Abstract
Background
Globally, there is no conclusive data on the pregnancy outcomes of patients with recurrent implantation failure (RIF) who received the next embryo transfer. The purpose of this study is to summarize the pregnancy outcomes of patients with RIF after embryo transfer and understand the disease burden of patients with RIF.
Methods
We searched for literature from databases such as PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials from inception to May 19, 2024, and extracted the pregnancy outcomes of patients with RIF in the blank control group, including implantation rate (IR), clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), miscarriage rate (MR), live birth rate (LBR), and ectopic pregnancy rate (EPR). Subsequently, meta-analyses of the rates were summarized and subgroup analyses were performed based on implantation failures, embryo type, fresh/frozen embryo transfer and regions.
Results
A total of 110 studies (14,159 patients) were included in the meta-analysis. Globally, the overall IR, CPR, OPR, MR, LBR, and EPR of patients with RIF were 19.3%, 29.4%, 24.6%, 19.9%, 23.0%, and 0.9%, respectively. No differences in pregnancy outcomes were found between RIF patients with three or more implantation failures and those with two or more implantation failures. RIF patients who transferred blastocyst achieved significantly higher IR, higher CPR, higher OPR, higher LBR and lower EPR, but no lower MR. There are differences in IR and CPR among patients with RIF in different regions, and no significant differences in other pregnancy outcomes.
Conclusion
This study summarizes the global pregnancy outcomes of patients with RIF who undergo subsequent embryo transfer. Pregnancy outcomes in patients with RIF may not be related to the number of implantation failures. Frozen blastocyst transfer is recommended for patients with RIF. Pregnancy outcomes in patients with RIF vary across regions.
Protocol registration
This study has been registered on PROSPERO (CRD 42024539968).
Supplementary Information
The online version contains supplementary material available at 10.1186/s12884-025-08372-8.
Keywords: Repeated implantation failure, Global, Implantation rate, Clinical pregnancy rate, Ongoing pregnancy rate, Live birth rate, Miscarriage rate
Introduction
Despite significant advances in assisted reproductive technology (ART), some people still fail to become pregnant after multiple embryo transfer (ET). Researchers define these patients as recurrent implantation failure (RIF) [1]. RIF may affect approximately 5–10% of IVF patients worldwide [2, 3]. The pathogenesis of RIF is complex and diverse, such as immune factors [4], flora imbalance [5], and endometrial receptivity [6]. Therefore, many treatments have been tried to improve the pregnancy outcomes of RIF patients [7]. However, there is currently a lack of large-sample comprehensive estimates of the pregnancy outcomes of RIF patients worldwide after the next ET [8].
Implantation rate (IR), clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), live birth rate (LBR) and miscarriage rate (MR) are important indicators for evaluating pregnancy outcomes of ART [9–11]. RIF is associated with suboptimal pregnancy outcomes [12, 13], yet the extent of the difference in pregnancy outcomes between RIF patients and those undergoing conventional IVF cycles remains unclear, and there is a lack of comprehensive and detailed data to support this observation. These indicators can be used to evaluate the difficulty and prognosis of pregnancy in the patients with RIF and further therapeutic effect. Some studies suggest that number of previous ET failures is associated with a decreased probability of success in clinical pregnancy and live birth [12, 14–16], while other research indicates that increasing the number of transfer attempts can improve patients’ overall probability of ultimately achieving a successful pregnancy [17]. Therefore, this estimate of pregnancy outcomes is indispensable and helps with the clinical management of patients, and can provide information to decision makers and improve health care planning and support. In addition, there is a lack of global statistical data as a basic reference for the degree of improvement in pregnancy outcomes after RIF treatment. A summary analysis of the pregnancy outcomes of RIF patients can provide a theoretical reference for future clinical trials.
The purpose of this study is to investigate the global rate of pregnancy outcomes in RIF, assess the global burden of RIF. We explored the pregnancy outcomes of patients with RIF who transferred different embryo types, as well as the differences in pregnancy outcomes in the next ET of RIF patients with different previous implantation failures. We also conduct subgroup analyses based on fresh or frozen ET cycles and different regions. This study provides a new clinical data for patients with RIF, and provides data support for the gap of clinical outcomes between patients with RIF and patients with conventional in vitro fertilization (IVF).
Methods
Study design
This meta-analysis was registered with PROSPERO (CRD42024539968) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. We only extracted the pregnancy outcomes data of the control group from included studies and performed a meta-analysis.
