Zusammenfassung
Hintergrund
Trotz Fortschritten insbesondere im Bereich des IVF-Labor leiden etwa 10 % der Kinderwunschpaare unter einem rezidivierenden Implantationsversagen (RIF). Neben allgemeinen Faktoren der Mutter werden Eigenschaften des Embryos und des Endometriums als Ursache diskutiert.
Ziel der Arbeit
Überblick über die Bedeutung der aktuellen diagnostischen Verfahren zur Untersuchung des Embryos sowie des Endometriums bei Patientinnen mit RIF.
Material und Methoden
Aktuelle Literaturrecherche und Zusammenfassung relevanter Studien und Übersichtsbeiträge zum Thema.
Ergebnisse
Neben Risikofaktoren wie hereditären und erworbenen Thrombophilien oder anatomischen Auffälligkeiten sind embryonale und endometriale Faktoren in den Blickpunkt gerückt. Die chromosomale Zusammensetzung und morphologische Entwicklung des Embryos können heute detaillierter untersucht werden. Mit neuen Techniken kann zudem die Implantationsfähigkeit des Endometriums genetisch, aber auch immunologisch bzw. infektiologisch analysiert werden. Als neue Risikofaktoren für RIF wird die chronische Endometritis sowie Veränderungen der natürlichen Killerzellen im Endometrium diskutiert.
Schlussfolgerungen
Kinderwunschpaare sollten vor einer Behandlung über die Erfolgsraten aufgeklärt werden. Mehrere erfolglose Kinderwunschbehandlungen stellen neben der finanziellen auch eine extreme psychische Belastung dar. Viele der aktuellen Risikofaktoren für RIF wurden lediglich an einer kleinen Studienpopulation untersucht. Vor Anwendung in der klinischen Routine sollten neue diagnostische Verfahren möglichst in prospektiven Studien mit ausreichender Fallzahl und einheitlich definiertem Patientinnenkollektiv untersucht werden. Nach aktuellem Stand müssen embryonale wie auch endometriale Faktoren für die Entstehung eines RIF verantwortlich gemacht werden.
Abstract
Background
Despite advanced techniques in reproductive medicine, about 10% of couples treated with assisted reproductive technology (ART) experience recurrent implantation failure (RIF). Besides other general maternal factors, the role of the embryo itself and the endometrium are now discussed.
Objectives
The diagnostic possibilities to examine the embryo and the endometrium in RIF patients are reviewed and discussed.
Materials and methods
Current, relevant research and review articles concerning embryological and endometrial factors are discussed.
Results
In addition to risk factors such as hereditary and acquired thrombophilia or anatomical abnormalities, embryonic and endometrial factors have come into focus. Nowadays, the chromosomal composition and morphological development of the embryo can be examined in more detail. Using new techniques, the properties of the endometrium for implantation can be analyzed from a genetically and immunological/infectiological perspective. Chronic endometritis and alterations of natural killer cells in the endometrium are discussed as new risk factors for RIF.
Conclusions
Couples should be educated about success rates before ART treatment. Several unsuccessful fertility treatments are not only a financial but also an extreme psychological burden. Many of the current risk factors for RIF have been studied only on the basis of a small study population. Before use in clinical routine, new diagnostic procedures should be investigated in prospective studies with a sufficient number of cases and a uniformly defined patient collective. According to the current state of knowledge, both embryonic and endometrial factors can be responsible for the development of RIF.
