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Pirtea, P. Recurrent Implantation Failure. Encyclopedia. Available online: https://encyclopedia.pub/entry/19485 (accessed on 05 December 2025).
Pirtea P. Recurrent Implantation Failure. Encyclopedia. Available at: https://encyclopedia.pub/entry/19485. Accessed December 05, 2025.
Pirtea, Paul. "Recurrent Implantation Failure" Encyclopedia, https://encyclopedia.pub/entry/19485 (accessed December 05, 2025).
Pirtea, P. (2022, February 16). Recurrent Implantation Failure. In Encyclopedia. https://encyclopedia.pub/entry/19485
Pirtea, Paul. "Recurrent Implantation Failure." Encyclopedia. Web. 16 February, 2022.
Recurrent Implantation Failure
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This entry is adapted from the peer-reviewed paper 10.3390/life12010039

Recurrent implantation failure (RIF) is an undefined, quite often, clinical phenomenon that can result from the repeated failure of embryo transfers to obtain a viable pregnancy. Careful clinical evaluation prior to assisted reproduction can uncover various treatable causes, including endocrine dysfunction, fibroid(s), polyp(s), adhesions, uterine malformations. 

reccurent implantation failure Assisted Reproductive Technique

1. Introduction

Assisted Reproductive Technique (ART) is a complex treatment with a variable percentage of success among patients and care providers. ART depends on several factors that are not always known and probably not always the same. The human reproduction natural limitations also apply to ART as well. Although we might imagine that controlled multiple ovulation and embryo selection might perform better, it remains limited.
When confronted with repeated ART failure, medical care providers should try to determine whether the cause is embryo or endometrium related, and they must also determine how many ART failures define true repeated implantation failure (RIF) [1].

