American Society for Reproductive Medicine recurrent implantation failure: a committee opinion

DEFINITION OF RECURRENT IMPLANTATION FAILURE (RIF)

Implantation is ‘‘the attachment and subsequent penetration by a blastocyst into the endometrium’’ (1). This process begins 5–7 days after oocyte fertilization. Clinically, implantation is observed initially with the presence of human chorionic gonadotropin (HCG) in serum or urine assays and further by identifying an intrauterine gestational sac on ultrasound (2,3). Implantation failure has been defined variably as an inability to reach one or both of these milestones. Multiple criteria have been used to define RIF, initially focusing on the number of unsuccessful treatment or transfer cycles; more recently, criteria have incorporated patient characteristics and embryo ploidy into the definition (4–6). Other criteria use predicted probabilities of success on the basis of models that include variables, such as the number of embryos transferred, patient age, and euploidy status. Some have argued that RIF is not a real clinical entity because it may simply represent a statistical aberration, and with successive transfers of euploid embryos, all patients will eventually have implantation (4, 7). A summary of these suggested definitions is presented in Table 1 (4, 5, 7–17). There currently is no uniformly accepted definition of RIF.

Summary statement

• Age-related aneuploidy generally is believed to be the principal cause of implantation failure, given that aneuploid blastocysts have very limited potential for sustained implantation or live birth.

Complexities with defining implantation in RIF studies

Previously, RIF has referred to the condition in which multiple embryo transfers have failed to result in clinical detection of pregnancy, via detection of HCG in laboratory assays or ultrasonographic evidence of implantation. The prevalence of RIF is uncertain because of the lack of a standardized definition. This document seeks to define RIF and provide an evidence-based approach to its management. Where evidence is lacking, expert consensus was used to provide clinical guidance.

The use of positive HCG levels to define implantation provides an opportunity to avoid overlap with recurrent pregnancy loss (RPL), which defines RPL as two pregnancy losses, including biochemical losses (18, 19). The use of HCG levels as part of an RIF definition is advantageous, as HCG levels are routinely checked 9–11 days after blastocyst and cleavage-stage embryo transfers, respectively. The variability of levels used to determine pregnancy may vary by laboratory and depend on the assays used. A recent consensus conference defined RIF as those patients not demonstrating a gestational sac (a clinical pregnancy) on ultrasound, despite a 95% chance of implantation following multiple embryo transfers (4). This definition would include patients with failed implantations and those with biochemical losses (4). A number of similar studies using ultrasound evidence of implantation have been published, and data from these studies provide an estimate of the number of embryos needed to transfer to achieve a diagnosis of RIF in various age groups to determine a 95% chance of implantation (Fig. 1). Studies using negative HCG levels in cycles to diagnose RIF were not available to determine a 95% chance of positive HCG in embryo transfer cycles. Nevertheless, our definition uses HCG as the marker of implantation.

Summary statement

• Inconsistent definitions have been used for RIF, and research is comprised largely of observational studies.

ASRM definition of RIF

On the basis of the available evidence, we recommend the following criteria be used in the definition of RIF: RIF should be defined as the failed implantation of the estimated number of good-quality blastocysts to achieve a 95% cumulative chance of a positive pregnancy test. Figure 1 provides an estimated number of embryos to transfer (euploid vs. nontested) to meet this definition; however, it may overestimate the number of transfers as the data are obtained from studies using ultrasound evidence of implantation rather than serum HCG levels (4, 7, 13, 20).

Summary statement

• According to ASRM, RIF should be defined as the failed implantation of the estimated number of good-quality blastocysts to achieve a 95% cumulative chance of a positive pregnancy test. Current literature suggests that RIF should be defined after 3–6 failed euploid-tested embryo transfers or after a number of untested embryo transfers, depending on age.
  
  

APPROACH TO RIF EVALUATION AND MANAGEMENT

It is important to acknowledge the challenges in providing evidence-based recommendations for the evaluation and management of RIF patients, given inconsistent definitions of RIF and limited randomized trials. This document synthesizes available research and expert opinion to propose a reasonable approach to patient care. In many cases, guidance is based on observational data and expert consensus. Further high-quality research is needed to establish evidence-based practice recommendations using a universally agreed-upon definition of RIF.

When evaluating a patient for RIF, a comprehensive review of the patient’s medical and reproductive history, imaging, and in vitro fertilization (IVF) cycle details is critical to identifying and addressing potential factors contributing to failed implantation. Optimizing or correcting certain factors may improve live birth rates (LBRs). The following provides a general framework to consider in the evaluation and management of patients with RIF (Table 2). However, if no clear, correctable cause is identified after a detailed review of the patient’s history, the ASRM Practice Committee advises that extensive testing is unnecessary. It is reasonable to proceed with additional embryo transfer procedures, as many patients will ultimately achieve pregnancy.

