Emerging trends and frontier research on recurrent implantation failure: a bibliometric analysis

Introduction

Recurrent implantation failure (RIF) refers to repeated unsuccessful pregnancy after several transfers of good-quality embryos. However, no internationally recognized definition for RIF has been established. Now, the widely accepted definition for RIF is the failure to achieve a clinical pregnancy in women under the age of 40 after at least four transfers of high-quality embryos in a minimum of three frozen or fresh cycles (1,2). RIF presents a significant clinical challenge for patients undergoing in vitro fertilization (IVF). Despite recent advances in IVF, RIF remains significantly high. Currently, the rate of successful IVF for frozen embryos is only 37.3% for women under the age of 35 years and 29.2% for those aged 41–42 years (3).

Many different risk factors can lead to RIF, and it is necessary to establish a standardized evaluation for these patients. Appropriate action and interventions are formulated based on the assessment results, and personalized treatments are provided. The two leading factors in RIF are the mother as a host and the embryo. There are several types of uterine pathology, including fibroids, polyps, and adhesions, that can affect implantation rates in patients receiving IVF (4). Hydrosalpinx refers to fluid-filled fallopian tubes. It is now recognized that women with hydrosalpinges undergoing IVF have only half the live birth rate (LBR) of women without hydrosalpinx (5). Ultrasonography, hysteroscopy, sonohysterography, combined hysteroscopy and laparoscopy, hysterosalpingography, and hydrosalpinges are used investigational tools in women with RIF (1). Correction of intra-uterine pathologies and salpingectomy/tubal occlusion procedures in some cases have been shown to increase implantation success in IVF cycles (6,7). The endometrium itself may also be the etiology of implantation failure. Endometrial damage, impaired uterine blood flow, and long-term contraceptive use are potential causes of a thin endometrium (4). Ultrasound examination of endometrial thickness and appearance is an easily performed means of assessing changes in endometrial morphology during the follicular phase. These RIF women with thin endometrium should be offered all available treatments (high-dose estrogen, aspirin, vaginal estrogen pills, and other drugs that may increase endometrial blood flow) (8). Failure to transfer embryos into the recipient endometrium during the appropriate implantation window has been implicated as a cause of RIF (9). The use of endometrial receptivity array (ERA) to assess endometrial receptivity and determine the window of implantation (WOI) may help improve outcomes for multiple implantation failure patients (10). RIF is mainly caused by uterine factors. However, there will inevitably be some cases due to embryonic factors. Embryo quality is affected by oocyte quality, sperm quality, parental chromosomal anomalies, etc. The ovarian response to gonadotrophin stimulation should be reviewed to select an appropriate ovarian stimulation protocol (1). Based on sperm DNA integrity testing results, providing medical treatment and selecting sperm with more minor DNA damage may be considered to improve sperm quality (1). RIF patients have a high percentage of chromosomally abnormal embryos, and the use of preimplantation genetic screening (PGS) and selection of chromosomally normal embryos for transfer can improve the implantation rate of RIF (8). However, even embryos that are defined as good quality may stop developing in utero. This may be due to intrinsic embryonic factors or suboptimal local conditions. It has been confirmed that blastocyst transfer, sequential embryo transfer (ET), embryo co-culture and zygote intrafallopian transfer can effectively overcome these obstacles (11). The hatching of blastocysts through the zona pellucida is an important step before implantation. Assisted hatching has been suggested increasing implantation rates in patients who have previously failed IVF cycles (11). Some of the newly introduced diseases and factors, such as chronic endometritis (CE), immunologic profile, and vaginal microbiota, maybe help pave the way toward new diagnostic and therapeutic strategies for RIF. CE as a contributing factor needs to be investigated in RIF. It is histologically defined by plasma cell infiltration in the endometrial stroma but can also be diagnosed by the use of hysteroscopy (12). A recent meta-analysis evaluating the relationship between CE and RIF concluded that treatment of CE may improve IVF outcomes in RIF women (13). If all tests for the embryo and the mother are normal, it is recommended to consider the possible contribution of immune factors to implantation failure. The test indicators to assess the patient’s immune balance include an abnormal tumor necrosis factor-α (TNF-α)/interleukin-10 (IL-10) ratio, elevated natural killer (NK) cells, T helper 1 (Th1)/Th2 ratio, and auto-antibodies (4,14). Immunological therapy has also been regarded as a potential intervention for repeated implantation failure. Peripheral blood mononuclear cell (PBMC) therapy has been reported to improve pregnancy outcomes for women with at least three previous IVF-ET failures (3). In recent years, it has been found that vaginal microbiota dysbiosis may be involved in RIF at different stages, such as gamete formation, implantation and delivery (15,16). The vaginal microbiota of pregnant women appears to be exclusively colonized by the Firmicutes phylum, with the Lactobacillus species (L. iners and L. crispatus) being the main species within this phylum. In contrast, women with implant failure after undergoing an assisted reproductive technology (ART) displayed a richer vaginal ecosystem and greater biodiversity (17). The IVF or IVF-intracytoplasmic sperm injection (ICSI) population with low levels of Lactobacillus in the vaginal sample were less likely to have successful embryo implantation (18). Fu et al. confirmed that vaginal microbiota could affect embryo implantation, and vaginal lactobacilli in unexplained RIF patients were significantly positively correlated with pregnancy rate (19). The change of vaginal microbial composition in RIF patients brings into the change of metabolite composition, which may be one of the important mechanisms leading to the pathogenesis of RIF. Fu et al. also found that 37 metabolites were significantly different between patients with unexplained RIF and those who achieved clinical pregnancy after the first ET cycle, and, among the 37 metabolites, inositol phosphate and 2',3-cyclic uridine monophosphate (UMP) were the top two metabolites (19). They were higher in the RIF group, while benzopyran and glycerophospholipids were lower in the RIF group. The metabolites may be essential for the implantation and maintenance of pregnancy. However, the relationship between the microbiome and RIF remains largely unknown, and further research is needed, which has clinical value for proposing meaningful interventions to improve RIF outcomes. There are other influential factors, such as maternal age, body mass index (BMI), smoking, and stress. Lifestyle interventions such as a healthier diet and regular exercise, smoking cessation, and taking care of mental health may positively impact people with RIF.

