therapie bei Patientinnen mit WSA anhand der internationalen Literatur erarbeitet. Insbesondere wurde auf die bekannten Risikofaktoren wie chromosomale, anatomische, endokrinologische, gerinnungsphysiologische, psychologische, infektiologische und immunologische Störungen eingegangen.
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References
- 1 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
- 2 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
- 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. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89: 1603
- 5 Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597
- 6 Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89: 1603
- 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 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
- 11 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
- 12 Ogasawara M, Aoki K, Okada S et al. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000; 73: 300-304
- 13 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
- 14 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
- 15 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010; 363: 1740-1747
- 16 Meza-Espinoza JP, Anguiano LO, Rivera H. Chromosomal abnormalities in couples with reproductive disorders. Gynecol Obstet Invest 2008; 66: 237-240
- 17 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
- 18 Sugiura-Ogasawara M, Ozaki Y, Katano K et al. Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med 2011; 29: 514-521
- 19 Raga F, Casan EM, Bonilla-Musoles F. Expression of vascular endothelial growth factor receptors in the endometrium of septate uterus. Fertil Steril 2009; 92: 1085-1090
- 20 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
- 21 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
- 22 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
- 23 Hay PE, Lamont RF, Taylor-Robinson D et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994; 308: 295-298
- 24 Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2007; 21: 375-390
- 25 Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 1999; 319: 220-223
- 26 Hirsch D, Levy S, Nadler V et al. Pregnancy outcomes in women with severe hypothyroidism. Eur J Endocrinol 2013; 169: 313-320
- 27 Abalovich M, Amino N, Barbour LA et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007; 92 (8 Suppl.) S1-S47
- 28 Negro R, Schwartz A, Gismondi R et al. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95: E44-E48
- 29 Benhadi N, Wiersinga WM, Reitsma JB et al. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160: 985-991
- 30 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
- 31 Metwally M, Saravelos SH, Ledger WL et al. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril 2010; 94: 290-295
- 32 Boots C, Stephenson MD. Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review. Semin Reprod Med 2011; 29: 507-513
- 33 Kentenich H, Brähler E, Kowalcek I et al., Hrsg. Fertilitätsstörungen – psychosomatisch orientierte Diagnostik und Therapie. Leitlinie und Quellentext (Revision). Gießen: Psychosozial-Verlag; 2013
- 34 Catherino WH. Stress relief to augment fertility: the pressure mounts. Fertil Steril 2011; 95: 2462-2463
- 35 Li W, Newell-Price J, Jones GL et al. Relationship between psychological stress and recurrent miscarriage. Reprod Biomed Online 2012; 25: 180-189
- 36 Schilling K, Toth B, Rösner 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
- 37 Läpple M. Streß als Erklärungsmodell für Spontanaborte (SA) und rezidivierende Spontanaborte (RSA). Zentralblatt für Gynäkologie 1988; 110: 325-335
- 38 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
- 39 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
- 40 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
- 41 Kwak-Kim J, Park JC, Ahn HK et al. Immunological modes of pregnancy loss. Am J Reprod Immunol 2010; 63: 611-623
- 42 Lash GE, Bulmer JN. Do uterine natural killer (uNK) cells contribute to female reproductive disorders?. J Reprod Immunol 2011; 88: 156-164
- 43 Hiby SE, Regan L, Lo W et al. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod 2008; 23: 972-976
- 44 Stagnaro-Green A, Roman SH, Cobin RH et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264: 1422-1425
- 45 Muller AF, Berghout A, Wiersinga WM et al. working group Thyroid Function Disorders of the Netherlands Association of Internal Medicine. Thyroid function disorders—Guidelines of the Netherlands Association of Internal Medicine. Neth J Med 2008; 66: 134-142
- 46 De Groot L, Abalovich M, Alexander EK et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2543-2565
- 47 Kurien BT, Scofield RH. Autoantibody determination in the diagnosis of systemic lupus erythematosus. Scand J Immunol 2006; 64: 227-235
- 48 Kumar A, Meena M, Begum N et al. Latent celiac disease in reproductive performance of women. Fertil Steril 2011; 95: 922-927
- 49 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
- 50 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
- 51 Toth B, Jeschke U, Rogenhofer N et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85: 25-32
- 52 Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009; 146: 369-383