The main outcomes were the rates of pregnancy outcomes, including IR, CPR, OPR, MR, LBR, and ectopic pregnancy rate (EPR) among patients with RIF. IR was calculated as the number of gestational sacs divided by the total number of embryos transferred. CPR was calculated as the number of cycles with observed gestational sacs divided by the total number of embryo transfer cycles. OPR was defined as the proportion of clinical pregnancies that lasted beyond 12 weeks. MR was defined as the number of ET cycles with pregnancy loss before 20 weeks, divided by the number of cycles with clinical pregnancy. LBR was defined as the delivery of one or more live births at 20 weeks or more of gestation. EPR was calculated as the number of cycles of transferred embryos which gestational sacs implanted outside the uterine cavity divided by the number of cycles with clinical pregnancy.
Information sources and search strategy
PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception dates to May 19th, 2024. Text search terms included “recurrent implantation failure”, “repeated implantation failure”, “recurrent embryo implantation failure”, “implantation rate”, “clinical pregnancy rate”, “ongoing pregnancy rate”, “miscarriage rate”, “live birth rate”, and “ectopic pregnancy rate”. The full search strategy is available in the Supplement material. In addition, we reviewed the reference lists of all relevant articles to identify any additional studies for inclusion. The included studies were re-assessed for eligibility before the final data analysis. The search was conducted independently by two researchers, with any discrepancies resolved by a third reviewer.
Selection process
Two reviewers independently screened literatures by title and abstract, followed by full-text screening using the predefined criteria outlined below. Any discrepancies were resolved through consultation with a third reviewer. Inclusion criteria: (1) RIF is defined as two or more failed IVF or intracytoplasmic sperm injection (ICSI) cycles; (2) pregnancy outcomes for RIF patients without treatment should be available; (3) the study must report at least one of the following outcomes: IR, CPR, OPR, MR, LBR, or EPR. Exclusion criteria: (1) use of donor gametes; (2) having a diagnosed medical or surgical sever disease in progress, such as hypertension, diabetes mellitus, heart disease, history of malignancy; (3) suffering from psychiatric disorders; (4) conference abstracts or case reports; (5) self-controlled studies; (6) no available data; (7) fewer than 20 participants in either the trial or control group; (8) the mean or median of number of embryos transferred in the control group is equal or greater than three.
Data collection
The collected data included first author’s name, publication year, country, study design, definition of RIF, interventions, controls, types of embryo transfer, sample size, pregnancy outcomes. Data extraction was performed by two independent reviewers using Epidata (Version 3.1). Any discrepancies were resolved by a third reviewer.
Risk of bias assessment
The risk of bias in the included studies was independently assessed by two reviewers using the Cochrane Risk of Bias tool (ROB 2.0) for randomized controlled trials (RCTs) and the ROBINS-I tool for observational studies [19, 20]. Any discrepancies were resolved through consultation with a third reviewer. The publication bias was detected through funnel plot, Egger’s test and trim-and-fill method.
Synthesis methods
All statistical analyses were performed using R software (version 4.3.2) with the “meta” package for meta-analysis. The primary outcome was the pooled estimate of event rates along with the corresponding 95% confidence interval (CI). Data were pooled and synthesized using a random-effects model. Heterogeneity across studies was assessed using the I² statistic. Since this meta-analysis focused on single-arm rates, the results were descriptive rather than comparing differences between groups, and thus an assessment of publication bias was not applicable.
Subgroup analysis
Subgroup analyses were performed based on geographical region (Asia, Europe, the Americas, the Middle East, and Oceania), number of ET failures (at least two or three), and type of embryo transfer (cleavage stage embryos or blastocysts). If a study reported pregnancy outcomes of transferred cleavage-stage embryos and blastocysts separately, the study was divided into two data items for statistical analysis. Additionally, we conducted separate analyses based on whether RIF patients received fresh or frozen-thawed ET cycle.
Results
Study characteristics
We screened the literature according to the PRISMA process, and a total of 110 studies involving 14,159 patients were included in this meta-analysis (Fig. 1). Among them, 44 studies were RCTs and 66 were non-RCTs. We summarized the publication time, country or region, study design, RIF diagnostic criteria, type of embryo transferred, sample size of the control group, the number of transferred embryos and pregnancy outcomes of the included studies. The diagnostic criteria for RIF in 50 studies were two or more implantation failures, and the remaining 60 studies were three or more implantation failures. A total of 11 studies separately reported the outcomes of cleavage-stage ET and blastocysts transfer, so they were listed as two data items. In 34 studies, patients in the control group were transferred with cleavage-stage embryos, 25 studies were transferred with blastocysts, 29 studies were transferred with cleavage-stage embryos or blastocysts, and 11 studies did not specify the type of embryo transferred. All patients with RIF received embryos that had not undergone euploid testing.
Fig. 1.
The flow chart of literature screening process by PRISMA
Among the included studies, 36 studies included patients with RIF who underwent fresh ET cycles, 47 studies included patients with RIF who underwent frozen ET cycles, 14 studies included patients with RIF who underwent fresh or frozen ET cycles, and the last 13 studies did not clearly state the transfer protocol. Detailed characteristics of the included studies are shown in Supplement Table S1.