Due to the attention of researchers and clinical workers to RIF patients, the studies have increased rapidly related to RIF, and a series of original articles and literature reviews have been published. The review by Pirtea et al. focused on whether the endometrial and embryonic assessments available today is helpful in treating RIF women (20). Moustafa et al. reviewed the diagnostic and therapeutic options in RIF emphasizing disorders of endometrial receptivity (21). Zohni et al. summarized the knowledge of normal human embryonic development, molecular aspects of endometrial-embryo interactions, and preimplantation genetic assessment, which will pave the way for new diagnostic and therapeutic strategies for RIF (22). Busnelli et al. conducted a systematic review and meta-analysis to assess the impact of different therapeutic approaches for RIF patients on subsequent IVF cycle outcomes (23). Although these articles provide valuable insights and research directions for RIF in general, the syntheses and analyses do not provide a complete picture of global RIF research. For example, useful knowledge about developments in the field, such as which are the most productive countries, institutions and journals; what national and institutional collaboration networks exist in the field; what are the narrative clusters in the research domain; and what are the hot research trends in the RIF field, are questions which difficult to answer utilizing traditional review methodologies. However, such information is handy for researchers to understand the past evolution of RIF and the structure of the RIF research field and identify the emerging research areas within the RIF domain. We introduce bibliometric analysis for additional analysis of all published literature on RIF over the last 20 years, which can provide additional insights and answer the above questions. Therefore, it may be beyond meta-analyses that do not highlight relationships between publications in the field or mere literature reviews that are not necessarily comprehensive enough.

Evaluative bibliometrics is a scientific quantitative analysis technique that combines mathematical and statistical methods to evaluate research performance. Bibliometric analysis utilizes published data to identify novel findings and current research trends in specific fields (24). Therefore, clinical practitioners and investigators are updated on the new practices that evoke new research ideas (25). Bibliometrics was first introduced in 1969 by Alan Richard, a famous British scientist, who first proposed the replacement of “statistical bibliography” with this method (26). In recent years, bibliometrics has attracted the attention of many researchers, resulting in the publication of numerous bibliometric studies in high-impact journals. Through this method, Sugimoto et al. performed a bibliometric analysis to identify sex-related reporting in medical research and found an increased probability of reporting sex in articles with female first and last authors (27). In their study, Zhai et al. conducted a bibliometric analysis to investigate trends of spinal ultrasound research and found that anesthesia use and adolescent idiopathic scoliosis are the major research foci in the foreseeable future (28). Bibliometric studies have extended to several other scientific fields, including obstetrics (29), health care (30,31), gastrointestinal diseases (32), tumors (33,34), cardiovascular disease (35), and ophthalmology (36,37).

To the best of our knowledge, bibliometric analyses on RIF are limited (none). CiteSpace and VOSviewer are currently the most common tools for visualizing and analyzing trends and patterns in scientific literature. In the present study, we used these tools to analyze the current trend in RIF-related research. Collaboration network analysis, reference cocitation analysis, and keyword co-occurrence and burst analyses were also performed.

Methods

Data source and search strategy

We searched through the Web of Science Core Collection (WoSCC) databases for recent articles on RIF. The papers had to have been published between 2000 and 2020. The key search words included (I) in vitro fertilization, IVF, intracytoplasmic sperm injection, ICSI, embryo transfer, etc.; (II) failed implantation, implantation failure, recurrent implantation failure, and repeated implantation failure. Only “articles” and “reviews” were considered. The search generated 1,764 articles and reviews. The papers were coded and input into scientometric software, including Microsoft Office Excel 2013 (Microsoft Corporation, Redmond, WA, USA), CiteSpace V (Drexel University, Philadelphia, PA, USA), and VOSviewer 1.6.10 (Leiden University, the Netherlands). Any disagreements were resolved through discussion. The data were collected and organized by two independent researchers.

Statistical analysis

The trend in RIF researches was analyzed using the WoSCC literature analysis tool. The number of publications in future years was predicted using the polynomial model expressed as f(x) = ax³ + bx² + cx + d, where f(x) is the number of publications and x is the year of publication. VOSviewer was used to construct a network map of countries/regions and organizations. CiteSpace V was used to construct a dual-map overlay of journals, identify cocited references, and capture keywords with strong burst strength. The CiteSpace was set as follows: link retaining factor (LRF) =2, look back years (LBY) =−1, e for top N(e) =2, period = (2000–2020), years per slice =2, and links (strength: cosine, scope: within slices), and criteria for the selection of items (country, keywords, and references) were adopted based on the situations.

Results

Annual publications and increased publication prediction

Our search generated 1,764 research papers on RIF, which included 1,477 articles and 287 reviews. Overall, we observed a gradual and steady increase in publications on RIF from 18 articles in 2000 to 262 articles in 2020. A sudden jump in the publication of papers occurred from 2019, peaking in 2020. The polynomial curve fitting revealed a strong positive correlation between the year of publication and the number of published articles and reviews [coefficient of determination (R²) =0.9715]. The specific numbers of papers per year are shown in Figure 1.

Figure 1 Time-trend distribution of articles in the field of RIF. RIF, recurrent implantation failure.

