Zusammenfassung
Etwa 1–3 % aller Paare mit Kinderwunsch erleiden wiederholte Fehlgeburten. Aufgrund des steigenden mütterlichen Alters bei der ersten Schwangerschaft, insbesondere in Westeuropa, gibt es eine zunehmende Tendenz, bereits Frauen mit 2 Fehlgeburten einer ausführlichen Diagnostik zu unterziehen, obwohl die WHO mindestens 3 aufeinanderfolgende Aborte als rezidivierendes Abortgeschehen definiert. Dabei sollte eine sinnvolle Abklärung primär alle relevanten Abortursachen umfassen, gleichzeitig aber auch kosteneffektiv sein sowie zu evidenzbasierten, therapeutischen Konsequenzen führen. Dies ist insbesondere vor dem Hintergrund der Fülle der vorliegenden aktuellen Daten und möglichen Therapieoptionen von entscheidender Bedeutung. Experimentelle therapeutische Ansätze sollten nur unter Studienbedingungen erprobt werden.
Abstract
About 1–3 % of all couples suffer recurrent miscarriages during their childbearing years. Due to the increase in maternal age at the first pregnancy, especially in Western Europe, there is a tendency to carry an extensive diagnostic work-up after two miscarriages, although the WHO definition of recurrent miscarriage defines it as three or more consecutive pregnancy losses. Causal clarification should primarily focus on possible risk factors for miscarriages while being cost-effective and leading to promising therapeutic consequences. In view of the large number of studies and therapeutic options, an evidence-based concept for diagnostic and therapeutic guidelines on recurrent miscarriages is essential. New treatment strategies need to be confirmed in large randomized placebo-controlled trials.
Schlüsselwörter
habituelle Aborte - evidenzbasierte Diagnostik - Therapie
Key words
recurrent miscarriages - evidence‐based diagnostic - treatment strategies
Literatur
1
Bohlmann M K, Schauf B, Luedders D W et al.
Aktuelles zur rationellen Diagnostik und Therapie habitueller Frühaborte.
Geburtsh Frauenheilk.
2007;
67
217-227
2
Stirrat G M.
Recurrent miscarriage.
Lancet.
1990;
336
673-675
3
Franssen M T, Korevaar J C, Leschot N J et al.
Selective chromosome analysis in couple with two or more miscarriages: case-control study.
BMJ.
2005;
331
137-141
4
Hinney B.
Habituelle Abortneigung.
Gynäkologe.
2007;
40
113-127
5
Goldenberg M, Sivan E, Sharabi Z et al.
Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions.
Hum Reprod.
1995;
10
2663-2665
6
Hickok L R.
Hysteroscopic treatment of the uterine septum: a clinician's experience.
Am J Obstet Gynecol.
2000;
182
1414-1420
7
Li T C, Makris M, Tomsu M et al.
Recurrent miscarriage: aetiology, management and prognosis.
Human Reprod Update.
2002;
8
463-481
8
Hornemann A, Luedders D W, Kumbartski M et al.
Anatomische Ursachen habitueller Aborte.
Gynäkologe.
2009;
42
11-16
9
Plesinac S, Plecas D, Babovic I.
Influence of uterine myomas on course and outcome of pregnancy.
Geburtsh Frauenheilk.
2006;
66
674-676
10
Steck T, Bussen S, Marzusch K.
Strategien zur Abortprophylaxe bei einer Vorgeschichte mit wiederholten Aborten. II. Infektionen, metabolische und endokrine Störungen, Schadstoffe und Gerinnungsdefekte.
Fertilität.
1997;
13
17-26
11
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
12
Abalovich M, Gutierrez S, Alcaraz G et al.
Overt and subclinical hypothyroidism complicating pregnancy.
Thyroid.
2002;
12
63-68
13
Negro R, Formoso G, Mangieri T et al.
Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.
J Clin Endocrinol Metab.
2006;
91
2587-2591
14
Oates-Whitehead R M, Haas D M, Carrier J A.
