Defining recurrent implantation failure: a profusion of confusion or simply an illusion?
2021; Elsevier BV; Volume: 116; Issue: 6 Linguagem: Inglês
10.1016/j.fertnstert.2021.10.023
ISSN1556-5653
AutoresAudrey Garneau, Steven L. Young,
Tópico(s)Endometriosis Research and Treatment
ResumoRecurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF. Recurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33964 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33964 The implantation of an embryo is fundamental to a successful pregnancy. It is contingent on the presence of a specific intrauterine environment, biologically intact embryo, and complex series of interactions between them. This process, necessary for species survival, must be strongly influenced by natural selection, but is curiously inefficient; most sexual intercourse does not result in a fertilized egg, and only a fraction of fertilized eggs can become an infant. Even with an apparently euploid embryo, a large determinant of successful conception, embryo transfer results in ongoing pregnancy <60% of the time (1Scott Jr., R.T. Ferry K. Su J. Tao X. Scott K. Treff N.R. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study.Fertil Steril. 2012; 97: 870-875Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Early abnormalities in implantation contribute to infertility by causing biochemical and first trimester losses, whereas later abnormalities are associated with pregnancy complications, such as miscarriage and preeclampsia (2Namiki T. Ito J. Kashiwazaki N. Molecular mechanisms of embryonic implantation in mammals: lessons from the gene manipulation of mice.Reprod Med Biol. 2018; 17: 331-342Crossref PubMed Scopus (32) Google Scholar). Recurrent implantation failure (RIF) is a poorly defined but devastating clinical scenario where pregnancy is not achieved after multiple embryo transfers. However, there is a profound lack of agreement about the definition of RIF and even some heterogeneity for the clinical determination of implantation and its failure. A standard definition of RIF would benefit the field by improving research study design and allowing the synthesis of independent studies. The data, thus created, would enhance our ability to determine specific causes, methods of diagnosis, and methods of treating and preventing RIF. This review aims to make progress toward a universally accepted definition of RIF by exploring what is known about implantation and its failure. To understand failure of implantation, factors necessary for implantation need to be determined. The endometrium is receptive to implantation during a few days of the menstrual cycle, a window dependent on adequate progesterone exposure and endometrial response (3Garrido-Gomez T. Dominguez F. Quiñonero A. Diaz-Gimeno P. Kapidzic M. Gormley M. et al.Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.Proc Natl Acad Sci U S A. 2017; 114: E8468-E8477Crossref PubMed Scopus (204) Google Scholar, 4Prapas Y. Prapas N. Jones E.E. Duleba A.J. Olive D.L. Chatziparasidou A. et al.The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.Hum Reprod. 1998; 13: 720-723Crossref PubMed Scopus (78) Google Scholar). Steroid action and complex molecular and cellular crosstalk between the blastocyst and endometrium are necessary for blastocyst apposition, attachment, and invasion (2Namiki T. Ito J. Kashiwazaki N. Molecular mechanisms of embryonic implantation in mammals: lessons from the gene manipulation of mice.Reprod Med Biol. 2018; 17: 331-342Crossref PubMed Scopus (32) Google Scholar, 5Paria B.C. Song H. Dey S.K. Implantation: molecular basis of embryo-uterine dialogue.Int J Dev Biol. 2001; 45: 597-605PubMed Google Scholar). The temporal window of endometrial receptivity occurs at the peak of progesterone production by the corpus luteum. The effects of the weeklong exposure to sufficient progesterone are marked by maximal secretory changes, spiral artery formation, edema, and epithelial surface changes, including pinopod formation (6Norwitz E.R. Schust D.J. Fisher S.J. Implantation and the survival of early pregnancy.N Engl J Med. 2001; 345: 1400-1408Crossref PubMed Scopus (951) Google Scholar). Clinical evidence of implantation can be obtained by the presence of human chorionic gonadotropin (hCG) in the maternal blood. Although cleavage-stage embryos on postovulatory day 3 express hCG mRNA, hCG does not enter the maternal circulation in clinically detectable amounts until trophoblast invasion and proliferation, postovulatory days 10–11 (5Paria B.C. Song H. Dey S.K. Implantation: molecular basis of embryo-uterine dialogue.Int J Dev Biol. 2001; 45: 597-605PubMed Google Scholar). Three weeks after ovulation, there is evidence of a gestational sac on ultrasound, and subsequently, ultrasound evidence of cardiac motion can reliably be detected 4.5 weeks after ovulation. Abnormalities of implantation can occur over a spectrum of time, and it is likely that abnormal implantation commonly underlies preeclampsia, intrauterine growth restriction, and pregnancy loss. For example, preeclampsia is strongly associated with shallow