Country/region and institutional analysis

The 1,764 articles were from 78 countries/regions (Figure 2). The top 10 countries/regions published a total of 1,447 (82%) articles. The top three countries/regions were the United States (n=336; 19%), China (n=300; 17%), and England (n=169; 9.6%). Additionally, 1,764 studies were performed by 2,195 research institutions (Figure 3). The top five leading universities in RIF research were the University of Valencia (n=45; 2.55%), Tel Aviv University (n=31; 1.76%), Tehran University of Medical Sciences (n=27; 1.53%), the Chinese University of Hong Kong (n=26; 1.47%), and the Academic Center for Education, Culture, and Research (Genetic Laboratory of Tabriz Branch of ACECR) (n=25; 1.42%).

Figure 2 Knowledge map of country/region co-occurrence in research on RIF during 2000–2020. RIF, recurrent implantation failure.

Figure 3 The distribution of organizations involved in RIF research. RIF, recurrent implantation failure.

Journal analysis

Journal citation analysis shows the distribution of knowledge sources in the RIF field. Table 1 shows the top 15 most active journals in RIF research. The top four journals include Fertility and Sterility (114 publications), Reproductive Biomedicine Online (112 publications), American Journal of Reproductive Immunology (111 publications), and Human Reproduction (103 publications). The impact factor (IF) for 11 (73.3%) of the 15 most influential journals was >3.000. The dual-map overlay of the journals is shown in Figure 4. The lines running from left to right represent the citation links. Four main citation paths are also shown. The two yellow paths indicate that articles published in molecular/biology/genetics journals and health/nursing/medicine journals are mainly cited in the studies published in molecular/biology/immunology journals. The two green paths indicate that articles published in molecular/biology/genetics journals and health/nursing/medicine journals are mainly cited in the studies published in medicine/medical/clinical journals.

Figure 4 The dual-map overlay of journals publishing studies on RIF (left: citing journals; right: cited journals). RIF, recurrent implantation failure.

Cocitation analysis

Knowledge of current RIF research was evaluated using the most cocited reference network. The network is composed of 933 unique nodes and 3,621 links (Figure 5A). The top 10 most cocited articles related to RIF are shown in Table 2. Each was cocited at most 108 times, and they include Coughlan [2014] published in Reproductive BioMedicine Online (108 cocitations), Cicinelli [2015] published in Human Reproduction (59 cocitations), Nastri [2015] published in The Cochrane Database of Systematic Reviews (53 cocitations), and Potdar [2012] published in Reproductive BioMedicine Online (53 cocitations). Clustering of the cocited references was performed using loglikelihood tests (LLR). In total, 110 clusters with a Q-value of 0.8345 and a weighted mean silhouette-value of 0.9444 (Figure 5B) were obtained. The largest cluster was the “preimplantation genetic screening” group, with a total of 79 references. The silhouette of this cluster was 0.921. The number of members in the second cluster, including “integrin” and “endometrial injury”, was 77, and their silhouettes were 0.949 and 0.981, respectively. Other active clusters include “platelet-rich plasma”, “granulocyte colony-stimulating factor”, “vascular endothelial growth factor”, “aneuploidy”, “chronic endometritis”, “extracellular vesicles”, “heparin”, and “uterine flushing”. From the timeline view (Figure 6), cluster #2 “endometrial injury”, cluster #3 “platelet-rich plasma”, cluster #7 “chronic endometritis”, and cluster #8 “extracellular vesicles” represented by the bright color were the latest studies in RIF.

Figure 5 The analysis of references. (A) Network map of document cocitations for RIF; (B) clustered network of cocited articles on RIF. RIF, recurrent implantation failure.

Figure 6 Timeline view of cocited references on RIF research. RIF, recurrent implantation failure.

Analysis of keywords

Keywords for constructing the knowledge map were extracted using CiteSpace. The words and the relationships among them were represented by 108 nodes and 742 links (Figure 7). The size of the circle is directly proportional to the co-occurring frequencies of a keyword, whereas the lines between the two circles reflect the strength of their co-occurrence relationship. The four most frequently used keywords were “in vitro fertilization” (n=487), “implantation failure” (n=462), “pregnancy” (n=319), and “women” (n=319). The topmost keywords based on centrality were “leukemia inhibitory factor” (0.54), “mice” (0.52), “aneuploidy” (0.51), and “expression” (0.49). Eighteen keywords had citation bursts. Figure 8 shows the base timeline (blue line) and the burst duration of a subject (red part). The top three keywords with the highest burst strength included “preimplantation genetic diagnosis” (15.92), “receptivity” (15.73), and “cytokine” (13.83) from 2000 to 2011, 2012 to 2017, and 2004 to 2011, respectively. In terms of the end year, citation bursts on “hysteroscopy” [2014–2020] and “improvement” [2016–2020] continued until 2020.

Figure 7 Knowledge map of keyword co-occurrence in the field of RIF. RIF, recurrent implantation failure.

Figure 8 Top 18 keywords with the strongest citation bursts in the research on RIF between 2000 and 2020. RIF, recurrent implantation failure.