2. RIF and the Endometrium

Implantation requires, apart from a quality blastocyst, a selective and receptive endometrium [2]. A suboptimal endometrial receptivity is suspected to be at the origin of 2/3 of implantation failures [3].
The histologic endometrial modifications that follow the variations in hormonal blood levels have been successively studied and quite well characterized [4]. Noyes et al. [5] argued, on a good basis, that on the assessment of secretory histologic modifications in the endometrium allowed for the assignment of endometrial dating. However, the role of endometrial dating as means to improve timing and implantation rates of transferred embryos has not been proven.
Recently, research has been directed towards defining the endometrial modifications during the window of implantation (WOI) and the expression of several important genes in the endometrium. More precisely, some authors suggested the endometrial receptivity analysis (ERA) test by an endometrial biopsy to assess the endometrial receptivity and the progress of endometrial changes [6].
Implantation relies on a cross-talk between the endometrium and the embryo, facilitated by several factors such as growth factors, cytokines, adhesion molecules, and transcription factors. Therefore, we might consider that RIF could be issued due to a modified endometrial receptivity. Modified, advanced or delayed, receptivity might induce modifications in the duration of WOI, which was previously believed to be identical for all women. The regulation and/or dysregulation of several key genes is implicated in the endometrial modifications during the WOI.
A recent publication by Ruiz-Alonso et al., identified the window of implantation modifications based on 238 genes among women with RIF by making use of the endometrial receptivity array (ERA) [7]. They reported that the window of implantation was modified in 25% of the women and that if the embryo transfer timing was modified according to the data obtained with the use of the ERA biopsy, the implantation rates were similar to those with a normal receptive endometrium WOI. In this study, patients’ mean ages were 38.4 ± 4.7 in the RIF group and 39.1 ± 5.1 in the control group, respectively. However, 34.9% of those in the RIF group and 59.1% of those in the control group obtained embryos issued from oocyte donation. Hashimoto et al. conducted a quite similar study in Japan [8], and with the use of the ERA biopsy test, they identified the endometrium receptivity prior to performing the embryo transfer. These authors did not identify a significant difference in implantation rates between the receptive group and the non-receptive group (32.8% vs. 31.6%, respectively). The actual data linking the ERA biopsy test and RIF is limited to a prospective non-randomized trial and three retrospective studies, all reporting that the frequency of a receptive endometrium could be slightly lower in those women with RIF when compared with controls after benefiting from an ERA biopsy test. These studies report that women with RIF had similar pregnancy rates to those in the control group when the endometrium was determined to be receptive on the ERA biopsy test. Recently, Simon et al., published a prospective study, analyzing the ART results after modifying the embryo transfers timing according to ERA biopsy test results, suggesting a type of personalized embryo transfer (PET) [9]. These authors adjusted the progesterone treatment duration guided by the ERA biopsy test results after decrypting the endometrial transcriptomic profile at the time of WOI [10]. This international study stretched over five years, performed in association with 16 IVF centers, and included in total 266 per-protocol patients divided into three groups, treated with antagonist or agonist controlled ovarian stimulation protocols with or without PGT-A. The study concluded, based on the pregnancy rate, that the personalized embryo transfer was more successful. On the contrary, the same authors reported, miscarriage rates were significantly higher in the PET group and no difference in the live birth rate (LBR) when compared with controls. These results strongly questioned the true value of the PET strategy [10]. In the end, the aforementioned study only strengthens those voices that doubt the efficacy of the ERA biopsy test for embryo transfer timing. The lack of efficacy with the use of PET strategy in concordance with the ERA biopsy test results was also validated by Neves et al. [11], who reported that in their study, ART outcomes were not improved in patients using ERA biopsy test results for PET. Likewise, in good prognosis patients, performing an ERA biopsy test in the cycle prior to the embryo transfer did not show to increase clinical pregnancy rates [11]. In the future, more studies with appropriate control groups and improved methodology are needed in order to validate the clinical relevance of the PET strategy.