Literatur
Thornhill AR, deDie-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA et al (2005) ESHRE PGD Consortium ‚Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)‘. Hum Reprod 20(1):35–48
Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ (2014) What exactly do we mean by ‚recurrent implantation failure‘? A systematic review and opinion. Reprod Biomed Online 28(4):409–423
Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C et al (2009) Chromosome instability is common in human cleavage-stage embryos. Nat Med 15(5):577–583
Simon A, Laufer N (2012) Assessment and treatment of repeated implantation failure (RIF). J Assist Reprod Genet 29(11):1227–1239
Koler M, Achache H, Tsafrir A, Smith Y, Revel A, Reich R (2009) Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure. Hum Reprod 24(10):2541–2548
Macklon NS, Brosens JJ (2014) The human endometrium as a sensor of embryo quality. Biol Reprod 91(4):98
Koot YE, Teklenburg G, Salker MS, Brosens JJ, Macklon NS (2012) Molecular aspects of implantation failure. Biochim Biophys Acta 1822(12):1943–1950
Das M, Holzer HE (2012) Recurrent implantation failure: gamete and embryo factors. Fertil Steril 97(5):1021–1027
Kadi S, Wiesing U (2016) The German IVF register as an instrument to document assisted reproductive technologies. Geburtshilfe Frauenheilkd 76(6):680–684
Demirol A, Gurgan T (2004) Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod Biomed Online 8(5):590–594
Zeyneloglu HB, Arici A, Olive DL (1998) Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization—embryo transfer. Fertil Steril 70(3):492–499
Meyer WR, Castelbaum AJ, Somkuti S, Sagoskin AW, Doyle M, Harris JE et al (1997) Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod 12(7):1393
Broughton DE, Moley KH (2017) Obesity and female infertility: potential mediators of obesity’s impact. Fertil Steril 107(4):840–847
Penzias AS (2012) Recurrent IVF failure: other factors. Fertil Steril 97(5):1033–1038
Rubio C, Bellver J, Rodrigo L, Bosch E, Mercader A, Vidal C et al (2013) Preimplantation genetic screening using fluorescence in situ hybridization in patients with repetitive implantation failure and advanced maternal age: two randomized trials. Fertil Steril 99(5):1400–1407
Pehlivan T, Rubio C, Rodrigo L, Romero J, Remohi J, Simon C et al (2003) Impact of preimplantation genetic diagnosis on IVF outcome in implantation failure patients. Reprod Biomed Online 6(2):232–237
Toth B, Wurfel W, Bohlmann M, Zschocke J, Rudnik-Schoneborn S, Nawroth F et al (2018) Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-level, AWMF registry number 015/050). Geburtshilfe Frauenheilkd 78(4):364–381
Blockeel C, Schutyser V, De Vos A, Verpoest W, De Vos M, Staessen C et al (2008) Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod Biomed Online 17(6):848–854
Yakin K, Ata B, Ercelen N, Balaban B, Urman B (2008) The effect of preimplantation genetic screening on the probability of live birth in young women with recurrent implantation failure; a nonrandomized parallel group trial. Eur J Obstet Gynecol Reprod Biol 140(2):224–229
Pontre JC, Ryan JP, Tan A, Hart RJ (2018) The interval transfer of a frozen-thawed embryo is more successful than a fresh embryo transfer for women undergoing IVF with recurrent implantation failure after cleavage stage embryo biopsy. Aust N Z J Obstet Gynaecol. https://doi.org/10.1111/ajo.12798
Valdes CT, Schutt A, Simon C (2017) Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 108(1):15–18
Boiso I, Veiga A, Edwards RG (2002) Fundamentals of human embryonic growth in vitro and the selection of high-quality embryos for transfer. Reprod Biomed Online 5(3):328–350
Milki AA, Hinckley MD, Gebhardt J, Dasig D, Westphal LM, Behr B (2002) Accuracy of day 3 criteria for selecting the best embryos. Fertil Steril 77(6):1191–1195
De Placido G, Wilding M, Strina I, Alviggi E, Alviggi C, Mollo A et al (2002) High outcome predictability after IVF using a combined score for zygote and embryo morphology and growth rate. Hum Reprod 17(9):2402–2409
Fisch JD, Rodriguez H, Ross R, Overby G, Sher G (2001) The Graduated Embryo Score (GES) predicts blastocyst formation and pregnancy rate from cleavage-stage embryos. Hum Reprod 16(9):1970–1975
Scott L, Alvero R, Leondires M, Miller B (2000) The morphology of human pronuclear embryos is positively related to blastocyst development and implantation. Hum Reprod 15(11):2394–2403
Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB (2000) Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril 73(6):1155–1158
Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM et al (2017) Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update 23(2):139–155
Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G et al (2014) Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod 29(6):1173–1181
Irani M, Reichman D, Robles A, Melnick A, Davis O, Zaninovic N et al (2017) Morphologic grading of euploid blastocysts influences implantation and ongoing pregnancy rates. Fertil Steril 107(3):664–670