Discussion

General information

Herein, we used visual tools to analyze recent trends in RIF research based on studies published from 2000 through 2020. We found a steady increase in the annual number of published studies on RIF over the past 20 years, underlining the global significance of RIF. In general, RIF has been reported by 78/230 (34%) of the countries/regions in the world. RIF has been reported most often in the United States, which may be related to the high uptake of IVF in the country. China ranks second and may be related to the recent spur in research in the country. For example, the National Natural Science Foundation Project Guide for 2021 mentioned the study of maternal-fetal metabolic interactions and pregnancy-related diseases (38). Based on the institutional knowledge map, universities are the main institutions performing studies on RIF. Four of the 10 most productive institutions include Tehran University of Medical Sciences [27], Genetic Laboratory of Tabriz Branch of ACECR [25], Shahid Beheshti University Medical Sciences [24], and Tabriz University of Medical Sciences [23], all in Iran, which developed collaborative research on IVF. Sometimes, network analysis between countries and institutions does not yield consistent results, which is mainly attributed to differences in institutional and technological advancement. For instance, Iranian scholars and research institutions have formed close cooperation in RIF research, whereas the United States and China have many institutions scattered around the country, with most performing independent research. Journal analysis provides important information on high-impact journals. In most cases, the journals with the most publications in a field take precedence when researchers make decisions on how to disseminate their findings. Our analyses revealed that the top 10 most active journals published approximately half (46%) of the total research outputs on RIF, underlining the relatively centralized distribution of RIF research findings. More than 100 research outputs have been published in the four most active journals, including the Fertility and Sterility, Reproductive Biomedicine Online, American Journal of Reproductive Immunology, and Human Reproduction journals. The IF for most of the top 10 most active journals in RIF was >3.000, and only one had an IF <2.000.

Intellectual base

Cocitation is a measure of the frequency of jointly cited documents (39). Cocitation analysis identifies the most recognized scholarly or intellectual works in a given field or subject. Therefore, we focused on the top 10 cocited studies to assess trends, patterns, and knowledge regarding RIF. Among them, two papers highlighted the definition and underlying causes of RIF and further described major therapeutic strategies for improving successful pregnancy and delivery (1,8). Three studies reported how endometrial injury impacts RIF after IVF. In their systematic review and meta-analysis, Potdar et al. reported that induction of endometrial injury in the cycle preceding ovarian stimulation improves the outcome of pregnancy in patients with regular RIF (40). A separate randomized controlled pilot study revealed that endometrial injury caused by Pipelle sampling increases the chances of successful implantation and pregnancy in women with a history of RIF (41). Nastri et al. reported comparable findings, where local endometrial injury between day 7 of the previous cycle and day 7 of the ET cycle was shown to increase the chance of successful pregnancy and live birth. In the same research, whether endometrial injury causes adverse events such as miscarriage, bleeding, or multiple pregnancies was uncertain (42). Two papers investigated the incidence and impact of CE on RIF patients after IVF. Bouet et al. found that CE promotes RIF. They further reported that office hysteroscopy complemented by an endometrial biopsy is a useful tool for CE diagnosis (43). Cicinelli and colleagues further underlined how untreated CE diminished the chances of successful IVF. However, they found that successful treatment restored the normal endometrial pattern and increased the chances of pregnancy (44). In addition, Polanski et al. reported a systematic review and provided an up-to-date overview of current definitions of RIF following these key features: (I) the number of unsuccessful cycles; (II) the number of embryos transferred; and (III) additional factors including ovarian reserve, the day of ET, the stage of embryo development, and outcomes of treatment (45). Lédée et al. found that 81.7% of RIF patients suffered from a spectrum of endometrial immune disorders, including overactivation and underactivation. However, treatment increases the likelihood of a LBR among these patients (46). Simon et al. revealed that female factors (including anatomical causes, endometrium, and thrombophilia) and embryonic factors (including genetics, sperm contribution, and immunologic factors) are the most important parameters affecting the outcome of IVF. Effective treatment options for these factors aimed at increasing the success of implantation were also described (11).

Among the top 10 cocited references, three papers by Potdar et al. [2012], Narvekar et al. [2010], and Nastri et al. [2015] belong to cluster #2, whereas two papers by Coughlan et al. [2014] and Polanski et al. [2014] belong to cluster #4. Two papers by Bouet et al. [2016] and Cicinelli et al. [2015] belong to cluster #7, whereas the remaining articles by Simon et al. [2012], Lédée et al. [2016], and Margalioth et al. [2006] belong to cluster #1, cluster #3, and cluster #5, respectively. The timeline view of the knowledge map was constructed to analyze the development trends of clusters in specific periods. In our study, we found that cluster #2 “endometrial injury”, cluster #3 “platelet-rich plasma”, and cluster #7 “chronic endometritis” remained in the spotlight in RIF research. In addition, cluster #8 “extracellular vesicles” has recently attracted the attention of researchers. For cluster #2, the most active citer (1) cited 23 articles of 77 member papers and entitled “Recurrent implantation failure: definition and management”. This study is also the most cocited paper on RIF research. In this paper, the authors summarize the overall conclusion of randomized controlled trials and systematic reviews on endometrial injury. They suggested that endometrial injury can be treated using hysteroscopy or a Pipelle sampler, which increases the chance of successful IVF. In cluster #3, the most active citing paper cited 11 (47) member papers and entitled “The role of immunotherapy in in vitro fertilization: a guideline”. This guideline evaluated the role of immunomodulating therapy in ART. Unfortunately, studies on numerous immunotherapies are lacking. Given the lack of robust evidence from well-designed randomized controlled trials, definitive recommendations regarding immunotherapies and IVF were not proposed. The most active citer (48) for cluster #7 cited 12 member papers. In this paper, 14–41% of patients with RIF were reported to suffer from CE, and compared with normal women, these groups of patients have lower implantation success rates after IVF-ET. Molecular microbial technology was further suggested to be able to accurately detect CE in patients intending to undergo IVF to reveal markers for better outcomes. The most active citer (49) in cluster #8 cited 11 member papers and reviewed endometrial factors, including CE, uterine peristalsis, and displacement of the WOI. Although extracellular vesicles have not been directly discussed, several studies show that extracellular vesicles in the normal endometria promote the proliferation of trophoblasts and may thus enhance the success of IVF (50-52). Therefore, alteration of the number of extracellular vesicles can prevent RIF. Cocitation analysis revealed that the knowledge and research development on RIF has primarily covered four aspects: concept or definition, underlying causes, therapeutic strategies, and factors affecting the success of IVF.