Based on the same ideologies, other groups proposed different receptivity tests. It is worth mentioning a receptivity test based on miRNA profiles and the expression of 11 genes selected for their role in the control of endometrial receptivity [11]. Other authors looked into the role of BCL6 expression in the endometrium and the likelihood and or relation of progesterone resistance in women with endometriosis as possible predictors of implantation failure [12]. Recent research showed that in patients with endometriosis, the ART outcomes are similar following frozen euploid blastocyst transfers and therefore validating the hypothesis that any possible detrimental effects endometriosis might exert over the endometrium could be neutralized or bypassed in hormonal substituted cycles used nowadays often for frozen embryo transfers (FET). In patients with unexplained or endometriosis-related infertility, an increased BCL6 expression has identified the endometrium [12]. Although the majority of patients with endometriosis have been found to present an aberrant BCL6 expression, the same may also occur in the absence of evident endometriosis. In any case, increased expression of BCL6, a transcriptional gene repressor, has been related to progesterone resistance by early interfering with progesterone signaling [13]. In patients with unexplained infertility following IVF treatments, a recent study performed by Almquist et al. reported a live birth rate of 11.5% and 58% in patients with and without increased BCL6 expression, respectively [14]. In a prospective non-randomized study, Likes et al., reported that GnRH agonist treatment or endometriotic surgical lesions management could significantly improve ART outcomes [15].
Other authors proposed the search for the ideal immunologic endometrial profile capable of optimizing implantation rates in RIF [16]. Their approach is interesting but not yet clinically validated with an RCT.
RIF has also been linked with the uterine natural killer cells (uNKS), but the exact role they carry remains still controversial. NK cell level and activity is just one aspect of the immune system involved in women suffering from infertility, and more and better data are needed in order to make this information clinically relevant. Given the menstrual cycles variations also due to hormonal fluctuations makes it extremely hard to measure or establish an immunological profile.
Chronic endometritis (CE) has been diagnosed in several patients with RIF. It is often described with minimal or no clinical symptoms of infection [17]. In the infertile women, Kushnir et al. reported that 45% had CE [18]. The relatively increased prevalence of CF of 14% in RIF patients was confirmed by Bouet et al. [19]. Traditionally CE has been diagnosed using histological examination, or hysteroscopy, and by bacterial culture. Nowadays, the CE diagnosis can be more accurate with the help of Immunohistochemistry CD 138 by identifying the number of stained plasma cells present, although the standard number required for a correct diagnosis has not yet been established. A newer method of CE diagnosis using RT-PCR in order to identify the bacterial DNA with a sensitivity of 75% and a specificity of 100% when compared with the results of other standard tests (hysteroscopy, histology, culture) [20]. The importance of the diagnosis was doubled by the ART outcomes after specific treatment. The implantation rate of those women cured of infection with antibiotics was 37%, compared with 17% in those that were not. The LBR in the IVF cycle after the antibiotic treatment was also 61% compared with 13% in those that did not benefit from antibiotic treatment [17]. It has also been suggested that in certain cases, it is not the chronic inflammation that interferes with implantation rates but rather the modification in the microbiome constituents [20].
Implantation failures could also be a result of several uterine pathologies as myomas, polyps, uterine septum, and intrauterine adhesions, as their prevalence is significant in the RIF population. These abnormalities can impact ART outcomes at times. Very often, these problems are asymptomatic and therefore sometimes underdiagnosed on transvaginal ultrasound, suggesting that other methods of uterine assessment are needed, such as diagnostic hysteroscopy. Several types of myomas can alter uterine contractility and impair several endometrial cytokine expressions. In the case of the uterine septum, women with this pathology have a decreased cumulative pregnancy rate, increased miscarriage rate, increased preterm birth rate, and increased incidence of malpresentation at delivery [21]. The presence of these uterine abnormalities can also disturb normal vascularization as well as induce a mechanical effect on both the endometrium and the myometrium with consequent altered HOXA gene expressions. Surgical treatment of uterine abnormalities can, in some cases, produce complications as intrauterine adhesions and/or infection that consequently can impair implantation.
The female reproductive tract microbiome has been investigated recently, also in relation to RIF. So far, two types of uterine microbial have been correlated to infertility: the Lactobacillus-dominated (>90% lactobacilli) and non-Lactobacillus-dominated (<90% lactobacilli with >10% of other bacteria). The last one is associated with decreased live birth rates [22]. The microbiome will probably be better understood in the future, but for now, data is still debated given that a different study found no correlation between lactobacilli concentration and pregnancy in ART and reported a dominance of other bacteria, such as Flavobacterium spp. [23].
Other add-ons, less used generally, as endometrial scratching or embryo glue have not yet been validated by the existing data.
Although controversial, platelet enriched plasma (PRP) uterine administration has gained a lot of attention recently, and medical providers looked into its use in the case of RIF. Recent findings in a systematic review suggest that PRP is an alternative treatment strategy in patients with thin endometrium and RIF [24]. Given the small amount of good quality data, further prospective, large, and high-quality randomized controlled trials (RCTs) are needed to identify the subpopulation that would most benefit from this PRP treatment.