- 53 Baumann K, Beuter-Winkler P, Hackethal A et al. 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 2013; 70: 518-521
- 54 Dizon-Townson D, Miller C, Sibai B et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005; 106: 517-524
- 55 Silver RM, Zhao Y, Spong CY et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 2010; 115: 14-20
- 56 Rai R, Backos M, Elgaddal S et al. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum Reprod 2002; 17: 442-445
- 57 Jivraj S, Makris M, Saravelos S et al. Pregnancy outcome in women with factor V Leiden and recurrent miscarriage. BJOG 2009; 116: 995-998
- 58 Bates SM, Greer IA, Middeldorp S et al. American College of Chest Physicians. 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-736S
- 59 Kowalik CR, Goddijn M, Emanuel MH et al. Metroplasty versus expectant management for women with recurrent miscarriage and a septate uterus. Cochrane Database Syst Rev 2011; (6) CD008576
- 60 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
- 61 Brix N, Secher NJ, McCormack CD et al. CERVO group. Randomised trial of cervical cerclage, with and without occlusion, for the prevention of preterm birth in women suspected for cervical insufficiency. BJOG 2013; 120: 613-620
- 62 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
- 63 Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 1984; 148: 140-146
- 64 Stray-Pedersen B, Stray-Pedersen S. Recurrent Abortion: the Role of Psychotherapy. In: Beard R, Sharp F, eds. Early Pregnancy Loss. Mechanisms and Treatment. London, Berlin, Heidelberg: Springer-Verlag; 1988: 433-440
- 65 ASRM Practice Committee. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98: 1103-1111
- 66 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
- 67 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
- 68 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
- 69 Coulam CB, Acacio B. Does immunotherapy for treatment of reproductive failure enhance live births?. Am J Reprod Immunol 2012; 67: 296-304
- 70 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
- 71 Ata B, Tan SL, Shehata F et al. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril 2011; 95: 1080-1085.e1-2
- 72 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
- 73 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
- 74 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006; (2) CD000112
- 75 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
- 76 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
- 77 Rychly DJ, DiPiro JT. Infections associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy 2005; 25: 1181-1192
- 78 Fellermann K. Adverse events of tumor necrosis factor inhibitors. Dig Dis 2013; 31: 374-378
- 79 Bernardi LA, Cohen RN, Stephenson MD. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Fertil Steril 2013; 100: 1326-1331
- 80 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
- 81 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; (2) CD002859
- 82 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
- 83 Brenner B, Hoffman R, Blumenfeld Z et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697
- 84 Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost 2003; 1: 433-438
- 85 Gris JC, Mercier E, Quéré I et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 3695-3699
- 86 Brenner B, Hoffman R, Carp H et al. LIVE-ENOX Investigators. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 3: 227-229
- 87 Dolitzky M, Inbal A, Segal Y et al. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86: 362-366
- 88 Badawy AM, Khiary M, Sherif LS et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28: 280-284
- 89 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
- 90 Laskin CA, Spitzer KA, Clark CA et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009; 36: 279-287
- 91 Visser J, Ulander VM, Helmerhorst FM et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost 2011; 105: 295-301
- 92 Monien S, Kadecki O, Baumgarten S et al. Use of heparin in women with early and late miscarriages with and without thrombophilia. Clin Appl Thromb Hemost 2009; 15: 636-644
- 93 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
- 94 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
- 95 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. Hum Reprod Update 2013; 19: 656-673
- 96 Check JH. The use of heparin for preventing miscarriage. Am J Reprod Immunol 2012; 67: 326-333
- 97 Gris JC. LMWH have no place in recurrent pregnancy loss: debate-against the motion. Thromb Res 2011; 127 (Suppl. 03) S110-S112
- 98 Ogasawara MS, Iinuma Y, Aoki K et al. Low-dose aspirin is effective for treatment of recurrent miscarriage in patients with decreased coagulation factor XII. Fertil Steril 2001; 76: 203-204
- 99 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
- 100 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
- 101 NICE. Ectopic Pregnancy and Miscarriage: Diagnosis and initial Management in early Pregnancy of ectopic Pregnancy and Miscarriage. London: National Collaborating Centre for Womenʼs and Childrenʼs Health; 2012
- 102 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