Research hotspots and frontiers

Current trends in RIF research were identified using burst detection methods. As shown in Figure 8, in the past 20 years, most studies have focused on “preimplantation genetic diagnosis”, “receptivity”, and “cytokines” in prospective women before IVF. “Hysteroscopy” and “improvement” have been among the new research foci since 2016.

Preimplantation genetic diagnosis (PGD)

Chromosomal abnormalities have been implicated in implantation failure. Among them, aneuploidy is the most frequent in normally developing embryos (53). PGD for aneuploidy screening (PGD-AS) has been developed to detect numeric aneuploidy in embryos of RIF couples (54). At present, PGD-AS is performed using fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH). Wilton et al. found that CGH was more effective than FISH in identifying chromosomally normal embryos (55). However, not all individuals with a history of RIF who undergo ART may benefit from PGS. Wilding et al. reported that PGS significantly increased the rate of successful pregnancy in women with a history of RIF (56). Taranissi et al. reported comparable findings (57). In contrast, randomized controlled trials have shown that PGS does not improve LBRs after IVF or ICSI (58). A separate randomized controlled trial revealed that PGS does not increase the successful implantation rates in women with repeated implantation failure (54). The conflicting evidence on the clinical value of PGS may be related to the heterogeneity of the patient population, study design, and other factors yet to be identified.

Receptivity

Endometrial receptivity is the period in which endometrial tissue allows normal embryo implantation and therefore pregnancy initiation (59,60). The common factors affecting endometrium receptivity include hysteromyoma, endometriosis, endometritis, hydrosalpinx, adenomyosis, changes in endogenous hormone levels, etc. (61,62). Some scholars believe that RIF is mainly related to poor endometrial receptivity (61). Optimal endometrial receptivity allows for normal implantation and stable pregnancy. Therefore, endometrial receptivity is important to evaluate. Most recently, the ERA was thought to accurately stratify the endometrium into ‘receptive’ or ‘nonreceptive’ groups based on the expression profile of 238 genes (59). However, a retrospective cohort study in RIF patients on the clinical usefulness of ERA revealed that this procedure does not improve pregnancy outcomes (10). In a related prospective controlled cohort study, the ERA test of endometrial biopsies revealed that there was no significant difference in the prevalence of a displaced ERA test result between the RIF and non-RIF groups (63). Overall, further studies are needed to identify endometrial factors associated with RIF.

Cytokines

Cytokines are small proteins secreted by immune cells and nonimmune cells. They mediate cellular and humoral immune responses and inflammatory responses related to tissue damage, participate in repair, and regulate the functioning of the endometrium, decidua, and cytotrophoblasts (64). After successful IVF-ET, implantation failure may be related to locally secreted cytokines, particularly those resulting from an imbalance in the secretion of Th1/Th2-based cytokines (65). Th1 cytokines are detrimental to pregnancy, whereas Th2 cytokines promote successful pregnancy. Overexpression of Th1-based cytokines promotes the Th2/Th1 transition, which affects the immunological response at the embryo implantation stage and may be the main reason for implantation failures (66-68). Ng et al. found that the numbers of CD3⁺/CD4⁺ TNF-α-producing cells and CD3⁺/CD8⁺ IL-10-producing cells were significantly high before pregnancy in the blood of women who experienced implantation failure after IVF (69). A separate randomized trial showed that after endometrial biopsy, a massive secretion of cytokines in the wound healing process might improve uterine receptivity and thus might have an additional favorable effect on the implantation of the blastocyst (70).

Hysteroscopy

Hysteroscopy is the direct observation of pathological and physiological disorders in the endometrium, as well as the treatment of abnormalities if any (71). A randomized controlled trial demonstrated that hysteroscopy findings are closely related to pregnancy success or failure and that routine office hysteroscopy before ICSI can detect infertility even in patients with normal ultrasound (72). In his meta-analysis, Cao et al. revealed that clinical pregnancy rate (CPR) and LBR were both significantly higher in RIF patients who underwent hysteroscopy than in those who did not (73). Endometrial injury and CE are the most recent attractive areas in RIF research (Figure 6), with hysteroscopy being central to research. Additionally, adding endometrial scratching to diagnostic hysteroscopy has been revealed to enhance implantation and pregnancy success rates in women with RIF (74,75). Numerous studies have found that hysteroscopy and immunohistochemistry offer superior CE diagnosis in RIF patients compared with other diagnostic techniques, such as transvaginal sonography, saline infusion/gel instillation sonography, 3D ultrasound scan, and hysterosalpingography. They also guide on the antibiotic treatment (43,76,77).

Improvement

RIF remains the major setback for IVF. Accordingly, IVF outcomes urgently need to be improved. In their systematic analysis, Yakin et al. summarized the current RIF treatments targeting either the embryo, the maternal immune system, the endometrium, or the sperm (78). During the last decade, researchers have focused on the effect of endometrial injury and immunotherapy on RIF and pregnancy outcomes. Based on a prospective and randomized controlled trial, endometrial injury improves the successful implantation and LBRs in RIF patients (75). Recently, Maleki-Hajiagha et al. in their systematic review, revealed that PBMCs increased the successful pregnancy rate in patients with a previous history of RIF and can be a useful therapeutic target for RIF (79). However, RIF is a complex phenomenon with numerous etiologies and pathophysiologies. Conflicting findings have been reported for these treatments and ART outcomes. For instance, one randomized controlled trial revealed that endometrial injury did not improve the pregnancy success rates in women with RIF (80). A separate systematic review found no association between the administration of PBMCs and LBRs in women with RIF (78). Therefore, how to improve ET outcomes for RIF patients remains unresolved.