Risk of bias assessment
The single-arm rate serves as a descriptive statistic rather than a measure of differences between groups. Consequently, there are no “positive” results or statistically significant findings, and publication bias was not assessed in this meta-analysis. The results of ROB and ROBINS-I are provided in the Supplement Sect. 3.
Implantation rate
A total of 72 studies reported IR, and IR for pooled patients with RIF after transfer of cleavage-stage embryos or blastocysts was 19.3% (95% CI: 16.8–21.8%). The IR of RIF patients with two or more implantation failures was 18.9%, while that of RIF patients with three or more implantation failures was 19.5%, with no significant difference between the two groups (P = 0.789). Subgroup analysis was performed according to the type of embryo, we found that the IR of patients transferred with blastocysts was higher than that of patients transferred with cleavage-stage embryos (28.4% vs. 15.4%, P < 0.0001). Patients with RIF who undergo frozen-thawed embryo transfer had a higher IR compared to fresh embryo transfer (23.8% vs. 16.1%, P = 0.003). In addition, there was significant difference in the IR of RIF patients in different regions (P = 0.044). The IR was the highest in Asia, reaching 22.8%, while the IR in the Middle East was the lowest, at 15.7% (Table 1).
Table 1.
The result of meta-analysis
| IR (95% CI) | I2 | CPR (95% CI) | I2 | OPR (95% CI) | I2 | MR (95% CI) | I2 | LBR (95% CI) | I2 | EPR (95% CI) | I2 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pooled patients with RIF | 0.193 (0.168–0.218) | 94.5% | 0.294 (0.273–0.315) | 86.0% | 0.246 (0.210–0.283) | 85.5% | 0.199 (0.167–0.232) | 72.7% | 0.230 (0.203–0.258) | 89.1% | 0.009 (0.001–0.021) | 23.6% |
| Subgroup analyses | ||||||||||||
| Previous transfer failures | P = 0.789 | P = 0.899 | P = 0.271 | P = 0.081 | P = 0.204 | P = 0.200 | ||||||
| Two or more implantation failures | 0.189 (0.152–0.230) | 96.2% | 0.292 (0.260–0.326) | 89.6% | 0.220 (0.166–0.278) | 86.6% | 0.230 (0.189–0.273) | 59.9% | 0.251 (0.215–0.288) | 89.2% | 0.013 (0.002–0.031) | 54.2% |
| Three or more implantation failures | 0.195 (0.164–0.229) | 91.6% | 0.295 (0.268–0.322) | 81.0% | 0.261 (0.216–0.310) | 84.0% | 0.172 (0.130–0.218) | 77.5% | 0.214 (0.175–0.255) | 86.9% | 0.013 (0.001–0.031) | 0.0% |
| Transferred embryo type | P < 0.0001 | P < 0.0001 | P = 0.021 | P = 0.550 | P = 0.027 | P = 0.062 | ||||||
| Cleavage-stage | 0.154 (0.127–0.183) | 90.0% | 0.261 (0.234–0.289) | 71.1% | 0.226 (0.175–0.280) | 78.2% | 0.189 (0.128–0.258) | 77.4% | 0.199 (0.160–0.240) | 77.4% | 0.026 (0.006–0.047) | 0.0% |
| Blastocyst | 0.284 (0.243–0.326) | 91.9% | 0.365 (0.326–0.406) | 88.2% | 0.318 (0.262–0.376) | 77.3% | 0.172 (0.127–0.223) | 75.1% | 0.295 (0.221–0.374) | 94.6% | 0.006 (0.000–0.012) | 0.0% |
| Fresh/Frozen ET cycle | P = 0.003 | P = 0.014 | P = 0.334 | P = 0.788 | P = 0.561 | P = 0.418 | ||||||
| Fresh | 0.161 (0.130–0.194) | 89.7% | 0.269 (0.239–0.300) | 70.2% | 0.227 (0.174–0.285) | 71.5% | 0.170 (0.121–0.224) | 49.0% | 0.227 (0.189–0.268) | 76.7% | 0.023 (0.000–0.053) | 0.0% |
| Frozen | 0.238 (0.199–0.278) | 94.1% | 0.327 (0.293–0.362) | 88.6% | 0.269 (0.211–0.331) | 88.9% | 0.174 (0.139–0.212) | 67.24% | 0.248 (0.192–0.308) | 92.2% | 0.010 (0.001–0.019) | 0.0% |
| Country or region | P = 0.044 | P = 0.003 | P = 0.055 | P = 0.175 | P = 0.245 | P = 0.448 | ||||||
| Asia | 0.228 (0.194–0.265) | 94.3% | 0.334 (0.302–0.366) | 88.3% | 0.286 (0.237–0.339) | 86.2% | 0.189 (0.150–0.230) | 77.0% | 0.247(0.210–0.285) | 89.6% | 0.011 (0.002–0.025) | 27.4% |
| Europe | 0.158 (0.106–0.218) | 88.9% | 0.269 (0.231–0.308) | 71.0% | 0.210 (0.147–0.280) | 74.9% | 0.249 (0.131–0.386) | 77.1% | 0.222 (0.134–0.323) | 88.3% | 0.002 (0.000–0.029) | 0.0% |
| America | 0.176 (0.094–0.277) | 85.0% | 0.273 (0.179–0.378) | 77.0% | 0.192 (0.060–0.371) | 74.4% | 0.399 (0.186–0.632) | 25.6% | 0.276 (0.160–0.410) | 85.3% | NA | |