GENETIC CAUSES

Aneuploidy

Age-related aneuploidy generally is believed to be the principal cause of implantation failure, given that aneuploid blastocysts ave very limited potential for sustained implantation or live birth (21–23). Euploid-tested embryos show significantly higher blastocyst development rates (68.2%) compared with chromosomally abnormal (42.8%, P< .0001) and mosaic (53.7%, P< .0001) embryos (24). Current data suggest that transfer of a single euploid-tested embryo transfer results in a positive pregnancy test in 45%–80% of transfers and a clinical intrauterine pregnancy in 30%–80% of transfers, depending on several factors, including embryo morphology and day of biopsy (25–27). A prospective trial in which 484 patients underwent transfer, blinded to preimplantation genetic testing for aneuploidy (PGT-A) results, 102 aneuploid embryos were transferred, and a positive pregnancy test was noted in 40% of these transfers, with 0% live birth (23). The prevalence of aneuploidy reported in women in their late 20s and early 30s is approximately 30% and increases with age, with the reported prevalence of aneuploidy of roughly 50% at age 38 and 90% at age 45 (20). No study has investigated specifically whether the implantation and LBRs in the RIF patient population improve after the use of PGT-A. However, given the prevalence of aneuploidy, use of PGT-A could be offered to patients who experience RIF with untested embryos in a shared decision-making model to investigate the contribution of embryo ploidy status as a potential etiology. Overall, PGT-A has not been shown to improve LBR in patients with infertility, and more data are needed to determine the utility of PGT-A in patients with RIF (28).

Summary statements

• Preimplantation genetic testing for aneuploidy could be offered to patients who experience RIF with untested embryos in a shared decision-making model to investigate the contribution of embryo ploidy status as a potential etiology. Overall, PGT-A has not been shown to improve LBR in patients with infertility, and more data are needed to determine the utility of PGT-A in patients with RIF (28).
• There is no evidence that PGT-A increases the chance of live birth for patients with RIF.

Inherited parental chromosomal abnormalities

While aneuploidy in embryos mostly originates from meiotic errors in oocytes, in some cases, it may arise from parental germline chromosomal abnormalities (29–31). Reciprocal balanced translocations and nonreciprocal Robertsonian translocations are the most common germline chromosomal abnormalities. In one study, preimplantation genetic testing for structural rearrangements (PGT-SR) was performed on 87 embryos from 22 couples in whom one partner carried a balanced translocation or an inversion, and 65.5% (n = 57/ 87) of these embryos had unbalanced or sporadic aneuploidies (32). Similarly, a study of 98 embryos from 21 couples with balanced or Robertsonian translocations identified 69.4% of aneuploid embryos using NGS (33). The risk of identifying parental germline chromosomal abnormalities may be higher in the RIF patient population, with translocations being the most common parental karyotype. In a study of 65 couples with no clinical pregnancy after ≥6 IVF cycles and ≥15 transferred embryos, karyotyping showed chromosomal abnormalities in 15.4% (n = 10/65, including 6 translocations, 2 mosaicism, 1 inversion, and 1 deletion) of couples (either male or female patient) (34, 35). More recent studies, however, suggest that the rate of parental chromosomal abnormalities is much lower. In a study of 615 patients (317 women and 298 men) who did not achieve a clinical pregnancy visible on ultrasound after 5.0 ± 1.9 sequential IVF/intracytoplasmic sperm injection cycles with fresh embryo transfers, chromosomal abnormalities were diagnosed in 2.1% of patients (n = 13/615, including 7 translocations, 3 mosaicism, 2 inversions, 1 deletion) (36). Separate studies of 219 and 111 patient couples with varying definitions of RIF found the rate of parental chromosomal abnormalities to be 2.5% and 3% in this population, respectively (37, 38).

Summary statement

• Parental karyotyping may be considered to investigate structural rearrangements as an underlying cause. If parental chromosomal abnormalities exist, genetic counseling is recommended, and PGT-SR testing may be offered.
  
  

Sperm DNA testing and potential treatment

While sperm DNA fragmentation is a possible etiology in RPL, little evidence exists to link sperm DNA fragmentation as a possible cause for patients with RIF (39). There are several techniques for measuring sperm DNA fragmentation, and it is not clear which is best at this time. There also is a lack of data to link RIF with abnormal sperm parameters or sperm aneuploidy. One small study evaluated partners of RIF patients (defined as at least three failed transfers with four good-quality embryos) and found no association of sperm DNA fragmentation and RIF (40). While there may be an association between DNA fragmentation and assisted reproductive technology failure, specific treatments have not been proven to improve outcomes (41).

Summary statement

• While sperm DNA fragmentation may be considered in the evaluation of RPL, there is insufficient evidence to recommend sperm DNA fragmentation testing in an RIF population (see Table 2).
  
  

STRUCTURAL CAUSES

Endometrial cavity evaluation before embryo transfer is a well-established step to rule out abnormalities of the female reproductive tract (including septate uteri, endometrial polyps, leiomyomas, and intrauterine adhesions). Sonohysterography (SHG) identifies more endometrial abnormalities compared with a hysterosalpingogram (HSG) (42). Three-dimensional transvaginal ultrasound (3D US) is another reliable method for assessing the uterine cavity (43). Furthermore, the presence of other structural factors, such as hydrosalpinges and adenomyosis, are suggested causes of implantation failure (17, 44). The management of septate uteri, intrauterine adhesions, and hydrosalpinges among all patients with infertility are discussed in other practice documents (45–47).

It is unclear whether the uterine cavity should be reevaluated after a diagnosis of RIF. It may be particularly helpful for patients with an inadequate endometrial thickness. Indeed, RIF patients may have new endometrial pathology after initial evaluation. In a study of women who failed to conceive after ≥3 IVF cycles, 18.2% had new pathology identified during hysteroscopy (48). A separate prospective trial of 266 women found that hysteroscopy detected abnormalities in almost 40% of RIF patients with ≥2 failed transfer cycles, and 48.1% of these abnormalities were not identified on HSG completed two months before hysteroscopy (49). However, in a randomized controlled trial (RCT) of 702 women, hysteroscopy did not improve outcomes among RIF patients with 2–4 failed IVF cycles ending in embryo transfer with normal endometrial appearance on transvaginal ultrasound (50). Given that some studies show benefit to the treatment of intrauterine pathology, it is reasonable to offer patients repeat uterine cavity evaluation in the setting of RIF.