Strengths and limitations

Compared to traditional reviews, this bibliometric analysis provided better insight into the knowledge, patterns, trends, and evolution of RIF research. Regarding limitations, however, first, given that we only searched through the WoSCC database for articles published between 2000–2020, some studies on RIF may have been missed. Second, bibliometric analysis usually favors older published articles but may fail to appreciate novel findings of recently published high-quality papers because of low citation frequency. Third, the number of citations alone may not fully quantify the benefits of research because citation rates are affected by many factors, such as the quality of citation, the IF of a given journal, author self-citation, and omission bias (25).

Conclusions

In the present bibliometric study, we identified a gradual and steady increase in publications on RIF since 2000. The United States was the leading country in RIF research, and most of the RIF studies were published in the journal of Fertility and Sterility. Notably, “hysteroscopy” and “improvement” reflected the latest foci and should be closely followed in RIF research.

Acknowledgments

Funding: This work was supported by the Youth Science and Technology Fund of Gansu Province (No. 21JR7RA387).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-703/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Coughlan C, Ledger W, Wang Q, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014;28:14-38. [Crossref] [PubMed]
2. Mascarenhas M, Jeve Y, Polanski L, et al. Management of recurrent implantation failure: British Fertility Society policy and practice guideline. Hum Fertil (Camb) 2021; Epub ahead of print. [Crossref] [PubMed]
3. Pourmoghadam Z, Soltani-Zangbar MS, Sheikhansari G, et al. Intrauterine administration of autologous hCG- activated peripheral blood mononuclear cells improves pregnancy outcomes in patients with recurrent implantation failure; A double-blind, randomized control trial study. J Reprod Immunol 2020;142:103182. [Crossref] [PubMed]
4. Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol 2018;16:121. [Crossref] [PubMed]
5. Cakiroglu Y, Tiras B. Determining diagnostic criteria and cause of recurrent implantation failure. Curr Opin Obstet Gynecol 2020;32:198-204. [Crossref] [PubMed]
6. Tsiami A, Chaimani A, Mavridis D, et al. Surgical treatment for hydrosalpinx prior to in-vitro fertilization embryo transfer: a network meta-analysis. Ultrasound Obstet Gynecol 2016;48:434-45. [Crossref] [PubMed]
7. Cenksoy P, Ficicioglu C, Yıldırım G, et al. Hysteroscopic findings in women with recurrent IVF failures and the effect of correction of hysteroscopic findings on subsequent pregnancy rates. Arch Gynecol Obstet 2013;287:357-60. [Crossref] [PubMed]
8. Margalioth EJ, Ben-Chetrit A, Gal M, et al. Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod 2006;21:3036-43. [Crossref] [PubMed]
9. Patel JA, Patel AJ, Banker JM, et al. Personalized Embryo Transfer Helps in Improving In vitro Fertilization/ICSI Outcomes in Patients with Recurrent Implantation Failure. J Hum Reprod Sci 2019;12:59-66. [Crossref] [PubMed]
10. Cozzolino M, Diaz-Gimeno P, Pellicer A, et al. Evaluation of the endometrial receptivity assay and the preimplantation genetic test for aneuploidy in overcoming recurrent implantation failure. J Assist Reprod Genet 2020;37:2989-97. [Crossref] [PubMed]
11. Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril 2012;97:1039-43. [Crossref] [PubMed]
12. Li Y, Yu S, Huang C, et al. Evaluation of peripheral and uterine immune status of chronic endometritis in patients with recurrent reproductive failure. Fertil Steril 2020;113:187-196.e1. [Crossref] [PubMed]
13. Vitagliano A, Saccardi C, Noventa M, et al. Effects of chronic endometritis therapy on in vitro fertilization outcome in women with repeated implantation failure: a systematic review and meta-analysis. Fertil Steril 2018;110:103-112.e1. [Crossref] [PubMed]
14. Shaulov T, Sierra S, Sylvestre C. Recurrent implantation failure in IVF: A Canadian Fertility and Andrology Society Clinical Practice Guideline. Reprod Biomed Online 2020;41:819-33. [Crossref] [PubMed]
15. Hyman RW, Herndon CN, Jiang H, et al. The dynamics of the vaginal microbiome during infertility therapy with in vitro fertilization-embryo transfer. J Assist Reprod Genet 2012;29:105-15. [Crossref] [PubMed]
16. Mrozikiewicz AE, Ożarowski M, Jędrzejczak P. Biomolecular Markers of Recurrent Implantation Failure-A Review. Int J Mol Sci 2021;22:10082. [Crossref] [PubMed]
17. Riganelli L, Iebba V, Piccioni M, et al. Structural Variations of Vaginal and Endometrial Microbiota: Hints on Female Infertility. Front Cell Infect Microbiol 2020;10:350. [Crossref] [PubMed]
18. Koedooder R, Singer M, Schoenmakers S, et al. The vaginal microbiome as a predictor for outcome of in vitro fertilization with or without intracytoplasmic sperm injection: a prospective study. Hum Reprod 2019;34:1042-54. [Crossref] [PubMed]
19. Fu M, Zhang X, Liang Y, et al. Alterations in Vaginal Microbiota and Associated Metabolome in Women with Recurrent Implantation Failure. mBio 2020;11:03242-19. [Crossref] [PubMed]
20. Pirtea P, de Ziegler D, Ayoubi JM. Recurrent Implantation Failure-Is It the Egg or the Chicken? Life (Basel) 2021;12:39. [Crossref] [PubMed]
21. Moustafa S, Young SL. Diagnostic and therapeutic options in recurrent implantation failure. F1000Res 2020;9:eF1000 Faculty Rev-208.