Van den Abbeel E, Balaban B, Ziebe S, Lundin K, Cuesta MJ, Klein BM et al (2013) Association between blastocyst morphology and outcome of single-blastocyst transfer. Reprod Biomed Online 27(4):353–361
Hill MJ, Richter KS, Heitmann RJ, Graham JR, Tucker MJ, DeCherney AH et al (2013) Trophectoderm grade predicts outcomes of single-blastocyst transfers. Fertil Steril 99(5):1283–1289.e1
Ahlstrom A, Westin C, Wikland M, Hardarson T (2013) Prediction of live birth in frozen-thawed single blastocyst transfer cycles by pre-freeze and post-thaw morphology. Hum Reprod 28(5):1199–1209
Alfarawati S, Fragouli E, Colls P, Stevens J, Gutierrez-Mateo C, Schoolcraft WB et al (2011) The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril 95(2):520–524
Rubio I, Galan A, Larreategui Z, Ayerdi F, Bellver J, Herrero J et al (2014) Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertil Steril 102(5):1287–1294e5
Kissin DM, Kawwass JF, Monsour M, Boulet SL, Session DR, Jamieson DJ et al (2014) Assisted hatching: trends and pregnancy outcomes, United States, 2000–2010. Fertil Steril 102(3):795–801
Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L (2012) Assisted hatching on assisted conception (in vitro fertilisation (IVF)) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD001894.pub5
Martins WP, Rocha IA, Ferriani RA, Nastri CO (2011) Assisted hatching of human embryos: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update 17(4):438–453
Lash GE, Bulmer JN (2011) Do uterine natural killer (uNK) cells contribute to female reproductive disorders? J Reprod Immunol 88(2):156–164
Bulmer JN, Williams PJ, Lash GE (2010) Immune cells in the placental bed. Int J Dev Biol 54(2–3):281–294
Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D (1991) Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 6(6):791–798
Moffett A, Shreeve N (2015) First do no harm: uterine natural killer (NK) cells in assisted reproduction. Hum Reprod 30(7):1519–1525
Moffett A, Colucci F (2014) Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest 124(5):1872–1879
Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD et al (2012) Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J 26(12):4876–4885
Lyall F, Robson SC, Bulmer JN (2013) Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension 62(6):1046–1054
Quenby S, Nik H, Innes B, Lash G, Turner M, Drury J et al (2009) Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod 24(1):45–54
Chen X, Mariee N, Jiang L, Liu Y, Wang CC, Li TC et al (2017) Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range. Am J Obstet Gynecol 217(6):680e1–680e6
Kuon RJ, Weber M, Heger J, Santillan I, Vomstein K, Bar C et al (2017) Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol. https://doi.org/10.1111/aji.12721
Seshadri S, Sunkara SK (2014) Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update 20(3):429–438
Ledee-Bataille N, Dubanchet S, Coulomb-L’hermine A, Durand-Gasselin I, Frydman R, Chaouat G (2004) A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization. Fertil Steril 81(1):59–65
Tuckerman E, Mariee N, Prakash A, Li TC, Laird S (2010) Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J Reprod Immunol 87(1–2):60–66
Lash GE, Bulmer JN, Li TC, Innes BA, Mariee N, Patel G et al (2016) Standardisation of uterine natural killer (uNK) cell measurements in the endometrium of women with recurrent reproductive failure. J Reprod Immunol 116:50–59
Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE (2014) 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 290(4):757–762
Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A (2008) Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 278(1):33–38
Tempfer CB, Kurz C, Bentz EK, Unfried G, Walch K, Czizek U et al (2006) A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril 86(1):145–148
Tang AW, Alfirevic Z, Turner MA, Drury JA, Small R, Quenby S (2013) 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 28(7):1743–1752
Granato D, Blum S, Rossle C, Le Boucher J, Malnoe A, Dutot G (2000) Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. JPEN J Parenter Enteral Nutr 24(2):113–118
Roussev RG, Ng SC, Coulam CB (2007) Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol 57(4):262–269
Roussev RG, Acacio B, Ng SC, Coulam CB (2008) Duration of intralipid’s suppressive effect on NK cell’s functional activity. Am J Reprod Immunol 60(3):258–263
Roussev RG, Dons’koi BV, Stamatkin C, Ramu S, Chernyshov VP, Coulam CB et al (2013) Preimplantation factor inhibits circulating natural killer cell cytotoxicity and reduces CD69 expression: implications for recurrent pregnancy loss therapy. Reprod Biomed Online 26(1):79–87
Mayer K, Meyer S, Reinholz-Muhly M, Maus U, Merfels M, Lohmeyer J et al (2003) 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 171(9):4837–4843
Coulam CB, Acacio B (2012) Does immunotherapy for treatment of reproductive failure enhance live births? Am J Reprod Immunol 67(4):296–304
Moraru M, Carbone J, Alecsandru D, Castillo-Rama M, Garcia-Segovia A, Gil J et al (2012) 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 68(1):75–84