References

  1. Pirtea, P.; Scott, R.T., Jr.; de Ziegler, D.; Ayoubi, J.M. Recurrent implantation failure: How common is it? Curr. Opin. Obstet. Gynecol. 2021, 33, 207–212.
  2. Macklon, N.S.; Brosens, J. The human endometrium as a sensor of embryo quality. Biol. Reprod. 2014, 91, 98.
  3. Craciunas, L.; Gallos, I.; Chu, J.; Bourne, T.; Quenby, S.; Brosens, J.J.; Coomarasamy, A. Conventional and modern markers of endometrial receptivity: A systematic review and meta-analysis. Hum. Reprod. Updat. 2019, 25, 202–223.
  4. Rock, J.; Bartlett, M.K. Biopsy studies of human endometrium: Criteria of dating and information about amenorrhea, menorrhagia, and time of ovulation. J. Am. Med. Assoc. 1937, 108, 2022–2028.
  5. Noyes, R.; Hertig, A.; Rock, J. Reprint of: Dating the endometrial biopsy. Fertil. Steril. 2019, 112, e93–e115.
  6. Bassil, R.; Casper, R.; Samara, N.; Hsieh, T.-B.; Barzilay, E.; Orvieto, R.; Haas, J. Does the endometrial receptivity array really provide personalized embryo transfer? J. Assist. Reprod. Genet. 2018, 35, 1301–1305.
  7. Ruiz-Alonso, M.; Blesa, D.; Gimeno, P.D.; Gómez, E.; Fernández-Sánchez, M.; Carranza, F.; Carrera, J.; Vilella, F.; Pellicer, A.; Simón, C. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil. Steril. 2013, 100, 818–824.
  8. Hashimoto, T.; Koizumi, M.; Doshida, M.; Toya, M.; Sagara, E.; Oka, N.; Nakajo, Y.; Aono, N.; Igarashi, H.; Kyono, K. Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: A retrospective, two-centers study. Reprod. Med. Biol. 2017, 16, 290–296.
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  10. Mahdian, S.; Pirjani, R.; Favaedi, R.; Movahedi, M.; Moini, A.; Shahhoseini, M. Platelet-activating factor and antiphospholipid antibodies in recurrent implantation failure. J. Reprod. Immunol. 2021, 143, 103251.
  11. Neves, A.R.; Devesa, M.; Martínez, F.; Garcia-Martinez, S.; Rodriguez, I.; Polyzos, N.P.; Coroleu, B. What is the clinical impact of the endometrial receptivity array in PGT-A and oocyte donation cycles? J. Assist. Reprod. Genet. 2019, 36, 1901–1908.
  12. Lessey, B.A.; Young, S.L. What exactly is endometrial receptivity? Fertil. Steril. 2019, 111, 611–617.
  13. Yoo, J.Y.; Kim, T.H.; Fazleabas, A.T.; Palomino, W.A.; Ahn, S.H.; Tayade, C.; Schammel, D.P.; Young, S.L.; Jeong, J.W.; Lessey, B.A. KRAS Activation and over-expression of SIRT1/BCL6 contributes to the pathogenesis of endometriosis and progesterone resistance. Sci. Rep. 2017, 7, 6765.
  14. Almquist, L.D.; Likes, C.E.; Stone, B.; Brown, K.R.; Savaris, R.; Forstein, D.A.; Miller, P.B.; Lessey, B.A. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: A cohort study. Fertil. Steril. 2017, 108, 1063–1069.
  15. Likes, C.E.; Cooper, L.J.; Efird, J.; Forstein, D.A.; Miller, P.B.; Savaris, R.; Lessey, B.A. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J. Assist. Reprod. Genet. 2019, 36, 483–490.
  16. Lédée, N.; Petitbarat, M.; Prat-Ellenberg, L.; Dray, G.; Cassuto, G.N.; Chevrier, L.; Kazhalawi, A.; Vezmar, K.; Chaouat, G. Endometrial immune profiling: A method to design personalized care in assisted reproductive medicine. Front. Immunol. 2020, 11, 1032.
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  19. Bouet, P.E.; El Hachem, H.; Monceau, E.; Gariépy, G.; Kadoch, I.J.; Sylvestre, C. Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: Prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis. Fertil. Steril. 2016, 105, 106–110.
  20. Moreno, I.; Cicinelli, E.; Garcia-Grau, I.; Gonzalez-Monfort, M.; Bau, D.; Vilella, F.; De Ziegler, D.; Resta, L.; Valbuena, D.; Simon, C. The diagnosis of chronic endometritis in infertile asymptomatic women: A comparative study of histology, microbial cultures, hysteroscopy, and molecular microbiology. Am. J. Obstet. Gynecol. 2018, 218, 602.e1–602.e16.
  21. Chan, Y.Y.; Jayaprakasan, K.; Tan, A.; Thornton, J.G.; Coomarasamy, A.; Raine-Fenning, N.J. Reproductive outcomes in women with congenital uterine anomalies: A systematic review. Ultrasound Obstet. Gynecol. 2011, 38, 371–382.
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  23. Franasiak, J.M.; Werner, M.D.; Juneau, C.R.; Tao, X.; Landis, J.; Zhan, Y.; Treff, N.R.; Scott, R.T. Endometrial microbiome at the time of embryo transfer: Next-generation sequencing of the 16S ribosomal subunit. J. Assist. Reprod. Genet. 2016, 33, 129–136.
  24. Maleki-Hajiagha, A.; Razavi, M.; Rouholamin, S.; Rezaeinejad, M.; Maroufizadeh, S.; Sepidarkish, M. Intrauterine infusion of autologous platelet-rich plasma in women undergoing assisted reproduction: A systematic review and meta-analysis. J. Reprod. Immunol. 2020, 137, 103078.
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