22. Zohni KM, Gat I, Librach C. Recurrent implantation failure: a comprehensive review. Minerva Ginecol 2016;68:653-67. [PubMed]
23. Busnelli A, Somigliana E, Cirillo F, et al. Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis. Sci Rep 2021;11:1747. [Crossref] [PubMed]
24. Ahmad P, Dummer PMH, Chaudhry A, et al. A bibliometric study of the top 100 most-cited randomized controlled trials, systematic reviews and meta-analyses published in endodontic journals. Int Endod J 2019;52:1297-316. [Crossref] [PubMed]
25. Brandt JS, Hadaya O, Schuster M, et al. A Bibliometric Analysis of Top-Cited Journal Articles in Obstetrics and Gynecology. JAMA Netw Open 2019;2:e1918007. [Crossref] [PubMed]
26. Pritchard A. Statistical bibliography or bibliometrics. Journal of Documentation 1969;25:348-9.
27. Sugimoto CR, Ahn YY, Smith E, et al. Factors affecting sex-related reporting in medical research: a cross-disciplinary bibliometric analysis. Lancet 2019;393:550-9. [Crossref] [PubMed]
28. Zhai X, Cui J, Shao J, et al. Global research trends in spinal ultrasound: a systematic bibliometric analysis. BMJ Open 2017;7:e015317. [Crossref] [PubMed]
29. Wu M, Wang Y, Yan C, et al. Study on subclinical hypothyroidism in pregnancy: a bibliometric analysis via CiteSpace. J Matern Fetal Neonatal Med 2022;35:556-67. [Crossref] [PubMed]
30. Churruca K, Pomare C, Ellis LA, et al. The influence of complexity: a bibliometric analysis of complexity science in healthcare. BMJ Open 2019;9:e027308. [Crossref] [PubMed]
31. Bhulani N, Miao TL, Norbash A, et al. Leadership in healthcare: A bibliometric analysis of 100 most influential publications. BMJ Leader 2020; [Crossref]
32. Bang CS, Lee JJ, Baik GH. The most influential articles in Helicobacter pylori research: A bibliometric analysis. Helicobacter 2019;24:e12589. [Crossref] [PubMed]
33. Miao Y, Zhang Y, Yin L. Trends in hepatocellular carcinoma research from 2008 to 2017: a bibliometric analysis. PeerJ 2018;6:e5477. [Crossref] [PubMed]
34. Akmal M, Hasnain N, Rehan A, et al. Glioblastome Multiforme: A Bibliometric Analysis. World Neurosurg 2020;136:270-82. [Crossref] [PubMed]
35. Devos P, Menard J. Bibliometric analysis of research relating to hypertension reported over the period 1997-2016. J Hypertens 2019;37:2116-22. [Crossref] [PubMed]
36. Mansour AM, Mollayess GE, Habib R, et al. Bibliometric trends in ophthalmology 1997-2009. Indian J Ophthalmol 2015;63:54-8. [Crossref] [PubMed]
37. Ruiz-Pomeda A, Álvarez-Peregrina C, Povedano-Montero FJ. Bibliometric study of scientific research on optometric visual therapy. J Optom 2020;13:191-7. [Crossref] [PubMed]
38. National Natural Science Foundation of China. National Natural Science Foundation Project Guide for 2021. 2021. Available online: https://www.nsfc.gov.cn/english/site_1/index.html
39. Yang Y, Chen G, Reniers G, et al. A bibliometric analysis of process safety research in China: Understanding safety research progress as a basis for making China’s chemical industry more sustainable. J Clean Prod 2020;263:121433. [Crossref]
40. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online 2012;25:561-71. [Crossref] [PubMed]
41. Narvekar SA, Gupta N, Shetty N, et al. Does local endometrial injury in the nontransfer cycle improve the IVF-ET outcome in the subsequent cycle in patients with previous unsuccessful IVF? A randomized controlled pilot study. J Hum Reprod Sci 2010;3:15-9. [Crossref] [PubMed]
42. Nastri CO, Lensen SF, Gibreel A, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2015;CD009517. [Crossref] [PubMed]
43. Bouet PE, El Hachem H, Monceau E, et al. Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis. Fertil Steril 2016;105:106-10. [Crossref] [PubMed]
44. Cicinelli E, Matteo M, Tinelli R, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 2015;30:323-30. [Crossref] [PubMed]
45. Polanski LT, Baumgarten MN, Quenby S, et al. What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion. Reprod Biomed Online 2014;28:409-23. [Crossref] [PubMed]
46. Lédée N, Petitbarat M, Chevrier L, et al. The Uterine Immune Profile May Help Women With Repeated Unexplained Embryo Implantation Failure After In Vitro Fertilization. Am J Reprod Immunol 2016;75:388-401. [Crossref] [PubMed]
47. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. The role of immunotherapy in in vitro fertilization: a guideline. Fertil Steril 2018;110:387-400.
48. Kitaya K, Takeuchi T, Mizuta S, et al. Endometritis: new time, new concepts. Fertil Steril 2018;110:344-50. [Crossref] [PubMed]
49. Bellver J, Simón C. Implantation failure of endometrial origin: what is new? Curr Opin Obstet Gynecol 2018;30:229-36. [Crossref] [PubMed]
50. Liu C, Yao W, Yao J, et al. Endometrial extracellular vesicles from women with recurrent implantation failure attenuate the growth and invasion of embryos. Fertil Steril 2020;114:416-25. [Crossref] [PubMed]
51. Liu C, Wang M, Zhang H, et al. Altered microRNA Profiles of Extracellular Vesicles Secreted by Endometrial Cells from Women with Recurrent Implantation Failure. Reprod Sci 2021;28:1945-55. [Crossref] [PubMed]
52. Liu C, Li L, Wang M, et al. Endometrial extracellular vesicles of recurrent implantation failure patients inhibit the proliferation, migration, and invasion of HTR8/SVneo cells. J Assist Reprod Genet 2021;38:825-33. [Crossref] [PubMed]