Summary statement

• For women diagnosed with RIF, it is reasonable to repeat the endometrial and tubal assessment with SHG, hysteroscopy, HSG, or 3D US. Hysteroscopy has the added benefit of treating uterine pathology detected at the time of cavity assessment.
  
  

Endometrial polyps

There is moderate evidence that endometrial polyps adversely impact endometrial receptivity and implantation in women trying to conceive. Endometrial polyps are associated with decreased expression of genes involved in implantation (51–53), and a single randomized trial demonstrated a significant increase in pregnancy rate (PR) following polypectomy before intrauterine insemination (54). However, there is a lack of evidence that polypectomy before IVF improves implantation or live birth (54).

Leiomyomas

While there is fair evidence that submucosal myomas impact clinical PRs in all patients by reducing embryo implantation, the role of intramural and subserosal leiomyomas, if any, is less clear (55). A 2018 meta-analysis including 9,189 IVF cycles reported that noncavity distorting intramural leiomyomas reduced the LBR (relative risk [RR], 0.82), clinical PR (RR 0.86), and implantation rate (RR 0.90) compared with controls; however, most of the studies included in this meta-analysis were retrospective and included leiomyomas of varying sizes (56). A 2023 systematic review and metaanalysis including 520 women with noncavity distorting leiomyomas and 1,392 controls found lower LBRs among women with 2–6 cm noncavity distorting intramural leiomyomas (57). Unfortunately, evidence to guide treatment remains lacking (57).

Summary statement

• On the basis of limited data, it is reasonable to offer women hysteroscopy for uterine cavity evaluation and removal of endometrial polyps and submucosal myomas. However, there is insufficient evidence to make recommendations about treatment for noncavity distorting leiomyomas.
  
  

Endometriosis

Endometriosis is a common condition that has been associated with infertility, although the mechanism of action remains unknown (58, 59). A large, systematic review and meta-analysis showed that women with known endometriosis and infertility have improved odds of pregnancy with either laparoscopy or GnRH agonist therapy (60). Unfortunately, there is no high-quality evidence comparing laparoscopy to GnRH agonist therapy (61, 62), and it is unclear what duration of GnRH agonist therapy to recommend (63, 64). These studies were not among women undergoing assisted reproductive technology. One large, retrospective, cohort study noted that RIF patients who had failed to become pregnant after the transfer of two blastocysts had higher clinical pregnancy and LBRs when treated with gonadotropin-releasing hormone (GnRH) agonist therapy and an aromatase inhibitor for two months before frozen embryo transfer (FET), compared with women receiving only GnRH agonist therapy for two months or no treatment (65). Although the prior study specifically excluded women with known endometriosis, the investigators theorized that the treatment was effective because of underlying undiagnosed endometriosis.

It has been proposed that women with RIF should undergo testing for endometriosis and treatment if found. B-cell Lymphoma 6 (BCL-6) is a key oncogene that is upregulated in endometriosis (66) and has been associated with poor reproductive outcomes in IVF cycles (67). Studies suggest BCL-6 has a 96% positive predictive value for a diagnosis of endometriosis compared with laparoscopy (68), and BCL-6–positive patients had higher implantation rates, clinical PRs, and LBRs when treated with either GnRH agonist therapy for 2 months or laparoscopic resection than women with expectant management before embryo transfer (69). A recent retrospective cohort study noted that the endometrial BCL-6 histologic score (HSCORE) was significantly lower in patients receiving exogenous progesterone exposure compared with natural cycle scores, questioning the validity and use of BCL-6 testing in differing FET cycle protocols (70). Additionally, a recent small case-control study of normal responders showed no association between BCL-6 expression and live birth outcomes in cohorts who failed one transfer vs. those attempting the first transfer, questioning the use of this test (71).

Summary statement

• Given the conflicting evidence regarding the validity of BCL-6 testing and efficacy of appropriate treatment, routine BCL-6 testing in women with RIF is not recommended. Limited evidence, while based on one retrospective cohort study, supports empiric treatment with GnRH agonists and/or aromatase inhibitors before embryo transfer in patients with RIF. However, further studies are needed to determine the most effective treatment regimen and the population most likely to benefit from the treatment.
  
  

Adenomyosis

A systematic review noted that adenomyosis is present in up to 25% of infertile women and is common particularly in women with RIF (72). This review noted that adenomyosis is associated with reduced implantation rates. A separate meta-analysis had similar findings and reported that either surgical treatment or GnRH agonist pretreatment increases PRs (73). Another systematic review suggested that the optimal treatment course might differ for patients with focal vs. diffuse adenomyosis; however, the investigators cautioned that the available literature is insufficient to guide treatment (74). None of these trials were in women with RIF specifically. More high-quality studies are needed to formulate evidence-based practice recommendations specifically for RIF patients with adenomyosis.

Summary statements

• Endometriosis and adenomyosis are prevalent in women with RIF, and higher-quality studies are needed to guide diagnosis and treatment.
• There is limited evidence to support the use of GnRH agonist or surgery in women with adenomyosis before embryo transfer.
• Precycle treatment with a GnRH agonist and an aromatase inhibitor before embryo transfer may be considered for patients with known or suspected adenomyosis or endometriosis and RIF.
• There is insufficient evidence currently to recommend routine BCL-6 testing in patients with RIF.
  