trophoblast invasion, deficient replacement of spiral artery endothelium by extravillous cytotrophoblasts, and alterations in blood flow leading to later manifestation of clinical disease (2Namiki T. Ito J. Kashiwazaki N. Molecular mechanisms of embryonic implantation in mammals: lessons from the gene manipulation of mice.Reprod Med Biol. 2018; 17: 331-342Crossref PubMed Scopus (32) Google Scholar, 6Norwitz E.R. Schust D.J. Fisher S.J. Implantation and the survival of early pregnancy.N Engl J Med. 2001; 345: 1400-1408Crossref PubMed Scopus (951) Google Scholar). Given the association of recurrent pregnancy loss and pregnancy complications, it might be useful to examine the association between RIF and those complications. To our knowledge, however, no studies have specifically examined such an association. Broadly, the causes of implantation failure may be categorized as embryonic, maternal, and endometrial-embryonic dyssynchrony. The chromosomal quality of an embryo impacts the ability of the embryo to implant successfully. Euploid embryos, regardless of age, have been shown to have significantly lower implantation failure rates, 18%–27%, compared with aneuploid embryos, 60%–76% (7Tiegs A.W. Tao X. Zhan Y. Whitehead C. Kim J. Hanson B. et al.A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy.Fertil Steril. 2021; 115: 627-637Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). However, transferring a euploid embryo does not preclude implantation failure; a study noted a 19%–33% implantation failure rate, depending on the definition used for implantation failure (8Reig A. Franasiak J. Scott Jr., R.T. Seli E. The impact of age beyond ploidy: outcome data from 8175 euploid single embryo transfers.J Assist Reprod Genet. 2020; 37: 595-602Crossref PubMed Scopus (36) Google Scholar). Outside of chromosomal euploidy, gene mutations and alterations in methylation have an uncertain impact on RIF. Specific gene mutations resulting in loss or deficiency of endometrial factors, including cytokines and transcription factors, have been associated with implantation failure in mice (9Gao F. Bian F. Ma X. Kalinichenko V.V. Das S.K. Control of regional decidualization in implantation: role of FoxM1 downstream of Hoxa10 and cyclin D3.Sci Rep. 2015; 5: 13863Crossref PubMed Scopus (32) Google Scholar, 10Pawar S. Starosvetsky E. Orvis G.D. Behringer R.R. Bagchi I.C. Bagchi M.K. STAT3 regulates uterine epithelial remodeling and epithelial-stromal crosstalk during implantation.Mol Endocrinol. 2013; 27: 1996-2012Crossref PubMed Scopus (95) Google Scholar). Although these discoveries help elucidate the complex molecular processes necessary for successful implantation, these mutations have not been identified in humans. Additionally, naturally occurring mutations causing implantation failure in mice have not been described, likely because of natural selection. Epigenetic changes in the embryo may also impact implantation (11Osman E. Franasiak J. Scott R. Oocyte and embryo manipulation and epigenetics.Semin Reprod Med. 2018; 36: e1-e9Crossref PubMed Scopus (22) Google Scholar). DNA methylation changes are essential in early embryo development, and methylation alterations have been found in embryos created from patients with long-standing infertility, although a causal relationship remains uncertain (12Denomme M.M. Haywood M.E. McCallie B.R. Schoolcraft W.B. Katz-Jaffe M.G. The prolonged disease state of infertility is associated with embryonic epigenetic dysregulation.Fertil Steril. 2021; 116: 309-318Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Several maternal factors may also play a role in embryo implantation. Although more recent studies have called into question the impact of endometrial thickness on live birth, it is impossible to ignore the data that strongly correlate pregnancy rate with endometrial thickness (13Shakerian B. Turkgeldi E. Yildiz S. Keles I. Ata B. Endometrial thickness is not predictive for live birth after embryo transfer, even without a cutoff.Fertil Steril. 2021; 116: 130-137Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 14Liu K.E. Hartman M. Hartman A. Luo Z.C. Mahutte N. The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers.Hum Reprod. 2018; 33: 1883-1888Crossref PubMed Scopus (188) Google Scholar). The available evidence supports that the pregnancy rate is strongly influenced by endometrial thickness seen on day of hCG. In addition to endometrial thickness, cellular and molecular alterations of the endometrium are critical for implantation. Studies have shown that there is a tight window, perhaps 2 days, during which normal implantation occurs (4Prapas Y. Prapas N. Jones E.E. Duleba A.J. Olive D.L. Chatziparasidou A. et al.The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.Hum Reprod. 1998; 13: 720-723Crossref PubMed Scopus (78) Google Scholar). Maternal age and associated embryonic euploidy are of critical importance to embryonic implantation. Pirtea et al. (15Pirtea P. De Ziegler D. Tao X. Sun L. Zhan Y. Ayoubi J.M. et al.Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.Fertil Steril. 