53. Caglar GS, Asimakopoulos B, Nikolettos N, et al. Preimplantation genetic diagnosis for aneuploidy screening in repeated implantation failure. Reprod Biomed Online 2005;10:381-8. [Crossref] [PubMed]
54. Blockeel C, Schutyser V, De Vos A, et al. Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod Biomed Online 2008;17:848-54. [Crossref] [PubMed]
55. Wilton L, Voullaire L, Sargeant P, et al. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil Steril 2003;80:860-8. [Crossref] [PubMed]
56. Wilding M, Forman R, Hogewind G, et al. Preimplantation genetic diagnosis for the treatment of failed in vitro fertilization-embryo transfer and habitual abortion. Fertil Steril 2004;81:1302-7. [Crossref] [PubMed]
57. Taranissi M, El-Toukhy T, Gorgy A, et al. Influence of maternal age on the outcome of PGD for aneuploidy screening in patients with recurrent implantation failure. Reprod Biomed Online 2005;10:628-32. [Crossref] [PubMed]
58. Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Fertil Steril 2010;93:364-73. [Crossref] [PubMed]
59. Miravet-Valenciano JA, Rincon-Bertolin A, Vilella F, et al. Understanding and improving endometrial receptivity. Curr Opin Obstet Gynecol 2015;27:187-92. [Crossref] [PubMed]
60. Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril 2019;111:611-7. [Crossref] [PubMed]
61. Tong R, Zhou Y, He Q, et al. Analysis of the guidance value of 3D ultrasound in evaluating endometrial receptivity for frozen-thawed embryo transfer in patients with repeated implantation failure. Ann Transl Med 2020;8:944. [Crossref] [PubMed]
62. Demirol A, Gurgan T. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod Biomed Online 2004;8:590-4. [Crossref] [PubMed]
63. Saxtorph MH, Hallager T, Persson G, et al. Assessing endometrial receptivity after recurrent implantation failure: a prospective controlled cohort study. Reprod Biomed Online 2020;41:998-1006. [Crossref] [PubMed]
64. Laird SM, Tuckerman EM, Li TC. Cytokine expression in the endometrium of women with implantation failure and recurrent miscarriage. Reprod Biomed Online 2006;13:13-23. [Crossref] [PubMed]
65. Lédée-Bataille N, Dubanchet S, Coulomb-L'hermine A, et al. A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization. Fertil Steril 2004;81:59-65. [Crossref] [PubMed]
66. Kalinka J, Radwan M. The impact of dydrogesterone supplementation on serum cytokine profile in women with threatened abortion. Am J Reprod Immunol 2006;55:115-21. [Crossref] [PubMed]
67. Clark DA, Manuel J, Lee L, et al. Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model. I. Synergistic effect of LPS and (TNF-alpha + IFN-gamma) on pregnancy loss. Am J Reprod Immunol 2004;52:370-8. [Crossref] [PubMed]
68. Bates MD, Quenby S, Takakuwa K, et al. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum Reprod 2002;17:2439-44. [Crossref] [PubMed]
69. Ng SC, Gilman-Sachs A, Thaker P, et al. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 2002;48:77-86. [Crossref] [PubMed]
70. Karimzadeh MA, Ayazi Rozbahani M, Tabibnejad N. Endometrial local injury improves the pregnancy rate among recurrent implantation failure patients undergoing in vitro fertilisation/intra cytoplasmic sperm injection: a randomised clinical trial. Aust N Z J Obstet Gynaecol 2009;49:677-80. [Crossref] [PubMed]
71. Gao M, Sun Y, Xie H, et al. Hysteroscopy prior to repeat embryo transfer may improve pregnancy outcomes for asymptomatic women with repeated implantation failure. J Obstet Gynaecol Res 2015;41:1569-76. [Crossref] [PubMed]
72. Elsetohy KA, Askalany AH, Hassan M, et al. Routine office hysteroscopy prior to ICSI vs. ICSI alone in patients with normal transvaginal ultrasound: a randomized controlled trial. Arch Gynecol Obstet 2015;291:193-9. [Crossref] [PubMed]
73. Cao H, You D, Yuan M, et al. Hysteroscopy after repeated implantation failure of assisted reproductive technology: A meta-analysis. J Obstet Gynaecol Res 2018;44:365-73. [Crossref] [PubMed]
74. Seval MM, Şükür YE, Özmen B, et al. Does adding endometrial scratching to diagnostic hysteroscopy improve pregnancy rates in women with recurrent in-vitro fertilization failure? Gynecol Endocrinol 2016;32:957-60. [Crossref] [PubMed]
75. Gürgan T, Kalem Z, Kalem MN, et al. Systematic and standardized hysteroscopic endometrial injury for treatment of recurrent implantation failure. Reprod Biomed Online 2019;39:477-83. [Crossref] [PubMed]
76. Zargar M, Ghafourian M, Nikbakht R, et al. Evaluating Chronic Endometritis in Women with Recurrent Implantation Failure and Recurrent Pregnancy Loss by Hysteroscopy and Immunohistochemistry. J Minim Invasive Gynecol 2020;27:116-21. [Crossref] [PubMed]
77. Yang R, Du X, Wang Y, et al. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients. Arch Gynecol Obstet 2014;289:1363-9. [Crossref] [PubMed]
78. Yakin K, Oktem O, Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: a systematic review and meta-analysis. Sci Rep 2019;9:3897. [Crossref] [PubMed]
79. Maleki-Hajiagha A, Razavi M, Rezaeinejad M, et al. Intrauterine administration of autologous peripheral blood mononuclear cells in patients with recurrent implantation failure: A systematic review and meta-analysis. J Reprod Immunol 2019;131:50-6. [Crossref] [PubMed]
80. Tk A, Singhal H, S, Premkumar P, et al. Local endometrial injury in women with failed IVF undergoing a repeat cycle: A randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2017;214:109-14. [Crossref] [PubMed]