  

TECHNICAL ISSUES RELATED TO EMBRYO TRANSFER

There is a paucity of high-quality evidence specific to patients with RIF to guide clinical practice; however, a systematic review and meta-analysis reported a relative reduction in clinical pregnancy of at least 24% when embryo transfer is difficult (75). While the cause of a difficult embryo transfer is not always known, a 2018 systematic review noted that cervical stenosis was the most common cause of difficult embryo transfer and that cervical dilation at least three weeks before embryo transfer results in a higher PR (76). A more recent, large, prospective, observational, cohort study noted that cervical abnormalities, including endocervical crypts and a tortuous cervical canal, and marked uterine anteversion were the most common causes of a difficult embryo transfer (77). Cervical dilation at least three weeks before transfer in patients with previous difficult transfers may result in higher PRs (76).

The ASRM has previously published a guideline on the evidence-based embryo transfer and recommends transabdominal ultrasound during embryo transfer, the use of a soft embryo transfer catheter, removal of cervical mucus, >1 cm from the fundus for embryo expulsion, and immediately withdrawing the embryo transfer catheter after embryo expulsion (78). While these recommendations improve pregnancy (and in some instances LBRs) among patients undergoing embryo transfer, no studies have been performed specifically for embryo transfers in patients with RIF.

Summary statement

• Although data are not specific to patients with RIF, ASRM embryo transfer guidelines should be followed to improve IVF success rates.
  
  

HORMONAL CAUSES

Hormonal testing and supplementation during fresh and FET cycles

Progesterone is critical for endometrial support and embryo implantation, and intramuscular progesterone has been shown to improve LBRs in non-RIF IVF populations. There are limited studies addressing optimal progesterone supplementation specifically in the RIF population. One prospective study compared 86 women with RIF, defined as lack of implantation after ≥3 high-quality embryo transfers, with 37 controls who underwent programmed FET cycles with vaginal progesterone supplementation. Serum progesterone levels on the day of embryo transfer were comparable in the RIF cohort and controls 39 nmol/L (15.6 ng/mL; 95% confidence interval [CI] 36.0–41.9 nmol/L) vs. 44 nmol/L (17.6 ng/mL; 95% CI, 38.6–49.3 nmol/L; P = .078) (79). Studies are limited with respect to progesterone levels on the day of transfer for programmed FET cycles with RIF patients using IM progesterone.

Summary statement

• There are insufficient data to recommend a particular progesterone supplementation protocol in RIF patients.
  
  

Endometrial Receptivity Testing

Endometrial receptivity is the ability of the endometrium to permit attachment and invasion of the blastocyst (80). The endometrial receptivity analysis (ERA) uses next generation sequencing to measure the expression of 248 genes to classify the endometrium as receptive or nonreceptive, providing an adjusted progesterone duration in a subsequent cycle for nonreceptive endometrium. Conflicting evidence remains on the use of ERA in RIF patients: initial studies demonstrated improved clinical outcomes, but recent studies found no improvement. A significant factor limiting the interpretation and comparison of results across studies remains the lack of a consistent definition for RIF.

One of the first prospective cohort studies evaluating the ERA provided preliminary data based on 8 RIF patients that a personalized embryo transfer (ET) on the basis of the ERA led to a 50% PR and 38.5% implantation rate (81). Since then, multiple recent retrospective studies have not shown an improvement in success rates following ERA testing. A retrospective study comparing 131 women with ≥1 prior failed ET with 91 controls who underwent an ERA test with subsequent FET found no difference in pregnancy outcomes (82). Similarly, another single-center, retrospective study of 24 patients with ≥1 failed euploid-tested embryo transfer compared with 119 controls showed no difference in implantation rate (55.6% vs. 65%) or PR (defined as a gestational sac containing an embryo with a heartbeat) (58.3 vs. 70.6%) following an ERA test (83). Another retrospective study included patients with a single previous failed transfer, both autologous transfers and donor transfers (84). Pregnancy outcomes were worse in both groups following ERA testing. A retrospective cohort study compared 67 RIF patients who underwent ERA and personalized FET to 32 RIF patients who underwent standardized FET, and again, there was no difference in pregnancy outcomes (85).

Two RCTs have been conducted for the ERA test. The first RCT was a multicenter, open-label RCT with 438 patients ≤37 years undergoing IVF with blastocyst transfer and was not limited to RIF patients (86). Despite a 50% dropout rate, an intention-to-treat analysis did not show improvement in clinical outcomes. A well-designed, double blind RCT at 31 sites included 767 women who underwent IVF, PGT-A, ERA testing, and FET (87); 381 women underwent FET of euploid embryo(s) on the basis of ERA testing results, and 386 control women underwent FET at standard timing, while blinded to ERA results. This study concluded that using ERA to guide the timing of a euploid-tested FET, compared with standard timing for transfer, did not significantly improve the LBR. A subsequent, secondary analysis of the same study investigating the diagnostic accuracy of the ERA demonstrated an area under the curve of 0.52, indicating the poor ability to predict implantation failure (88). These studies specifically excluded women with RIF defined as >2 failed embryo transfers, which may limit the generalizability of the results (89).

Summary statement

• There is insufficient evidence to support routine use of ERA testing in RIF patients.
  