2021; 115: 45-53Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar) showed that the implantation rates of single euploid embryos are 70%, 60%, and 60% in subsequent transfers, with cumulative implantation of 70%, 88%, and 95%. The investigators used this data to call into question the existence of a significant number of patients who have persistent problems with implantation (15Pirtea P. De Ziegler D. Tao X. Sun L. Zhan Y. Ayoubi J.M. et al.Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.Fertil Steril. 2021; 115: 45-53Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). However, the population studied was particularly one of good prognosis, with a mean age of 35 years, antimüllerian hormone level of 3 ng/mL, and body mass index of 25 kg/m2. The study also had a high dropout rate between transfers that could obscure a reduction in rates as transfer numbers increased. Other studies show that women with multiple implantation failures have a lower chance of future success. For example, an observational study of 118 patients with RIF found that 49% of these patients had a live birth in a 5.5-year follow-up period; however, approximately 50% of patients with RIF did not realize their family goals (16Koot Y.E.M. Hviid Saxtorph M. Goddijn M. de Bever S. Eijkemans M.J.C. Wely M.V. et al.What is the prognosis for a live birth after unexplained recurrent implantation failure following IVF/ICSI?.Hum Reprod. 2019; 34: 2044-2052Crossref PubMed Scopus (26) Google Scholar). Another recent observational study found that women receiving a euploid embryo transfer were less likely to have a live birth if they had a history of greater than 2 implantation failures, 36% compared with 47% in those without this reproductive history (17Cimadomo D. Capalbo A. Dovere L. Tacconi L. Soscia D. Giancani A. et al.Leave the past behind: women's reproductive history shows no association with blastocysts' euploidy and limited association with live birth rates after euploid embryo transfers.Hum Reprod. 2021; 36: 929-940Crossref PubMed Scopus (21) Google Scholar). There are other specific maternal causes of implantation failure to consider, although several are arguably exclusion criteria for the diagnosis of RIF. Examples of such scenarios include inflammatory states associated with communicating hydrosalpinx and chronic endometritis. The impact of hydrosalpinges has been well documented in multiple randomized controlled trials, and chronic endometritis has been associated with a threefold decrease in implantation rates (18Johnson N. van Voorst S. Sowter M.C. Strandell A. Mol B.W. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.Cochrane Database Syst Rev. 2010; 2010CD002125Google Scholar, 19Johnston-MacAnanny E.B. Hartnett J. Engmann L.L. Nulsen J.C. Sanders M.M. Benadiva C.A. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization.Fertil Steril. 2010; 93: 437-441Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). Intracavitary lesions such as submucosal myomas and endometrial polyps also increase the odds of implantation failure (20Tulandi T. Marzal A. Redefining reproductive surgery.J Minim Invasive Gynecol. 2012; 19: 296-306Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 21Casini M.L. Rossi F. Agostini R. Unfer V. Effects of the position of fibroids on fertility.Gynecol Endocrinol. 2006; 22: 106-109Crossref PubMed Scopus (245) Google Scholar, 22Makker A. Goel M.M. Uterine leiomyomas: effects on architectural, cellular, and molecular determinants of endometrial receptivity.Reprod Sci. 2013; 20: 631-638Crossref PubMed Scopus (23) Google Scholar). Endometriosis may also cause implantation failure, as studies show that the treatment of endometriosis by either gonadotropin-releasing hormone agonist or surgical management improves outcomes (23Georgiou E.X. Melo P. Baker P.E. Sallam H.N. Arici A. Garcia-Velasco J.A. et al.Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.Cochrane Database Syst Rev. 2019; 2019CD013240Google Scholar, 24Jacobson T.Z. Duffy J.M. Barlow D. Farquhar C. Koninckx P.R. Olive D. Laparoscopic surgery for subfertility associated with endometriosis.Cochrane Database Syst Rev. 2010; CD001398Crossref Scopus (0) Google Scholar). There are many additional possible etiologies for RIF, including antiphospholipid antibody syndrome, polycystic ovary syndrome, obesity, and smoking, although several causes remain unexplained. Lesser defined causes may involve specific haplotypes or additional immunological causes. A comprehensive description of these causes is beyond the scope of this review. Dyssynchrony between endometrial and embryonic developments may also play a role in the failure of implantation. The length of progesterone exposure in the uterus is critical, although the assessment of this is difficult (4Prapas Y. Prapas N. Jones E.E. Duleba A.J. Olive D.L. Chatziparasidou A. et al.The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.Hum Reprod. 