Rezidivierende Spontanaborte: ein Vergleich internationaler Leitlinien

Zusammenfassung

Während etwa 30% aller Frauen in ihrem Leben einen Spontanabort erleben, beträgt die Inzidenz für rezidivierende (habituelle) Spontanaborte 1 – 3% abhängig von der angewandten Definition. Zu den etablierten Risikofaktoren zählen endokrine, anatomische, infektiologische, genetische, hämostaseologische und immunologische Faktoren. Die Diagnostik ist jedoch durch teilweise divergierende Empfehlungen der jeweiligen internationalen Fachgesellschaften erschwert. Der vorliegende Artikel soll daher einen Vergleich der bestehenden internationalen Leitlinienempfehlungen geben. Hierzu werden die Leitlinien der ESHRE, ASRM, der DGGG/OEGGG/SGGG sowie die Empfehlungen des RCOG analysiert. Es zeigt sich, dass eine Abklärung bereits nach 2 klinischen Schwangerschaften indiziert ist und die Diagnostik anhand eines standardisierten Fahrplans erfolgen sollte, der die häufigsten Ursachen für wiederholte Spontanaborte umfasst. Die Leitlinien sind sich einig, dass der Ausschluss anatomischer Malformationen, eines Antiphospholipidsyndroms sowie von Schilddrüsendysfunktionen erfolgen sollte. Darüber hinaus empfehlen die Leitlinien die Durchführung einer Chromosomenanalyse beider Partner präkonzeptionell (oder aus dem Abortmaterial). Andere Risikofaktoren sind zum einen aufgrund fehlender diagnostischer Kriterien (Lutealphaseninsuffizienz), zum anderen aufgrund des unterschiedlichen Alters der Leitlinien (chronische Endometritis) nicht von allen Fachgesellschaften in die Empfehlungen aufgenommen. Zusätzlich haben unterschiedliche gesundheitsökonomische und Konsensusaspekte im Rahmen der Leitlinienerstellung Einfluss auf die einzelnen Empfehlungen. Das Verständnis der zugrunde liegenden Entscheidungsprozesse sollte in der Praxis dazu führen, dass für das jeweilige Paar die individuell beste Diagnostik und die sich daraus ableitende Therapie angeboten wird.