| Middle East | 0.157 (0.117–0.201) | 89.8% | 0.248 (0.218–0.279) | 64.7% | 0.184 (0.131–0.242) | 59.2% | 0.182 (0.132–0.237) | 37.6% | 0.200 (0.159–0.244) | 80.7% | 0.027 (0.000–0.120) | 27.39% |
| Oceania | NA | 0.255 (0.193–0.320) | 86.0% | NA | NA | 0.185 (0.131–0.244) | 89.1% | NA | ||||
IR implantation rate, CPR clinical pregnancy rate, OPR ongoing pregnancy rate, MR miscarriage rate, LBR live birth rate, EPR ectopic pregnancy rate, RIF recurrent implantation failure, NA not available, ET embryo transferred. The bold represents the p-values are less than 0.05.
Clinical pregnancy rate
A total of 120 studies reported CPR, and CPR for pooled patients with RIF after cleavage-stage embryos or blastocyst transfer was 29.4% (95% CI: 27.3–31.5%). The CPR was 29.2% for RIF patients with two or more implantation failures, while the CPR was 29.5% for RIF patients with three or more implantation failures. No significant difference was found between the two groups (P = 0.899). According to subgroup analysis of the type of embryo transferred, we found that the CPR of patients transferred blastocysts was significantly higher than that of patients transferred cleavage-stage embryos (36.5% vs. 26.1%, P < 0.0001). Patients with RIF who undergo frozen-thawed embryo transfer had a higher CPR compared to fresh embryo transfer (32.7% vs. 26.9%, P = 0.014). In addition, we also found that the CPR in different regions was different (P = 0.003). The CPR was the highest in Asia, reaching 33.4%, while the CPR in the Middle East was the lowest, at 24.8% (Table 1).
Ongoing pregnancy rate
Thirty-eight studies reported OPR, and OPR for pooled patients with RIF after cleavage-stage embryos or blastocyst transfer was 24.6% (95% CI: 21.0–28.3%). The OPR was 22.0% for RIF patients with two or more implantation failures, while the OPR was 26.1% for RIF patients with three or more implantation failures. No significant difference was found between the two groups (P = 0.271). Subgroup analysis was performed according to the type of embryo transfer, we found that the OPR of patients transferred blastocysts was higher than that of patients transferred cleavage-stage embryos (31.8% vs. 22.6%, P = 0.021). No differences were found in the OPR between patients with RIF who received fresh or frozen-thawed embryo transfer (P = 0.334). In addition, although no difference in the OPR of RIF patients in different regions (P = 0.055), the highest OPR was 28.6% in Asia, while the lowest was 18.4% in the Middle East (Table 1).
Miscarriage rate
A total of 76 studies reported MR, and the pooled MR in patients with RIF was 19.9% (95% CI: 16.7–23.2%). Although not statistically significant, we found that the MR in RIF patients with three or more implantation failures was lower than that in RIF patients with two or more implantation failures (17.2% vs. 23.0%, P = 0.081). No significant difference was found between the blastocyst transfer and the cleavage-stage embryo transfer in MR (P = 0.550). No difference was also found in fresh or frozen-thawed embryo transfer cycle (P = 0.788). In addition, we found no significant difference in MR in different regions (P = 0.175) (Table 1).
Live birth rate
A total of 77 studies reported LBR, and for pooled patients with RIF, LBR after transfer of cleavage-stage embryos or blastocysts was 23.0% (95% CI: 20.3–25.8%). The LBR was 25.1% for RIF patients with two or more implantation failures, while the LBR was 21.4% for RIF patients with three or more implantation failures, and no significant difference was found between the two groups (P = 0.204). The LBR was significantly higher in patients transferred with blastocysts than in patients transferred with cleavage-stage embryos (29.5% vs. 19.9%, P = 0.027). No difference was found between fresh and frozen-thawed embryo transfer cycle in LBR (P = 0.561). In addition, we found no significant difference in the LBR in different regions (P = 0.245) (Table 1).