1998; 13: 720-723Crossref PubMed Scopus (78) Google Scholar). Testing for the displacement of the window of implantation by endometrial receptivity assay has emerged as a possible way to evaluate receptiveness of the endometrium; data remains controversial as to whether this is beneficial in patients who experience RIF (25Cozzolino M. Diaz-Gimeno P. Pellicer A. Garrido N. Evaluation of the endometrial receptivity assay and the preimplantation genetic test for aneuploidy in overcoming recurrent implantation failure.J Assist Reprod Genet. 2020; 37: 2989-2997Crossref PubMed Scopus (49) Google Scholar, 26Simón C. Gómez C. Cabanillas S. Vladimirov I. Castillón G. Giles J. et al.A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF.Reprod Biomed Online. 2020; 41: 402-415Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). However, the molecular mechanisms underlying the action of estrogen-induced and progesterone-induced cellular changes and bidirectional communication with the embryo cannot be overlooked. These intricate steps likely offer an opportunity for error, not otherwise clinically relevant or testable. To define implantation failure, it is necessary to first define successful implantation and implantation rate. Currently, there are several different ways to determine the implantation rate. An obvious approach is to use serum hCG as a surrogate for trophoblast invasion. Data reported to the Society for Assisted Reproductive Technology measure the implantation rate as the number of gestational sacs/number of embryos transferred, as this allows a definition on the basis of the number that implanted per number transferred. However, the Society for Assisted Reproductive Technology definition cannot account for embryos that were implanted but lost before ultrasound. An additional definition used in some studies is the sustained implantation rate, which is the number of embryos with cardiac activity per number of embryos transferred. The sustained implantation rate is useful clinically as it tracks closely with live birth. With each of these definitions, the absence of the appropriate finding (hCG, sac, and cardiac motion) represents a failed treatment cycle, although it remains unclear whether failure at each of these points have the same or similar causes. For example, biochemical losses seem to occur with similar frequency with aneuploid and euploid embryos, whereas failure to achieve detectable hCG is approximately half as likely for aneuploid embryos (7Tiegs A.W. Tao X. Zhan Y. Whitehead C. Kim J. Hanson B. et al.A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy.Fertil Steril. 2021; 115: 627-637Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). It would seem useful to track all 3 definitions, at least in research, and report on all 3 until a universal definition is applied. It is significant to note that a distinction, or lack thereof, between miscarriage and implantation failure needs to be better established, especially, given the adverse perinatal outcomes associated with patients having recurrent miscarriage (27Field K. Murphy D.J. Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: a retrospective cohort study.Hum Reprod. 2015; 30: 1239-1245Crossref PubMed Scopus (40) Google Scholar). Additionally, there may be a long-term impact of recurrent loss, such as an increased risk of myocardial infarction, that may warrant specific screening in patients at high risk (28Kharazmi E. Dossus L. Rohrmann S. Kaaks R. Pregnancy loss and risk of cardiovascular disease: a prospective population-based cohort study (EPIC-Heidelberg).Heart. 2011; 97: 49-54Crossref PubMed Scopus (98) Google Scholar). Once a definition of implantation is determined, the definition of its failure is obvious. However, as noted above, the definition remains unclear. The aim of a definition of RIF should be to identify those women who have an abnormally low chance of pregnancy per embryo, to provide prognostic data and allow interventions that may improve implantation in subsequent transfers. Currently, there is heterogeneity in criteria deemed indicative of RIF between types of providers, clinics, and geographic location. A recent international survey of 735 clinicians highlights the heterogeneity of currently used clinical criteria (27Field K. Murphy D.J. Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: a retrospective cohort study.Hum Reprod. 2015; 30: 1239-1245Crossref PubMed Scopus (40) Google Scholar). In this survey, 84% of clinicians defined RIF on the basis of the number of embryos transferred, with the largest group (45%) defining RIF as failure of 3 fresh or frozen embryo transfers. Interestingly, factors such as location of the clinic (European vs. non-European) and private vs. public were correlated with the definition used (29Cimadomo D. Craciunas L. Vermeulen N. Vomstein K. Toth B. Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists.Hum Reprod. 