  

INFLAMMATORY AND HEMATOLOGIC CONDITIONS

Vaginal and endometrial cavity microbiome alterations

Recent data have demonstrated that the uterine cavity and placenta are colonized with bacteria (90). Like the vaginal microbiota, the endometrial bacterial species usually is dominated by Lactobacilli (L. iners and L. crispatus) (91). Lactobacilli produce many important chemicals that are thought to be beneficial for embryo implantation and development (92), including lactic acids, bacteriocins, and hydrogen peroxide, which contribute to the inhibition of pathogens (93). A study of 35 women with infertility who underwent endometrial fluid sampling during IVF demonstrated a significant decrease in implantation rates (60.7% vs. 23.1%; P = .02), pregnancy (70.6% vs. 33.3%; P = .03), ongoing pregnancy (58.8% vs. 13.3%; P = .02), and live birth (58.8% vs. 6.7%; P = .002) rates in women who did not have a Lactobacillus-dominated (>90% Lactobacillus spp.) endometrial microbiota profile (94).

In 2020, Fu et al. (95) characterized the vaginal microbiota and metabolomes of patients with unexplained RIF, with patients who achieved clinical pregnancy in the first FET cycle serving as controls. On the basis of 16S rRNA gene sequencing of the vaginal microbiota, the vaginal Lactobacillus showed a significant positive correlation with the PR, and the RIF group presented higher microbial diversity than the control group (P = .016) (95). A recent study in 2022 interrogated uterine fluid from women with RIF. Of the 48 samples analyzed, 61 microRNAs (miRNAs) in uterine fluid were differentially expressed compared with healthy women (96). Interestingly, these miRNAs were expressed in endometrial epithelial cells and previously have been associated with endometrial receptivity and RIF. These data suggest the microbiome within the uterine cavity may be associated with a lack of implantation; however, further data are needed to determine if screening and treatment are appropriate for patients with RIF.

Chronic endometritis

The presence of pathogenic bacterial species can have an adverse effect on PRs and reproductive outcomes (94). The uterine cavity has been interrogated as a potential etiology for RIF. Over the last decade, studies have revealed the potential association between poor reproductive outcomes and endometritis, particularly chronic endometritis (CE) (97). A limitation of the current literature, however, is the use of varied testing methods, biopsy timing, and diagnostic criteria for defining CE. Chronic endometritis may be diagnosed with an endometrial biopsy demonstrating the presence of stromal plasma cells on histology and CD138+ plasma cells on immunohistochemistry, although there is no agreed-upon diagnostic criteria with respect to the number of plasma cells for diagnosing CE (98, 99). Hysteroscopy also may be used for diagnosis, with a sensitivity of 86% and specificity of 87% (100). Endometrial culture of bacteria and/or yeast growth also has been used in diagnosing CE (99). The standard treatment is antibiotic therapy, as the most common etiology is infection with Escherichia coli, Enterococcus faecalis, and Streptococcus agalactiae (98).

A 2015 retrospective study by Cicinelli et al. (101) evaluated 106 women with unexplained infertility and RIF and found that in women with CE, who received treatment and subsequently underwent IVF, those women who had normal repeat examinations had a significantly higher PR and LBR compared with women who had persistent signs of CE despite treatment (65.2 vs. 33.0%, P = .039; 60.8 vs. 13.3%, P = .02, respectively). A meta-analysis demonstrated similar results in 2018, wherein women receiving antibiotic therapy (without the histologic confirmation of CE cure) did not show any advantage in comparison with untreated controls (ongoing pregnancy rate [OPR]/LBR, cerebroplacental ratio [CPR], and insulin resistance [IR]). Patients with cured CE showed higher OPR/LBR (odds ratio [OR], 6.81), CPR (OR, 4.02), and IR (OR ,3.24) than patients with persistent CE (102). Additionally, a systematic review by Cheng et al. (103) in 2022 demonstrated that antibiotic treatment in women with RIF was associated with improved PRs when the condition was confirmed cured by a control biopsy. A recent systematic review and meta-analysis also demonstrated deleterious effects of CE on OPR/LBR, as women with CE had lower OPR/LBR (OR, 1.97, P = .02) compared with those without CE. The CE cure increased OPR/LBR (OR, 5.33, P< .0001). This study went on to restrict analysis to severe CE (≥5 plasma cells per high powered field [HPF]) compared with mild CE (1–4 plasma cells/HPF) and found those with severe CE had lower OPR/LBR (OR, 0.43, P = .003) compared with those with mild CE. The investigators hypothesized that the impact of CE may be focused only on those with ≥5 plasma cells/HPF (104). It is important to highlight the limitation of existing literature, given that existing studies are all observational, with varying definitions of CE and RIF, and with varying antibiotic treatments (i.e., doxycycline 200 mg/day, ciprofloxacin 1 g/day, and metronidazole 1 g/day for 14 days) (104).

Giulini et al. (98) assessed a cohort of 27 women with RIF who had an endometrial biopsy that showed the presence of CD56 and CD138 positive cells, which underwent treatment with prednisone and doxycycline, while those with only CD56 cells detected underwent treatment with prednisone. After treatment, the clinical PR was 25.9% in all patients, and for those with marked endometritis (>10% CD56+ cells), the LBR was 29.4%.

Summary statements

• There is some evidence from observational studies to support testing for CE and/or antibiotic treatment in patients with RIF. While one study suggests that a test of cure may be valuable, the lack of consensus on defining endometritis on pathology limits the generalizability of this strategy.
• Further research is needed, with prospectively randomized controlled trials, in this population to determine the best diagnostic and treatment strategy for CE in RIF patients.
  
  

Endometrial scratch

The incitation of endometrial injury in patients with RIF has been suggested previously to demonstrate benefit in patients with prior failed transfers (105). The endometrial biopsy, in theory, triggers local inflammation within the endometrial cavity, resulting in the release of cytokines and growth factors to enhance the implantation process (106). There have been conflicting data regarding the impact of endometrial injury on LBRs. Vitagliano et al. (106) performed a metaanalysis in 2018; although the endometrial injury group had a higher LBR (RR, 1.38; 95% CI, 1.05–1.80), there was no difference in outcomes in FET cycles.