Ectopic pregnancy rate
A total of 24 studies reported EPR, and the pooled EPR in patients with RIF was 0.9% (95% CI: 0.1–2.1%). According to the subgroup analysis of different implantation failures, the EPR of patients with two or more implantation failures and those with three or more implantation failures was both 1.3%. However, we found that the EPR in RIF patients who transferred blastocysts was numerically lower than that in RIF patients transferred cleavage-stage embryos (0.6% vs. 2.6%, P = 0.062). No difference was found between fresh and frozen-thawed embryo transfer cycle in EPR (P = 0.418). In addition, we showed that there was no significant difference in the EPR in RIF patients from different regions (P = 0.448) (Table 1).
Heterogeneity and publication bias
With the exception of EPR, meta-analyses of other pregnancy outcomes showed high heterogeneity (I2 > 50%; Table 1). Egger’s test results suggested possible publication bias in the CPR, LBR and EPR analyses (P = 0.0003, P = 0.0356 and P = 0.0002, respectively). However, their funnel plots were generally symmetrical. The trim-and-fill analysis showed that the confidence intervals for CPR, LBR and EPR largely overlapped with the original results after adding the hypothesized studies, indicating that the meta-analysis results are reliable. Egger’s test, funnel plots, and trim-and-fill analysis for all analyses are presented in the Supplement.
Discussion
This meta-analysis provides a comprehensive global overview of pregnancy outcomes among patients with RIF. By synthesizing data from 110 studies involving 14,159 RIF patients across multiple countries, we identified significant heterogeneity in pregnancy outcomes. These outcomes were influenced by the type of embryos transferred, the number of previous implantation failures, fresh or frozen ET cycle, and regional factors. Our findings underscore the biological, clinical, and demographic factors that govern pregnancy success in RIF patients. This analysis offers valuable insights for clinical decision-making and identifies key opportunities for advancing patient management strategies.
The pooled IR for patients with RIF was 19.3%, with CPR and LBR at 29.4% and 23.0%, respectively. These results highlight the substantial challenges in achieving successful pregnancies in RIF patients, especially compared to the general IVF population, whose CPR often ranges from 40% to 50% [21–24]. This discrepancy underscores the need for enhanced strategies tailored to the unique challenges faced by patients with RIF [25, 26]. The number of embryos transferred influences pregnancy outcomes in patients with RIF. Therefore, we excluded studies with a mean or median number of embryos transferred of 3 or more to ensure that the results better represent pregnancy outcomes in the RIF population. However, this did not completely eliminate heterogeneity between studies. Most studies transferred one or two embryos, but some patients with RIF still desire to transfer more embryos to achieve a clinical pregnancy. While statistical methods cannot completely eliminate bias caused by the different number of embryos transferred, it appears to be more consistent with clinical practice and more representative of the clinical population.
Meta-analyses of rates typically exhibit high heterogeneity [27, 28], and our study is no exception. Heterogeneity generally arises from clinical and statistical heterogeneity [29]. We believe that heterogeneity in meta-analyses of rates is generally due to clinical heterogeneity, but our subgroup analyses did not reduce heterogeneity. Therefore, heterogeneity may arise from differences in sample size or study design among the included studies.
Our subgroup analysis revealed nuanced insights regarding the impact of previous implantation failures. While the overall trends did not show statistically significant differences in outcomes between patients with two or more failures versus those with three or more, the higher MR (23.0%) in the former group suggests potential variations in patient profiles or treatment approaches. Conversely, although no statistical difference, patients with three or more failures demonstrated a slightly lower MR (17.2%, P = 0.081). This may be related to the fact that patients with a high number of failures have a higher probability of receiving euploid embryos, although the embryos were not tested before transfer.
Subgroup analyses in our study also revealed that transferring blastocysts yielded higher CPR, OPR, and LBR compared to cleavage-stage embryos. Specifically, among patients with RIF, CPR for blastocyst transfer (unknown euploid) was 36.5%, significantly outperforming cleavage-stage transfers at 26.1%. Our findings and prior evidences suggested the pregnancy outcomes transferring blastocyst is better than that of cleavage-stage embryo [30, 31]. The extended culture period of blastocysts facilitates better selection of high-quality embryos [32]. This also might be related to the synchronization of embryo development and the endometrial receptivity window, contributing to improved pregnancy outcomes [33].
Interestingly, our findings showed that blastocyst transfer was associated with a lower ectopic pregnancy rate compared to cleavage-stage transfers (0.6% vs. 2.6%, P = 0.062). This finding highlights the potential benefit of synchronizing embryo development with endometrial receptivity. The conclusion also found in larger cohorts of the general IVF population [9, 34]. The EPR in both groups were 1.3%, regardless of the number of prior implantation failures.