Schlüsselwörter

Abort - Genetik - Infertilität

Publication History

Received: 08 December 2020

Accepted after revision: 01 February 2021

Article published online:
23 April 2021

• References/Literatur

• 1 [Anonymous] 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
• 2 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 doi:10.1016/j.fertnstert.2012.06.048
• 3 Practice Committee of the American Society for Reproductive Medicine. Electronic address aao. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2020; 113: 533-535 doi:10.1016/j.fertnstert.2019.11.025
• 4 Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597 doi:10.1097/01.gco.0000194112.86051.26
• 5 Nybo Andersen AM, Wohlfahrt J, Christens P. et al. Maternal age and fetal loss: population based register linkage study. BMJ 2000; 320: 1708-1712 doi:10.1136/bmj.320.7251.1708
• 6 ESHRE Guideline Group on RPL. Bender Atik R, Christiansen OB. et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018: hoy004 doi:10.1093/hropen/hoy004
• 7 Toth B, Wurfel W, Bohlmann M. et al. Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050). Geburtshilfe Frauenheilkd 2018; 78: 364-381 doi:10.1055/a-0586-4568
• 8 Royal College of Obstetricians & Gynaecologists. The investigation and treatment of Couples with recurrent first-trimester and second-trimester miscarriage. RCOG Green-top Guideline 2011; No 17. . Accessed September 25, 2020 at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf
• 9 De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519-528
• 10 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 doi:10.1136/bmj.38498.669595.8F
• 11 Barber JC, Cockwell AE, Grant E. et al. Is karyotyping couples experiencing recurrent miscarriage worth the cost?. BJOG 2010; 117: 885-888 doi:10.1111/j.1471-0528.2010.02566.x
• 12 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 doi:10.1136/bmj.38735.459144.2F
• 13 Hirshfeld-Cytron J, Sugiura-Ogasawara M, Stephenson MD. Management of recurrent pregnancy loss associated with a parental carrier of a reciprocal translocation: a systematic review. Semin Reprod Med 2011; 29: 470-481 doi:10.1055/s-0031-1293201
• 14 Sugiura-Ogasawara M, Ozaki Y, Katano K. et al. Uterine Anomaly and Recurrent Pregnancy Loss. Semin Reprod Med 2011; 29: 514-521 doi:10.1055/s-0031-1293205
• 15 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 doi:10.1093/humrep/deg030
• 16 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 doi:10.1016/j.fertnstert.2008.07.1768
• 17 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
• 18 Valle RF, Ekpo GE. Hysteroscopic metroplasty for the septate uterus: review and meta-analysis. J Minim Invasive Gynecol 2013; 20: 22-42 doi:10.1016/j.jmig.2012.09.010
• 19 Rikken JFW, Verhorstert KWJ, Emanuel MH. et al. Septum resection in women with a septate uterus: a cohort study. Human Reprod 2020; 35: 1578-1588 doi:10.1093/humrep/dez284
• 20 Bailey AP, Jaslow CR, Kutteh WH. Minimally Invasive Surgical Options for Congenital and Acquired Uterine Factors Associated with Recurrent Pregnancy Loss. Womenʼs Health 2015; 11: 161-167 doi:10.2217/WHE.14.81
• 21 Conforti A, Alviggi C, Mollo A. et al. The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol 2013; 11: 118 doi:10.1186/1477-7827-11-118
• 22 Di Guardo F, Della Corte L, Vilos GA. et al. Evaluation and treatment of infertile women with Asherman syndrome: an updated review focusing on the role of hysteroscopy. Reprod Biomed Online 2020; 41: 55-61 doi:10.1016/j.rbmo.2020.03.021
• 23 Bosteels J, Weyers S. Outpatient treatment for uterine polyps. BMJ 2015; 350: h1469 doi:10.1136/bmj.h1469
• 24 Zhang H, He X, Tian W. et al. Hysteroscopic Resection of Endometrial Polyps and Assisted Reproductive Technology Pregnancy Outcomes Compared with No Treatment: A Systematic Review. J Minim Invasive Gynecol 2019; 26: 618-627 doi:10.1016/j.jmig.2018.10.024
• 25 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 doi:10.3109/14767058.2010.547963
• 26 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 doi:10.1034/j.1600-0897.2002.01105.x
• 27 Ugwumadu A, Manyonda I, Reid F. et al. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003; 361: 983-988 doi:10.1016/S0140-6736(03)12823-1
• 28 McQueen DB, Perfetto CO, Hazard FK. et al. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril 2015; 104: 927-931 doi:10.1016/j.fertnstert.2015.06.044
• 29 Cicinelli E, Matteo M, Tinelli R. et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 2015; 30: 323-330 doi:10.1093/humrep/deu292
• 30 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 doi:10.1016/S0015-0282(02)03247-8
• 31 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 doi:10.1210/jc.2006-1123
• 32 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 doi:10.1093/humrep/den022
• 33 Anselmo J, Cao D, Karrison T. et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292: 691-695 doi:10.1001/jama.292.6.691
• 34 Wang Y, Zhao H, Li Y. et al. Relationship between recurrent miscarriage and insulin resistance. Gynecol Obstet Invest 2011; 72: 245-251 doi:10.1159/000325165
• 35 Triggianese P, Perricone C, Perricone R. et al. Prolactin and natural killer cells: evaluating the neuroendocrine-immune axis in women with primary infertility and recurrent spontaneous abortion. Am J Reprod Immunol 2015; 73: 56-65 doi:10.1111/aji.12335
• 36 Li W, Ma N, Laird SM. et al. The relationship between serum prolactin concentration and pregnancy outcome in women with unexplained recurrent miscarriage. J Obstet Gynaecol 2013; 33: 285-288 doi:10.3109/01443615.2012.759916