A recent RCT of 200 patients who underwent at least two unsuccessful programmed FET transfers found that the rate of live birth in the endometrial injury group (51%) was significantly higher than that of the control group (36%; P = .032) (107). In contrast, a large RCT in 2019 evaluated 1,364 women undergoing IVF in either fresh or frozen embryo cycles demonstrated no difference in LBRs between endometrial scratch and control groups (adjusted OR, 1.00; 95% CI, 0.78–1.27). There was no evidence of any benefit of endometrial injury in those with ≥2 failed FET cycles (108).

Summary statement

• Overall, evidence suggests that endometrial injury is not effective and is not recommended in the treatment of RIF.
  
  

Thrombophilias

Thrombophilias have long been theorized as a potential cause of RIF, perhaps stemming from the previously established association of antiphospholipid antibody syndrome with RPL (18). Studies evaluating the potential effects of antiphospholipid antibody syndrome (APAS) on embryo implantation have shown no clear association between APAS and RIF. In patients without APAS, studies examining the potential benefits of taking heparin or low molecular weight heparin have shown conflicting results (109–111), without clear evidence that these agents confer a benefit.

Summary statement

• There are insufficient data to support routine testing for APAS in women with RIF, and there is insufficient evidence to support routine use of anticoagulation.
  
  

Immune therapies

The use of several immune agents has been reviewed previously in an ASRM practice guideline, which currently is being updated (112). Intravenous fat emulsion has previously been suggested to improve implantation rates for RIF patients by suppressing natural killer cell cytotoxicity. There is insufficient evidence to recommend intravenous fat emulsion therapy in RIF patients (112). Insufficient evidence also exists to suggest the use of granulocyte colony-stimulating factor for therapy in RIF patients at this time (112). Intravenous immunoglobulin also is not recommended for the treatment of RIF patients (18). An ASRM practice document from 2018 entitled ‘‘The role of immunotherapy in vitro fertilization: a guideline’’ is available and reviews data for immunotherapy agents in more detail.

Human chorionic gonadotropin has an important role in stimulating the secretion of various cytokines that are associated with the transformation of the endometrium to the secretory phase and, therefore, has been suggested as a means of improving the chance of implantation in women with RIF (113). In a meta-analysis that included data from 15 RCTs and 2,736 participants with infertility, intrauterine HCG infusion before ET resulted in a significantly higher LBR than in women who did not undergo HCG infusion (44.89% vs. 29.76%; OR, 1.89; 95% CI, 1.41–2.53). This analysis was limited by variation in HCG infusion methodology and dosing, and there was significant statistical heterogeneity in some of the outcome measures (113). Prior data regarding the efficacy of intrauterine infusion on implantation and PR are conflicting, and there are no high-quality data specifically examining intrauterine HCG infusion in patients with RIF. These studies have conflicting results, with no clear benefit, and additional RCTs are needed to determine if HCG infusion benefits RIF patients.

Etanercept and adalimumab are tumor necrosis factor-α inhibitors used commonly in women with rheumatoid arthritis, which has been associated with an increased incidence of infertility (114) and diminished ovarian reserve (115). A single-arm, prospective study of 91 women with RIF, who had failed at least three IVF cycles with five good-quality embryos transferred, showed an approximate 76% implantation rate and 63% LBR following treatment with etanercept. This study was limited by a small sample size and a lack of a control group (116). Currently, there is insufficient evidence for the use of etanercept in women with RIF, and use should be limited to properly designed RCTs (112).

Intrauterine infusion of platelet rich plasma (PRP) has been proposed as a mechanism for treating patients with RIF. PRP mediates its effects through cytokines and growth factors produced by platelets. The theoretical benefits of PRP for patients undergoing assisted reproduction are thought to be due to the stimulated growth and enhanced vascular development of the patient’s endometrial tissue, as well as intrinsic anti-inflammatory effects (117). While several studies and one meta-analysis demonstrated potential benefits of intrauterine PRP infusion in women with RIF and thin endometrium during embryo transfer cycles, there was wide variation in the definition of RIF for patients included in these studies, as well as with respect to the suspected etiology of RIF (118, 119). Dose and timing of PRP administration and key outcome measures vary significantly between studies. In addition, most studies lack a control group. While further study is warranted, there is insufficient evidence to support the use of PRP in patients with RIF currently.

Summary statement

• While immunomodulatory agents have been associated with a possible benefit for patients with RIF, further studies are needed to determine which treatments offer benefit. Currently, there is insufficient evidence to support the routine use of immunologic therapies for RIF patients.
  
  

LIFESTYLE FACTORS

Tobacco use

Limited studies currently exist on the direct correlation between factors, such as obesity, tobacco use, and alcohol use in RIF, but the adverse effect of tobacco use on fertility has been well-established. Women who are exposed to tobacco (active and passive) have elevated follicle-stimulating hormone levels (120) and a shorter interval to menopause. Estradiol levels are lower in women who use tobacco during IVF treatment (121). A meta-analysis in 1997 demonstrated that tobacco use was associated with decreased PRs, and smokers required almost twice as many cycles as nonsmokers to achieve pregnancy (122). Additionally, tobacco users had 40% fewer oocytes retrieved, depending on the timing and amount of tobacco used (123). A study by Van Voorhis et al. (124) demonstrated a 50% decrease in implantation rates and OPRs in women who smoked during treatment.

Summary statement

• Women should stop smoking before infertility treatments.
  