Our results revealed that frozen-thawed ET cycles in patients with RIF had higher IR and CPR than fresh ET cycles. In the non-RIF population, although fresh ET is associated with a shorter time to clinical pregnancy [35], some studies have suggested that frozen ET has better pregnancy outcomes than fresh ET [36, 37]. This is consistent with our results. However, no higher LBRs were found after frozen ET in patients with RIF than in fresh cycles, possibly due to other causes of pregnancy loss. Although not statistically significant, our results and previous studies suggested that the incidence of EPR is slightly lower in frozen ET cycles than in fresh ET cycles [38].
Regional differences in pregnancy outcomes were also evident. Patients in Asia exhibited higher CPR and IR compared to patients in the Middle East, where the lowest outcomes were recorded. Such disparities may reflect variations in healthcare infrastructure, access to advanced reproductive technologies, and differences in population characteristics [39]. For instance, advanced ART practices are more prevalent in Asia, contributing to better outcomes, while resource limitations in certain Middle Eastern regions may account for the observed lower success rates. These findings emphasize the need for global standardization and equitable distribution of ART resources.
Despite its strengths, this meta-analysis has several limitations. First, variability in the definition of RIF across studies poses challenges in standardizing comparisons, which may limit the generalizability of our findings. While most studies define RIF as two or more failed IVF or ICSI cycles, discrepancies in the inclusion criteria and diagnostic thresholds persist. The 2023 ESHRE Guideline redefines RIF based on cumulative embryo transfers and maternal age, integrating PGT-A status [25]. These evolving definitions may affect which patients are classified as having RIF, thus contributing to the bias observed in reported outcomes. Furthermore, the inclusion of both RCTs and observational studies introduces heterogeneity, although this was addressed using a random-effects model. Additionally, pregnancy outcomes in ART are significantly influenced by factors such as age, BMI, and the etiology of infertility. However, due to data constraints, stratified analyses based on these variables could not be performed in this study. The absence of longitudinal data on live birth and neonatal outcomes also limits our ability to evaluate the long-term benefits and risks associated with ART interventions.
Global efforts to standardize RIF diagnostic criteria and treatment protocols are essential for addressing the heterogeneity observed in outcomes [3, 40]. Moreover, initiatives aimed at improving access to advanced ART techniques in underserved regions could help bridge the gap in pregnancy outcomes. Collaborative research efforts that leverage global datasets would enable more comprehensive analyses of RIF and provide the basis for evidence-based interventions that improve equity in treatment success.
Conclusion
This study focuses on the pregnancy outcomes of RIF patients worldwide, providing valuable data for future research. The pregnancy outcomes in RIF patients appear to be unrelated to the number of prior embryo transfer failures. Patients with RIF may be more suitable for frozen blastocyst transfer to achieve better pregnancy outcomes. Improving the live birth rate in patients with RIF remains a significant challenge. Pregnancy outcomes in patients with RIF show regional disparities, and multifaceted management strategies may be necessary.
Supplementary Information
Acknowledgements
We would like to thank the patients with RIF participated in the included studies and all researchers.
Abbreviations
- ART
Assisted reproductive technology
- CI
Confidence interval
- CPR
Clinical pregnancy rate
- ET
Embryos transfer
- EPR
Ectopic pregnancy rate
- ICSI
Intracytoplasmic sperm injection
- IR
Implantation rate
- IVF
In vitro fertilization
- LBR
Live birth rate
- MR
Miscarriage rate
- OPR
Ongoing pregnancy rate
- PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- RCTs
Randomized controlled trials
- ROB
Risk of Bias tool
- ROBINS-I
Risk of Bias in Non-Randomized Studies of Interventions
- RIF
Recurrent implantation failure
Authors’ contributions
Yunan He and Xiexiong Zhao conceived and designed the study. Yunan He, Ge Chen, and Xiexiong Zhao selected articles and extracted the data. Yunan He, Ge Chen, and Xiexiong Zhao analyzed the data. Yunan He, Ge Chen, and Xiaoxiao Su wrote the manuscript. Xiexiong Zhao and Shaole Shi contributed to the writing of final version of the manuscript. All authors agreed and reviewed the final version of the manuscript.
Funding
The China Postdoctoral Science Foundation (Certificate Number: 2025M772416).
Data availability
The original data in the study are involved in the Supplementary Material. Further inquiries can be directed to the corresponding author.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Ge Chen, Email: gegewuchen@126.com.
Xiexiong Zhao, Email: zhaoxiexiong@csu.edu.cn.