Progestogen for preventing miscarriage.
Cochrane Database Syst Rev.
2003;
(4)
CD003511
15
Daya S.
Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials.
Br J Obstet Gynaecol.
1989;
96
275-280
16
Nardo L G, Sallam H N.
Progesterone supplementation to prevent recurrent miscarriage and to reduce implantation failure in assisted reproduction cycles.
Reprod Biomed Online.
2006;
13
47-57
17
Szekeres-Bartho J.
Regulation of NK cell cytotoxicity during pregnancy.
Reprod Biomed Online.
2008;
16
211-217
18
Szekeres-Bartho J, Balasch J.
Progestagen therapy for recurrent miscarriage.
Human Reprod update.
2008;
14
27-35
19
Bohlmann M K, Lüdders D W, Baumann K et al.
Use of progestogen during pregnancy.
Gynäkol Endokrinol.
2008;
6
171-176
20
Rai R, Backos M, Rushworth F et al.
Polycystic ovaries and recurrent miscarriage – a reappraisal.
Hum Reprod.
2000;
15
612-615
21
Craig L B, Ke R W, Kutteh W H.
Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss.
Fertil Steril.
2002;
78
487-490
22
Jakubowicz D J, Iuorno M J, Jakubowicz S et al.
Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.
J Clin Endocrinol Metab.
2002;
87
524-529
23
Clifford K, Rai R, Watson H et al.
Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.
BMJ.
1996;
312
1508-1511
24
Rey E, Kahn S K, David M et al.
Thrombophilic disorders and fetal loss: a metaanalysis.
Lancet.
2003;
361
901-908
25
Pihusch R, Buchholz T, Lohse P et al.
Thrombophilic gene mutations and recurrent spontaneous abortion: Prothrombin increases the risk in the first trimester.
Am J Reprod Immunol.
2001;
46
124-131
26
Brenner B, Nowak-Göttl U, Kosch A et al.
Diagnostic studies for thrombophilia in women on hormonal therapy and during pregnancy, and children.
Arch Pathol Lab Med.
2002;
126
1296-1303
27
Buchholz T, Lohse P, Rogenhofer N et al.
Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages.
Hum Reprod.
2003;
18
2473-2477
28
Menge S, Müller-Lantzsch C, Keck C et al.
Recurrent spontaneous abortion: causes and therapeutic options.
Geburtsh Frauenheilk.
2004;
64
573-583
29
Brenner B, Sarig G, Weiner Z.
Thrombophilic polymorphisms are common in women with fetal loss without apparent cause.
Thromb Haemost.
1999;
82
6-9
30
Makris M.
Hyperhomocysteinemia and thrombosis.
Clin Lab Haematol.
2000;
22
133-143
31
Nelen W L, Blom H J, Steegers E A et al.
Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.
Fertil Steril.
2000;
74
1196-1199
32
Bohlmann M K, von Wolff M, Rossmann H et al.
MTHFR-Polymorphismen und Homocysteinspiegel bei Paaren mit habituellen Aborten.
Arch Gyn Obstet.
2004;
270
FV-E1.2
S13
33
Ghosh K, Shetty S, Vora S et al.
Successful pregnancy outcome in women with bad obstetric history and recurrent fetal loss due to thrombophilia: effect of unfractionated heparin and low-molecular weight heparin.
Clin Appl Thromb Hemost.
2008;
14
174-179
34
Gris J C, Mercier E, Quere I et al.
Low-molecular weight heparin versus lowdose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Blood.
2004;
103
3695-3699
35
Brenner B, Hoffman R, Carp H LIVE-ENOX Investigators et al.
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
36
Laskin C A, Spitzer K A, Clark C A 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
37
Badawy A M, Khiary M, Sherif L S et al.
Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology.
J Obstet Gynaecol.
2008;
28
280-284
38
Rai R, Cohen H, Dave M et al.
Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
BMJ.