  

Obesity

Obesity is a significant health problem for many women suffering from infertility and may contribute to its pathogenesis. Significant changes in uterine receptivity and markers of decidualization, the process in which fibroblastic endometrial stromal cells differentiate into secretory decidual cells, are altered in women with obesity (125). In women with obesity and polycystic ovarian syndrome, which frequently are concomitant conditions, endometrial abnormalities have been noted because of alterations in glucose metabolism, compensatory hyperinsulinemia from an insulin-resistant state, and hyperandrogenism (126).

Obesity has multi-factorial effects on infertility; however, differences within the endometrium of women with obesity have been studied, and significant endometrial transcriptomic differences between obese and nonobese women have been noted. In 2017, Comstock et al. (127) analyzed the transcriptomic profile of endometrial gene alterations during the window of implantation in infertile patients with obesity. They discovered several alterations in genes involved in chemokine, cytokine, and immune system activity, as well as in the structural extracellular matrix and protein-binding molecular functions. Obesity is associated with significant endometrial transcriptomic differences as compared with nonobese subjects, and larger variations were noted as body mass index increased. These abnormalities within the endometrium of infertility patients with obesity may contribute to the lower implantation rates and increased miscarriage rates (127). However, a recent study, which followed women who reported either weight gain or weight loss in a period between two embryo transfer cycles, reported no increased embryo transfer success for patients with weight loss (128). This study did not specify precycle obesity or include RIF patients only.

Summary statement

• Patients should be encouraged to achieve healthy weights before pregnancy attempts and pregnancy to optimize outcomes (129), although the time required for weight loss must be weighed against the impact of advancing age on treatment outcomes.
  
  

Alcohol use

Few studies evaluate the risk of alcohol use and fertility treatments. A 2003 multicenter, prospective study evaluated 221 couples with female infertility and found that female alcohol consumption was associated with a 13% decrease in the number of eggs aspirated (95% CI, -2% to -23%, for one additional drink per day, 1 year before the IVF or gamete intrafallopian transfer attempt), an increase in risk of not achieving pregnancy by 2.86 times (95% CI, 0.99– 8.24, 1 month prior), and an increase in risk of miscarriage by 2.21 times (95% CI, 1.09–4.49, 1 week before the procedure) (130). Alcohol has been shown to have detrimental effects during pregnancy. Current recommendations include abstinence from alcohol, as there has been no safe level of alcohol use in pregnancy (131), and those trying to become pregnant should strictly limit alcohol use and not consume more than one or two alcoholic drinks once or twice a week (132).

Summary statement

• While lifestyle interventions have not been demonstrated to improve outcomes in patients with RIF, a healthy lifestyle and cessation of smoking, tobacco, and illicit drug use are recommended for general health for both partners and before pregnancy (133).
  
  

THIRD-PARTY REPRODUCTION

Recurrent implantation failure is diagnosed after multiple failed embryo transfers, which constitutes a significant risk of psychosocial distress for patients. Patients with multiple failed transfers should be offered social support following negative outcomes. The use of a gestational carrier can be considered after several failed embryo transfers (134).

FUTURE AREAS OF RESEARCH

In this document, RIF is defined as a recurrent lack of implantation, which is defined as a lack of a positive pregnancy test after embryo transfer. Assisted reproductive technology provides the opportunity to differentiate failed implantation from pregnancy loss. Factors contributing to RIF and treatments for RIF likely differ from those of RPL. Defining RIF and conducting research in the population is necessary to advance the treatment of infertility.

Future directions in the management of RIF include further investigation into the roles of specific factors that may be critical to embryo development, apposition, adhesion, and invasion of the endometrium (135). Currently, research is underway to investigate the role of HOXA-10 and E-cadherin, of which expression is reduced in women with RIF (136). Matrix metalloproteinases are proteins that have a crucial role in implantation, and for which dysregulation may contribute to RIF (137). A study investigating the use of quinolone antibiotics and corticosteroids to upregulate matrix metalloprotein activity showed a benefit in patients with RIF (138); however, further research is needed to determine whether these results are reproducible and generalizable.

Studies examining the expression and receptivity of progesterone receptors in patients with RIF have suggested that differences in progesterone receptor expression and phosphorylation may be associated with RIF (139). Progesterone binding elicits signaling that is critical to the formation of normal, decidual tissue, and abnormal progesterone receptor expression has been associated with adenomyosis and polycystic ovary syncrome (125). More recently, MicroRNAs (miRNAs) have been shown to play a critical role in embryo implantation. Variation in miRNA expression between aneuploid and euploid-tested embryos and in prereceptive vs. receptive endometrial tissue has been reported, as have variants in miRNA signaling in women with and without a diagnosis of RIF (125). Further investigation into the role of miRNA signaling in RIF and potential therapeutic avenues based on this are needed.

Summary statement

• High-quality research is needed to formulate evidence-based practice recommendations for RIF patients using a uniformly agreed-upon definition.
  