2021; 36: 305-317Crossref PubMed Scopus (72) Google Scholar). Individual investigators have proposed specific definitions. Tan et al. (30Tan B.K. Vandekerckhove P. Kennedy R. Keay S.D. Investigation and current management of recurrent IVF treatment failure in the UK.BJOG. 2005; 112: 773-780Crossref PubMed Scopus (127) Google Scholar) suggested a definition of failure to achieve a pregnancy after 3 completed in vitro fertilization (IVF) cycles. Two additional studies defined RIF as 3 unsuccessful cycles of IVF with at least 2 embryos of high quality or failure of clinic pregnancy after 4 good quality embryo transfers with at least 3 fresh or frozen IVF cycles in women aged 3 failed embryo transfers with high-quality embryos or the failed transfer of ≥10 embryos in multiple transfers (3Garrido-Gomez T. Dominguez F. Quiñonero A. Diaz-Gimeno P. Kapidzic M. Gormley M. et al.Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.Proc Natl Acad Sci U S A. 2017; 114: E8468-E8477Crossref PubMed Scopus (204) Google Scholar, 10Pawar S. Starosvetsky E. Orvis G.D. Behringer R.R. Bagchi I.C. Bagchi M.K. STAT3 regulates uterine epithelial remodeling and epithelial-stromal crosstalk during implantation.Mol Endocrinol. 2013; 27: 1996-2012Crossref PubMed Scopus (95) Google Scholar, 16Koot Y.E.M. Hviid Saxtorph M. Goddijn M. de Bever S. Eijkemans M.J.C. Wely M.V. et al.What is the prognosis for a live birth after unexplained recurrent implantation failure following IVF/ICSI?.Hum Reprod. 2019; 34: 2044-2052Crossref PubMed Scopus (26) Google Scholar, 33Thornhill A.R. deDie-Smulders C.E. Geraedts J.P. Harper J.C. Harton G.L. Lavery S.A. et al.ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'.Hum Reprod. 2005; 20: 35-48Crossref PubMed Scopus (354) Google Scholar, 34Ata B. Kalafat E. Somigliana E. A new definition of recurrent implantation failure on the basis of anticipated blastocyst aneuploidy rates across female age.Fertil Steril. 2021; 116: 1320-1327Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). The American Society for Reproductive Medicine has not published specific criteria. A critical problem with these definitions is that there are many important factors influencing implantation success that are not accounted for, including oocyte and uterine age, length of infertility, euploidy (and how this was determined), systemic diseases, lifestyle issues (e.g., obesity or smoking), uterine structural abnormalities, chronic endometritis, and presence of endometriosis. Some of these are routinely screened for, and others are not but might be if RIF is diagnosed. Obviously, the lack of implantation of a high-quality blastocyst in a 28-year-old woman with absent tubes as her only infertility factor would be much less likely than a 39-year-old woman with transfer of untested, cleavage-stage embryos. Thus, recently, investigators have suggested personalized definitions of implantation failure. Embryo aneuploidy (and, therefore, oocyte age) is arguably the most important contributing factor to failure of assisted reproductive technology. For this reason, Ata et al. (34Ata B. Kalafat E. Somigliana E. A new definition of recurrent implantation failure on the basis of anticipated blastocyst aneuploidy rates across female age.Fertil Steril. 2021; 116: 1320-1327Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar) proposed a new definition of RIF that accounts for anticipated euploidy rate on the basis of age, using a statistical model. The statistical simulation found that no age category was associated with a 95% probably of successful implantation with 6 embryos transferred. Rather, a 95% probability of success was not reached until 7 blastocysts were transferred in women aged <35 years. The needed number of embryos increased with age; at 38 years of age, 10 blastocysts were needed, and at the age of 42 years, there was no practical number that allowed a 95% probability of implantation. Of course, the number needed would be reduced, if euploid embryos are transferred. Rozen et al. (35Rozen G. Rogers P. Teh W.T. Stern C.J. Polyakov A. An algorithm to personalise the diagnosis of recurrent implantation failure based on theoretical cumulative implantation rate.Hum Reprod. 2021; 36: 1463-1468Crossref PubMed Scopus (14) Google Scholar) suggested using a theoretical implantation rate to create a personalized diagnosis of RIF and account for many of the aforementioned factors, but the investigators did not provide a way to calculate the theoretical implantation rate, and large-scale data taking all of these factors into account are lacking. In conclusion, RIF does not have a universal definition. Clinical experience tells us that some women have a greatly reduced chance of embryo implantation. These women, if they possess an adequate supply of euploid oocytes, often are able to conceive with further IVF attempts, since the chances are seldom 0%. However, the emotional and financial burdens of these choices are high, and the chance of success is certainly not optimal. Therefore, a practical definition of RIF is needed to inform both research and clinical practices. We propose that large-scale data be applied to allow personalization of the diagnosis by modeling multiple factors. Until we have the ability to more fully personalize, definitions should, at a minimum, account for the risk of aneuploidy as a significant factor governing implantation. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33964
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