References
- 1.Cimadomo 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(2):305–17. [DOI] [PubMed] [Google Scholar]
- 2.Ma J, Gao W, Li D. Recurrent implantation failure: a comprehensive summary from etiology to treatment. Front Endocrinol. 2022;13:1061766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pirtea P, Cedars MI, Devine K, Ata B, Franasiak J, Racowsky C, Toner J, Scott RT, de Ziegler D, Barnhart KT. Recurrent implantation failure: reality or a statistical mirage? Consensus statement from the July 1, 2022 Lugano workshop on recurrent implantation failure. FERTIL STERIL. 2023;120(1):45–59. [DOI] [PubMed] [Google Scholar]
- 4.Ebrahimi F, Omidvar-Mehrabadi A, Shahbazi M, Mohammadnia-Afrouzi M. Innate and adaptive immune dysregulation in women with recurrent implantation failure. J Reprod Immunol. 2024;164:104262. [DOI] [PubMed] [Google Scholar]
- 5.Lafioniatis A, Samara AA, Makaritsis PK, Dafopoulos S, Sotiriou S, Dafopoulos K. Understanding the role of female genital tract microbiome in recurrent implantation failure. J Clin Med. 2024. 10.3390/jcm13113173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hiraoka T, Osuga Y, Hirota Y. Current perspectives on endometrial receptivity: a comprehensive overview of etiology and treatment. J Obstet Gynaecol Res. 2023;49(10):2397–409. [DOI] [PubMed] [Google Scholar]
- 7.He Y, Tang R, Yu H, Mu H, Jin H, Dong J, et al. Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: a systematic review and network meta-analysis. J Assist Reprod Genet. 2023;40(10):2343–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fang Q, Qiao Z, Luo L, Bai S, Chen M, Zhang X, et al. Predictive models of recurrent implantation failure in patients receiving ART treatment based on clinical features and routine laboratory data. Reprod Biol Endocrinol. 2024;22(1):32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Arian SE, Hessami K, Khatibi A, To AK, Shamshirsaz AA, Gibbons W. Endometrial receptivity array before frozen embryo transfer cycles: a systematic review and meta-analysis. Fertil Steril. 2023;119(2):229–38. [DOI] [PubMed] [Google Scholar]
- 10.Huang P, Ou Y, Tang N, Chen J, Wen Q, Li J, et al. Peri-implantation estradiol level has no effect on pregnancy outcome in vitro fertilization- embryo transfer. FRONT ENDOCRINOL. 2024;15:1326098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Perez-Milan F, Caballero-Campo M, Carrera-Roig M, Moratalla-Bartolome E, Dominguez-Arroyo JA, Alcazar-Zambrano JL, Alonso-Pacheco L, Carugno JA. Hydrosalpinx treatment before in-vitro fertilization: systematic review and network meta-analysis. Ultrasound Obst Gyn. 2025;65(4):414-426. [DOI] [PMC free article] [PubMed]
- 12.Fang Y, Jingjing F, Tiantain C, Huanhuan X, Qiaohua H. Impact of the number of previous embryo implantation failures on IVF/ICSI-ET pregnancy outcomes in patients younger than 40 years: a retrospective cohort study. FRONT ENDOCRINOL. 2023;14:1243402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Curfs M, Cohlen BJ, Slappendel EJ, Schoot DC, Derhaag JG, van Golde R, van der Heijden GW, Baart EB, Smeenk J, Ritfeld V, et al. A multicentre double-blinded randomized controlled trial on the efficacy of laser-assisted hatching in patients with repeated implantation failure undergoing IVF or ICSI. HUM REPROD. 2023;38(10):1952–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jia Y, Ai Z, Zhu X, Che Z, Pratikshya A, Tang S, et al. Analysis of predictors of clinical pregnancy and live birth in patients with RIF treated with IVF-ET technology: a cohort study based on a propensity score approach. Front Med. 2024;11:1348733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Almohammadi A, Choucair F, El TL, Burjaq H, Albader M, Cavanillas AB, et al. The reproductive potential of vitrified-warmed euploid embryos declines following repeated uterine transfers. Reprod Biol Endocrinol. 2024;22(1):23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Sun Y, Zhang Y, Ma X, Jia W, Su Y. Determining diagnostic criteria of unexplained recurrent implantation failure: a retrospective study of two vs three or more implantation failure. FRONT ENDOCRINOL. 2021;12:619437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Pirtea P, De Ziegler D, Tao X, Sun L, Zhan Y, Ayoubi JM, et al. Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers. Fertil Steril. 2021;115(1):45–53. [DOI] [PubMed] [Google Scholar]
- 18.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. ANN INTERN MED. 2009;151(4):W65-94. [DOI] [PubMed] [Google Scholar]
- 19.Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ-BRIT MED J. 2016;355:i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Sterne J, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ-BRIT MED J. 2019;366:l4898. [DOI] [PubMed] [Google Scholar]