  

SUMMARY

• Inconsistent definitions have been used for RIF, and research is comprised largely of observational studies.
• According to ASRM, RIF should be defined as the failed implantation of the estimated number of good-quality blastocysts to achieve a 95% cumulative chance of a positive pregnancy test. Current literature suggests that RIF should be defined after 3–6 failed euploid-tested embryo transfers or after a number of untested embryo transfers, depending on age.
• Age-related aneuploidy generally is believed to be the principal cause of implantation failure, given that aneuploid blastocysts have very limited potential for sustained implantation or live birth.
• In patients who experience RIF, PGT-A could be offered with untested embryos in a shared decision-making model to investigate the contribution of embryo ploidy status as a potential etiology. Overall, PGT-A has not been shown to improve LBR in patients with infertility, and more data are needed to determine the use of PGT-A in patients with RIF (28).
• There is no evidence that PGT-A increases the chance of live birth for patients with RIF.
• Parental karyotyping may be considered to investigate structural rearrangements as an underlying cause. If parental chromosomal abnormalities exist, genetic counseling is recommended, and PGT-SR testing may be offered.
• While sperm DNA fragmentation may be considered in the evaluation of RPL, there is insufficient evidence to recommend sperm DNA fragmentation testing in an RIF population (see Table 2).
• For women diagnosed with RIF, it is reasonable to repeat the endometrial and tubal assessment with SHG, hysteroscopy, HSG, or 3D US. Hysteroscopy has the added benefit of treating uterine pathology identified during cavity assessment.
• On the basis of limited data, it is reasonable to offer women hysteroscopy for uterine cavity evaluation and removal of endometrial polyps and submucosal myomas. However, there is insufficient evidence to make recommendations about treatment for noncavity distorting leiomyomas.
• Given the conflicting evidence regarding the validity of BCL-6 testing and efficacy of appropriate treatment, routine BCL-6 testing in women with RIF is not recommended. Limited evidence, while based on one retrospective cohort study, supports empiric treatment with GnRH agonists and/or aromatase inhibitors before embryo transfer in patients with RIF. However, further studies are needed to determine the most effective treatment regimen and the population most likely to benefit from the treatment.
• Endometriosis and adenomyosis are prevalent in women with RIF, and higher-quality studies are needed to guide diagnosis and treatment.
• There is limited evidence to support the use of GnRH agonist or surgery in women with adenomyosis before embryo transfer.
• Precycle treatment with a GnRH agonist and an aromatase inhibitor before ET may be considered for patients with known or suspected adenomyosis or endometriosis and RIF.
• Although data are not specific to patients with RIF, ASRM ET guidelines should be followed to improve IVF success rates.
• There is insufficient data to recommend a particular progesterone supplementation protocol in RIF patients.
• There is insufficient evidence to support routine use of ERA testing in RIF patients.
• There is some evidence from observational studies to support testing for CE and/or antibiotic treatment in patients with RIF. While one study suggests that a test of cure may be valuable, the lack of consensus on defining endometritis on pathology limits the generalizability of this strategy.
• Further research is needed, with prospectively randomized controlled trials, in this population, to determine the best diagnostic and treatment strategy for CE in RIF patients.
• Overall, evidence suggests that endometrial injury is not effective and is not recommended in the treatment of RIF.
• There are insufficient data to support routine testing for APAS in women with RIF, and there is insufficient evidence to support routine use of anticoagulation.
• While immunomodulatory agents have been associated with a possible benefit for patients with RIF, further studies are needed to determine which treatments offer benefit. Currently, there is insufficient evidence to support the routine use of immunologic therapies for RIF patients.
• Patients should be encouraged to achieve healthy weights before pregnancy attempts and pregnancy to optimize outcomes (129), although the time required for weight loss must be weighed against the impact of advancing age on treatment outcomes.
• While lifestyle interventions have not been demonstrated to improve outcomes in patients with RIF, a healthy lifestyle and cessation of smoking, tobacco, and illicit drug use are recommended for general health for both partners and before pregnancy (133).
• High-quality research is needed to formulate evidence-based practice recommendations for RIF patients using a uniformly agreed-upon definition.
  
  

CONCLUSIONS

• When evaluating a patient for RIF, a comprehensive review of the patient’s medical and reproductive history, imaging, and IVF cycle details is critical to identify and address potential factors contributing to failed implantation, as correcting certain factors may improve LBRs.
• If no clear, correctable cause is identified after a detailed review of the patient’s history, the ASRM Practice Committee advises that extensive testing is unnecessary. It is reasonable to proceed with ET procedures, as many patients ultimately will achieve pregnancy.
• High-quality research is needed to formulate evidence-based practice recommendations for RIF patients using a uniformly agreed-upon definition.
  
  

Acknowledgments

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other management plans may be appropriate, taking into account the individual patient's needs, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The following members of the ASRM Practice Committee participated in the development of this document: Clarisa Gracia, M.D., M.S.C.E.; Paula Amato, M.D.; Rebecca Flyckt, M.D.; Elizabeth Ginsburg M.D.; Robert Brannigan, M.D.; Denny Sakkas, Ph.D.; Suneeta Senapati, M.D.; Ryan Smith, M.D.; Torie C. Plowden, M.D., M.P.H.; Madeline Brooks, M.P.H., M.B.A.; Jessica Goldstein, R.N.; Karl Hansen, M.D., Ph.D.; Micah Hill, D.O.; Sangita Jindal, Ph.D.; Suleena Kalra, M.D., M.S.C.E.; Tarun Jain, M.D.; Bruce Pier, M.D.; Jared Robins, M.D., M.B.A.; Chevis N Shannon, Dr.P.H., M.P.H., M.B.A.; Anne Steiner, M.D., M.P.H.; Cigdem Tanrikut, M.D.; and Belinda Yauger, M.D. The Practice Committee acknowledges the special contribution of Bruce Pier, M.D.; Erica Chang, M.D.; Jessica Lentscher, M.D.; Edward McClellan, M.D.; David Schirmer, M.D.; and Bo Yu, M.D., M.P.H. in the preparation of this document. All committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest on the basis of the relationships disclosed did not participate in the discussion or development of this document.

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