1997;
314
253-257
39
Miyakis S, Lockshin M D, 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
40
Heilmann L, v Tempelhoff G F, Pollow K.
Antiphospholipid syndrome in obstetrics.
Clin Appl Thromb Hemost.
2003;
9
143-150
41
Empson M, Lassere M, Craig J C et al.
Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials.
Obstet Gynecol.
2002;
99
135-144
42
Scholz C, Rogenhofer N, Jeschke U.
Schwangerschaft und maternales Immunsystem.
Der Gynäkologe.
2009;
42
25-30
43
Wegmann T G, Lin H, Guilbert L.
Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?.
Immunol Today.
1993;
14
353-356
44
Clark D A.
Immunological factors in pregnancy wastage: fact or fiction.
Am J Reprod Immunol.
2008;
59
277-300
45
Tomczak S, Briese V, Kunkel S.
Serum placental protein 14 (PP14) levels in patients with threatened abortion.
Arch Gynecol Obstet.
1996;
258
165-169
46
Moffett-King A.
Natural killer cells and pregnancy.
Nat Rev Immunol.
2002;
2
656-663
47
Quenby S, Farquharson R.
Uterine natural killer cells, implantation failure and recurrent miscarriage.
Reprod Biomed Online.
2006;
13
24-28
48
Shakhar K, Rosenne E, Loewenthal R et al.
High NK cell activity in recurrent miscarriage: what are we really measuring?.
Hum Reprod.
2006;
21
2421-2425
49
Salamonsen L A, Hannan N J, Dimitriadis E.
Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation.
Sem Reprod Med.
2007;
25
437-444
50
Okamoto N, Uchida A, Takakura K.
Suppression by human placenta protein 14 of natural killer cell activity.
Am J Reprod Immunol.
1991;
26
137-142
51
Tulppala M, Julkunen M, Tiitinen A.
Habitual abortion is accompanied by low serum levels of placental protein 14 in the luteal phase of the fertile cycle.
Fertil Steril.
1995;
63
792-795
52
Toth B, Roth K, Kunert-Keil C.
Glycodelin protein and mRNA is downregulated in human first trimester abortion and partially upregulated in mole pregnancy.
J Histochem Cytochem.
2008;
56
477-485
53
van Mourik M S M, Heijnen C J, Macklon N S.
Embryonic implantation: cytokines, adhesion molecules and immune cells in establishing an implantation environment.
J Leukocyt Biol.
2009;
85
4-19
54
Scott J R.
Immunotherapy for recurrent miscarriage.
Cochrane Database Syst Rev.
;
(1)
CD000112
55 Rai R. Should immunotherapy be used in RPL? – Against. Carp HJA Recurrent Pregnancy Loss. Causes, Controversies and Treatment. London; Informa Healthcare 2007: 189-192
56
Porter T F, LaCoursiere Y, Scott J R.
Immunotherapy for recurrent miscarriage (review).
Cochrane Database Syst Rev (online).
2006;
(2)
CD000112
57 Heilmann L, Dietl J, Ludwig M et al. Diagnostik und Therapie beim wiederholten Spontanabort. AWMF-Leitlinien-Register Nr. 015/050.
58
Stricker R B, Winger E E.
Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin.
Am J Reprod Immunol.
2005;
54
390-396
59
Christiansen O B, Pedersen B, Rosgaard A et al.
A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage.
Human Reprod.
2002;
17
809-816
60
Christiansen O B, Nielsen H S.
Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work?.
Chem Immunol Allergy.
2005;
88
117-127
61
Hutton B, Sharma R, Fergusson D et al.
Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
BJOG.
2007;
114
134-142
62
Kiprov D D, Nachtigall R D, Weaver R C et al.
The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities.
Am J Reprod Immunol.
1996;
36
228-234
Dr. med. Nina Rogenhofer
Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Klinikum der Universität München Campus Großhadern
Marchioninistraße 15
81377 München
Email: nina.rogenhofer@med.uni-muenchen.de