• 37 Jordan J, Craig K, Clifton DK. et al. Luteal phase defect: the sensitivity and specificity of diagnostic methods in common clinical use. Fertil Steril 1994; 62: 54-62 doi:10.1016/s0015-0282(16)56815-0
• 38 Vanky E, Stridsklev S, Heimstad R. et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 2010; 95: E448-E455 doi:10.1210/jc.2010-0853
• 39 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 doi:10.1111/ppe.12142
• 40 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: s1-s7 doi:10.1210/jc.2007-0141
• 41 Vissenberg R, Manders VD, Mastenbroek S. et al. Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction. Hum Reprod Update 2015; 21: 378-387 doi:10.1093/humupd/dmv004
• 42 Bernardi LA, Cohen RN, Stephenson MD. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Fertil Steril 2013; 100: 1326-1331 doi:10.1016/j.fertnstert.2013.07.1975
• 43 [Anonym] Erhöhter TSH-Wert in der Hausarztpraxis. S2k-Leitlinie. AWMF-Register-Nr. 053-046 DEGAM-Leitlinie Nr. 18 ed. . Accessed October 19, 2020 at: https://www.awmf.org/leitlinien/detail/ll/053-046.html
• 44 Shah D, Nagarajan N. Luteal insufficiency in first trimester. Indian J Endocrinol Metab 2013; 17: 44-49 doi:10.4103/2230-8210.107834
• 45 Ogasawara M, Kajiura S, Katano K. et al. Are serum progesterone levels predictive of recurrent miscarriage in future pregnancies?. Fertil Steril 1997; 68: 806-809 doi:10.1016/s0015-0282(97)00328-2
• 46 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.e433 doi:10.1016/j.fertnstert.2016.10.031
• 47 Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009; 146: 369-383 doi:10.1111/j.1365-2141.2009.07786.x
• 48 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 doi:10.1371/journal.pmed.1000292
• 49 Arachchillage DRJ, Makris M. Inherited Thrombophilia and Pregnancy Complications: Should We Test?. Semin Thromb Hemost 2019; 45: 50-60 doi:10.1055/s-0038-1657782
• 50 Bohlmann MK. Effects and effectiveness of heparin in assisted reproduction. J Reprod Immunol 2011; 90: 82-90 doi:10.1016/j.jri.2011.03.004
• 51 Clark P, Walker ID, Langhorne P. et al. 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 doi:10.1182/blood-2010-01-267252
• 52 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 doi:10.1056/NEJMoa1000641
• 53 Schleussner E, Kamin G, Seliger G. et al. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med 2015; 162: 601-609 doi:10.7326/M14-2062
• 54 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
• 55 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 doi:10.1160/TH10-05-0334
• 56 Rogenhofer N, Bohlmann MK, Beuter-Winkler P. et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol 2014; 93: 385-392 doi:10.1007/s00277-013-1892-0
• 57 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010; 363: 1740-1747 doi:10.1056/NEJMcp1005330
• 58 Derksen RH, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004; 50: 1028-1039 doi:10.1002/art.20105
• 59 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 doi:10.1111/j.1538-7836.2006.01753.x
• 60 Perricone C, de Carolis C, Perricone R. Pregnancy and autoimmunity: a common problem. Best Pract Res Clin Rheumatol 2012; 26: 47-60 doi:10.1016/j.berh.2012.01.014
• 61 Carp HJ, Shoenfeld Y. Recurrent spontaneous abortions in antiphospholipid syndrome: natural killer cells – an additional mechanism in a multi factorial process. Rheumatology (Oxford) 2007; 46: 1517-1519 doi:10.1093/rheumatology/kem219
• 62 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 doi:10.1007/s10620-008-0242-x
• 63 Tersigni C, Castellani R, de Waure C. et al. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update 2014; 20: 582-593 doi:10.1093/humupd/dmu007
• 64 Hadziselimovic F, Geneto R, Buser M. Celiac disease, pregnancy, small for gestational age: role of extravillous trophoblast. Fetal Pediatr Pathol 2007; 26: 125-134 doi:10.1080/15513810701563637
• 65 Christiansen OB. A fresh look at the causes and treatments of recurrent miscarriage, especially its immunological aspects. Hum Reprod Update 1996; 2: 271-293 doi:10.1093/humupd/2.4.271
• 66 Claus R, Hickstein H, Külz T. et al. Identification and management of fetuses at risk for, or affected by, congenital heart block associated with autoantibodies to SSA (Ro), SSB (La), or an HsEg5-like autoantigen. Rheumatol Int 2006; 26: 886-895 doi:10.1007/s00296-005-0101-4
• 67 Tincani A, Rebaioli CB, Taglietti M. et al. Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus. Rheumatology (Oxford) 2006; 45 (Suppl. 04) iv8-iv13 doi:10.1093/rheumatology/kel308
• 68 Toth B, Vomstein K, Togawa R. et al. The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage. Reprod Biol Endocrinol 2019; 17: 72 doi:10.1186/s12958-019-0514-7
• 69 Kuon RJ, Vomstein K, Weber M. et al. The “killer cell story” in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells. J Reprod Immunol 2017; 119: 9-14 doi:10.1016/j.jri.2016.11.002
• 70 Hamulyák EN, Scheres LJ, Marijnen MC. et al. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev 2020; (05) CD012852
• 71 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 doi:10.1093/humupd/dmz048
• 72 Kolte AM, Westergaard D, Lidegaard O. et al. Chance of live birth: a nationwide, registry-based cohort study. Hum Reprod 2021;
• 73 Bernardi LA, Plunkett BA, Stephenson MD. Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation. Fertil Steril 2012; 98: 156-161 doi:10.1016/j.fertnstert.2012.03.038
• 74 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
• 75 Kitaya K. Prevalence of chronic endometritis in recurrent miscarriages. Fertil Steril 2011; 95: 1156-1158
• 76 Kitaya K, Matsubayashi H, Yamaguchi K. et al. Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications. Am J Reprod Immunol 2016; 75: 13-22