- 21.Fauser B, Adamson GD, Boivin J, Chambers GM, de Geyter C, Dyer S, Inhorn MC, Schmidt L, Serour GI, Tarlatzis B, et al. Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature. HUM REPROD UPDATE. 2024;30(2):153–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ishihara O, Jwa SC, Kuwahara A, Ishikawa T, Kugu K, Sawa R, et al. Assisted reproductive technology in Japan: a summary report for 2016 by the ethics committee of the Japan society of obstetrics and gynecology. Reprod Med Biol. 2019;18(1):7–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Smeenk J, Wyns C, De Geyter C, Kupka M, Bergh C, Cuevas SI, De Neubourg D, Rezabek K, Tandler-Schneider A, Rugescu I, et al. ART in Europe, 2019: results generated from European registries by ESHREdagger. HUM REPROD. 2023;38(12):2321–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Stevens BL, Roumen R, Smits L, Derhaag J, Romano A, van Golde R, den Hartog JE. Pregnancy rate and time to pregnancy after recurrent implantation failure (RIF)-a prospective cohort follow-up study. J ASSIST REPROD GEN. 2024;41(11):3061–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Cimadomo D, de Los SM, Griesinger G, Lainas G, Le Clef N, McLernon DJ, Montjean D, Toth B, Vermeulen N, Macklon N. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023;2023(3):hoad023. [DOI] [PMC free article] [PubMed]
- 26.Mascarenhas M, Jeve Y, Polanski L, Sharpe A, Yasmin E, Bhandari HM. Management of recurrent implantation failure: british fertility society policy and practice guideline. Hum Fertil. 2022;25(5):813–37. [DOI] [PubMed] [Google Scholar]
- 27.Barry R, Anderson J, Tran L, Bahji A, Dimitropoulos G, Ghosh SM, et al. Prevalence of mental health disorders among individuals experiencing homelessness: a systematic review and meta-analysis. JAMA Psychiatr. 2024;81(7):691–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Movahed F, Haji HF, Heidari A, Dehbozorgi M, Ataei M, Vahidi F, et al. COVID-19 vertical transmission from mothers to neonates: a systematic review and meta-analysis of 204 studies. J Infect Public Heal. 2025;18(9):102825. [DOI] [PubMed] [Google Scholar]
- 29.Giraudeau B, Caille A, Eldridge SM, Weijer C, Zwarenstein M, Taljaard M. Heterogeneity in pragmatic randomised trials: sources and management. BMC Med. 2022;20(1):372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Li Y, Liu S, Lv Q. Single blastocyst stage versus single cleavage stage embryo transfer following fresh transfer: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2021;267:11–7. [DOI] [PubMed] [Google Scholar]
- 31.Glujovsky D, Farquhar C, Quinteiro RA, Alvarez SC, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Db Syst Rev. 2016(6):CD002118. [DOI] [PubMed]
- 32.Wei H, Zhu B, Deng L, Zeng M, Duan J. Optimal embryo management strategies for patients undergoing antagonist protocols in IVF treatment. J Assist Reprod Genet. 2024. 10.1007/s10815-024-03365-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Karaki RZ, Samarraie SS, Younis NA, Lahloub TM, Ibrahim MH. Blastocyst culture and transfer: a step toward improved in vitro fertilization outcome. Fertil Steril. 2002;77(1):114–8. [DOI] [PubMed] [Google Scholar]
- 34.Jin XY, Li C, Xu W, Liu L, Wei ML, Fei HY, et al. Factors associated with the incidence of ectopic pregnancy in women undergoing assisted reproductive treatment. Chinese Medi J. 2020;133(17):p2054-2060. [DOI] [PMC free article] [PubMed]
- 35.Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. COCHRANE DB SYST REV. 2021;2(2):CD011184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Yang M, Lin L, Sha C, Li T, Gao W, Chen L, et al. Which is better for mothers and babies: fresh or frozen-thawed blastocyst transfer? BMC Pregnancy Childbirth. 2020;20(1):559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wang CH, Hu XQ. A systematic review of clinical efficacy of frozen-thawed embryos and fresh embryos in in-vitro fertilization cycles. Cryobiology. 2021;100:19–25. [DOI] [PubMed] [Google Scholar]
- 38.Decleer W, Osmanagaoglu K, Meganck G, Devroey P. Slightly lower incidence of ectopic pregnancies in frozen embryo transfer cycles versus fresh in vitro fertilization-embryo transfer cycles: a retrospective cohort study. Fertil Steril. 2014;101(1):162–5. [DOI] [PubMed] [Google Scholar]
- 39.Inhorn MC, Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update. 2015;21(4):411–26. [DOI] [PubMed] [Google Scholar]
- 40.Rozen G, Polyakov A. Tackling the RIF mirage with theoretical cumulative implantation rate. Fertil Steril. 2023;120(1):210. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
The original data in the study are involved in the Supplementary Material. Further inquiries can be directed to the corresponding author.