Meng L, Lin J, Chen L, Wang Z, Liu M, Liu Y et al (2016) Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch Gynecol Obstet 294(1):29–39
Stephenson MD, Kutteh WH, Purkiss S, Librach C, Schultz P, Houlihan E et al (2010) Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 25(9):2203–2209
Ata B, Tan SL, Shehata F, Holzer H, Buckett W (2011) A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril 95(3):1080–1085.e1-2
Ensom MH, Stephenson MD (2011) A two-center study on the pharmacokinetics of intravenous immunoglobulin before and during pregnancy in healthy women with poor obstetrical histories. Hum Reprod 26(9):2283–2288
Winger EE, Reed JL (2008) Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves live birth rates in women with recurrent spontaneous abortion. Am J Reprod Immunol 60(1):8–16
Zhang T, Huang C, Du Y, Lian R, Mo M, Zeng Y et al (2017) Successful treatment with intrauterine delivery of dexamethasone for repeated implantation failure. Am J Reprod Immunol. https://doi.org/10.1111/aji.12766
Bouet PE, El Hachem H, Monceau E, Gariepy G, Kadoch IJ, Sylvestre C (2016) Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis. Fertil Steril 105(1):106–110
Cicinelli E, Matteo M, Tinelli R, Lepera A, Alfonso R, Indraccolo U et al (2015) Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 30(2):323–330
Kitaya K, Matsubayashi H, Takaya Y, Nishiyama R, Yamaguchi K, Takeuchi T et al (2017) Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol 78(5):e12719
Liu B, Mariee N, Laird S, Smith J, Li J, Li TC (2014) The prognostic value of uNK cell count and histological dating in the mid-luteal phase of women with reproductive failure. Eur J Obstet Gynecol Reprod Biol 181:171–175
Bayer-Garner IB, Korourian S (2001) Plasma cells in chronic endometritis are easily identified when stained with syndecan-1. Mod Pathol 14(9):877–879
Liu Y, Chen X, Huang J, Wang CC, Yu MY, Laird S et al (2018) Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure. Fertil Steril 109(5):832–839
Cicinelli E, Resta L, Nicoletti R, Zappimbulso V, Tartagni M, Saliani N (2005) Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod 20(5):1386–1389
Cicinelli E, Matteo M, Trojano G, Mitola PC, Tinelli R, Vitagliano A et al (2018) Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol. https://doi.org/10.1111/aji.12782
Moreno I, Franasiak JM (2017) Endometrial microbiota-new player in town. Fertil Steril 108(1):32–39
Selman H, Mariani M, Barnocchi N, Mencacci A, Bistoni F, Arena S et al (2007) Examination of bacterial contamination at the time of embryo transfer, and its impact on the IVF/pregnancy outcome. J Assist Reprod Genet 24(9):395–399
Moreno I, Codoner FM, Vilella F, Valbuena D, Martinez-Blanch JF, Jimenez-Almazan J et al (2016) Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 215(6):684–703
Noyes RW, Hertig AT, Rock J (1975) Dating the endometrial biopsy. Am J Obstet Gynecol 122(2):262–263
Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB, Ireland K et al (2004) A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 81(5):1333–1343
Diaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Alama P, Pellicer A et al (2011) A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 95(1):50–60e1–15
Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Gomez E, Fernandez-Sanchez M, Carranza F et al (2013) The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 100(3):818–824
Tan J, Kan A, Hitkari J, Taylor B, Tallon N, Warraich G et al (2018) The role of the endometrial receptivity array (ERA) in patients who have failed euploid embryo transfers. J Assist Reprod Genet 35(4):683–692
Simon C, Vladimirov IK, Castillon Cortes G, Ortega I, Cabanillas S, Vidal C et al (2016) Prospective, randomized study of the endometrial receptivity analysis (ERA) test in the infertility work-up to guide personalized embryo transfer versus fresh transfer or deferred embryo transfer. Fertil Steril 106(3):e46–e47
Lucas ES, Dyer NP, Murakami K, Lee YH, Chan YW, Grimaldi G et al (2016) Loss of endometrial plasticity in recurrent pregnancy loss. Stem Cells 34(2):346–356
Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Bhattacharya S et al (2015) Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD009517.pub2
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R.-J. Kuon und B. Toth sind Gesellschafter der Reprognostics GbR. K. Vomstein gibt an, dass kein Interessenkonflikt besteht.
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T. Strowitzki, Heidelberg
G. Griesinger, Lübeck
H. Kentenich, Berlin
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Vomstein, K., Toth, B. & Kuon, RJ. Implantationsversagen: Embryo, Endometrium oder beides?. Gynäkologische Endokrinologie 16, 160–168 (2018). https://doi.org/10.1007/s10304-018-0200-4
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DOI: https://doi.org/10.1007/s10304-018-0200-4
Schlüsselwörter
- Uterine natürliche Killerzellen
- Chronische Endometritis
- Embryomorphologie
- Präimplantationsdiagnostik
- Endometriales Mikrobiom