{"paper_id":"001b24d3-0d6c-4b8f-bd82-ee358f2a9506","body_text":"The effectiveness of immunotherapies for patients with repeated implantation failure: a systematic review and network meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effectiveness of immunotherapies for patients with repeated implantation failure: a systematic review and network meta-analysis Mengqi Liu, Yuan Yuan, Yan Qiao, Xi Sui, Yuzhu Tang, Ping Yin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1270989/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: This study compared clinical pregnancy outcomes of repeated implantation failure (RIF) patients treated with immunotherapies using a network meta-analysis. Methods: Publications are determined by searching the Pubmed, Embase and web of science databases. The search date is from the establishment of the database till August 2021. The outcomes were clinical pregnancy rate (CPR), live birth rate (LBR) and implantation rate (IR). The Cochrane bias risk assessment tool was applied to evaluate the quality of the study, and Stata 14.0 was used for the network meta-analysis. Results: A total of 16 RCTs including 2008 participants were included. The network meta-analysis results show that PBMC, PRP and SC-GCSF can significantly improve CPR compared with LMWH (PBMC: OR = 2.15; 95% CI, 1.21-3.83; PRP: OR = 2.38; 95% CI, 1.08-5.24; SC-GCSF: OR = 2.46; 95% CI, 1.05-5.72). The LBR of PRP was significantly higher than IU-GCSF (OR = 3.81; 95% CI, 1.22-11.86), LMWH (OR = 4.38; 95% CI, 1.50-12.90) and Intralipid (OR = 3.85; 95% CI, 1.03-14.29), and the LBR of PBMC was also significantly better than that of LMWH (OR = 2.35; 95% CI, 1.14-4.85). Furthermore, PRP treatment significantly improved IR compared with LMWH treatment (OR = 2.81; 95% CI, 1.07-7.4). Discussion: Based on the limited evidence from existing RCTs, PBMC and PRP seem to be the best therapeutic options for RIF patients. However, due to research quantity restrictions, more top-quality researches are required in the future to obtain additional high-level evidence. repeated implantation failure immunotherapies network meta-analysis pregnancy outcome Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Repeated implantation failure (RIF) is unable to achieve a clinical pregnancy after multiple cycles of fertilization in vitro and cumulative transfer of multiple high-quality embryos in patients undergoing assisted reproductive techniques [ 1 ]. Due to the complexity of the causes of RIF and the high diversity of patients, different academic organizations and researchers have attempted to propose clear diagnostic criteria, but no consensus has been generated to date. The current widely-used definition of RIF by Coughlan et al. is that, for a woman under the age of 40 years, the unsuccessful clinical pregnancy after at least 4 good-quality embryos transfer within minimum three fresh or frozen cycles[ 2 , 3 ]. Implantation is a very complicated process and there are plenty of factors that contribute to RIF, either maternal or embryonic origin. The embryo, as a homozygous hemizygous antigen, is subject to a variety of factors for its successful implantation [ 1 , 4 ]. After embryo transferred into uterus cavity, the endometrium must be receptive for the embryo synchronizedly and the maternal immune system must tolerate the continued presence of the paternal alloantigen during the pregnancy [ 5 ]. In the absence of common factors as uterine abnormalities, hormonal or metabolic disorders, infections, immunological factors, thrombophilias as well as severe male factors, abnormal immunological response could result in a defected maternal-fetal immunotolerance and impaired endometrium receptivity. In order to restore the underlying immunological imbalance, some immunotherapies have been introduced to enhance clinical outcomes in women with unexplained RIF. [ 6 – 8 ]. The immunotherapeut ic agents mainly are low-molecular-weight heparin (LMWH), intravenous immunoglobulin (IVIG), intrauterine human chorionic gonadotropin (hCG), subcutaneous (SC) or intrauterine (IU) infusion of granulocyte colony stimulating factor (GCSF), peripheral blood mononuclear cells (PBMCs), and intrauterine autologous platelet-rich plasma (PRP) [ 9 – 12 ]. However, there is much conflicting evidence and the comparable effectiveness of these immunotherapies in the setting of RIF is unrevealed. Therefore, our study uses a network meta-analysis to compare the effectiveness of the most widely used immunotherapies for RIF treatment, in order to provide an evidence basis for clinical application. Methods Search strategy Publications are determined by searching the Pubmed, Embase and web of science databases. The search date is from the establishment of the database till August 2021, and the search language was limited to English. The following terms were applied for this search: repeated implantation failure, recurrent implantation failure, intravenous immunoglobulin, PBMC, G-CSF, IVIG, PRP, Intralipid, Glucocorticoid, hCG, LMWH and Aspirin. Selection criteria Strict literature inclusion and exclusion criteria were established. The selected documents must be qualified as follows: (1) These studies are randomized controlled trials; (2) The study participants had two or more episodes of implantation failure; (3) The experimental group was treated with immunotherapy, and the control group was given with the standard care/placebo/no immunotherapy; (4) The study includes at least one outcome (clinical pregnancy rate (CPR), live birth rate (LBR) and implantation rate (IR)). Research was excluded as any of the following conditions: (1) The data is incomplete or cannot be used for statistical analysis; (2) Non-authoritative documents such as reviews, letters, conference abstracts, and reviews. Data extraction Two authors independently derived the relevant data from the qualified literature, additionally, the extracted content included: the first author of the literature, publication year, research type, total number of people included, age, RIF inclusion criteria and outcome indicators, etc. The Cochrane quality evaluation system was utilized to access the quality of the involved randomized control trials. If the opinions of the two authors disagree, the third author will make the judgment. Statistical analysis The Stata 14.0 was used to accomplish the network meta-analysis under the consistency model. The odds ratio (OR) was analyzed for dichotomous outcomes with 95% CI. A paired meta-analysis was performed using a fixed-effects model based on the main results. I 2 is used to assess heterogeneity, and I 2 ≥ 50% indicates statistical heterogeneity. The surface under the cumulative ranking (SUCRA) is to evaluate the likelihood that each intervention is the most beneficial or safest treatment. A greater SUCRA value means the higher treatment efficacy. A comparison-correction funnel chart was used to assess publication bias. Results Overall, 3350 documents were identified according to the searching criteria. 901 duplicate articles were eliminated, and 2379 literatures were eliminated after the title and abstract examining. The remaining 70 publications’ full text was read, and 16 RCTs meeting the requirements were finally included (Figure 1). A total of 16 RCTs including 2008 participants were included [ 13 – 28 ]. Among them, 3 are LMWH, 6 are GCSF, 4 are PBMC, one is hCG, one is intralipid, and 2 are PRP. Since studies of Glucocorticoid and IVIG do not meet the selection criteria, n o study was included here. The age of the sample population is between 30.51 and 37.8. Table 1 demonstrates the baseline characteristics of the involved studies. Next, Figure 2 indicates the assessment of these selected studies’ quality using the Cochrane risk of bias tool. Table 1 Baseline characteristics of included studies study Study design RIF criteria Invention No. of patients Age (Year) BMI (kg/m2) No. of transferred embryos (mean) Urman 2009 Randomized open-labeled pilot trial Three or more previously failed fresh embryo transfer cycles LMWH (administered LMWH at a dose of 1 mg/kg/day starting on the day after oocyte retrieval) 75 34.0±5.0 - 2.6±0.7 Control (received no medication besides progesterone gel on the day after oocyte retrieval) 75 34.8±5.8 - 2.6±0.8 Berker 2011 Prospective, quasi-randomized, controlled study at least two consecutive failed cycles of intracytoplasmic sperm injection and embryo transfer (ICSI-ET) LMWH (administered LMWH at a standard dose of 40 mg/0.4 mL per day starting on the day of oocyte retrieval) 104 31.3±4.9 - 2.4±0.6 Control 103 31.2±5.0 - 2.5±0.6 Aleyasin 2016 Prospective randomized openlabel controlled trial Failure of implantation in at least three consecutive IVF attempts, in which three embryos of high-grade quality are transferred in each cycle subcutaneous GCSF (A single dose of 300 µg G-CSF administered subcutaneously 1 h before the embryo transfer) 56 33.5±4.2 - 2.3 ± 0.6 Control (did not receive any additional treatment before the embryo transfer) 56 32.4±5.2 - 2.5 ± 0.6 Davari-Tanha 2016 Randomized double blind placebo control trial three times implantation failure when there was history of transferring at least four good quality embryos without uterine or thrombophilic factors. intrauterine GCSF (At the time of oocyte retrieval one ml of G-CSF (300 µg/ml) was administered by a Trans cervical Cook catheter for embryo transfer slowly into uterine cavity) 40 35.5 ± 4.32 25.2 ± 1.8 - Control (a catheter pass through the cervix without any injection) 20 35.4 ± 4.01 24.8 ± 1.3 - Eftekhar 2016 Randomised controlled trial two or more episodes of implantation failure intrauterine GCSF (received uterine infusion of 300 µg (0.5ml) recombinant human GCSF (300 µg) by the use of IUI catheter after ovarian puncture under general anesthesia) 45 32.55 ± 4.61 - 2.11 ± 0.77 Control (the standard treatment) 45 31.75 ± 5.16 - 2.35 ± 0.71 Madkour 2016 Randomised controlled trial at least two previous failures of implantation after IVF/intra-cytoplasmic spermatozoa injection (ICSI) (mean = 3) PBMC (Intrauterine administration of PBMC prior to fresh embryo transfer) 27 34.74 ± 4.17 - - Control 27 34.44 ± 3.86 - - Yu 2016 Prospective randomized study Patients who had not experienced successful pregnancy despite three or more IVF-ET sessions PBMC (intrauterine administration of autologous PBMC activated by HCG in vitro before ET) 93 31.08±3.95 - - Control (undergoing ET without a previous intrauterine administration of autologous PBMC) 105 31.22±5.12 - - Arefi 2018 Randomised controlled trial the history of more than two previous IVF/Intracytoplasmic sperm injection-embryo transfer (ET) failures despite transfer of at least two good-quality embryos in each attempt. subcutaneous GCSF (receive 300 µg (0.5 ml) recombinant human G-CSF subcutaneously which was injected 30 min before blastocyst embryo transfer) 32 34.53 ± 5.50 - 3.31 ± 0.85 Control 20 34.05 ± 6.5 - 3.20 ± 0.95 Nobijari 2019 Prospective randomized study a history of at least one RIF PBMC (a blood sample was collected 5 days before the scheduled frozenthawed embryo transfer; PBMCs were isolated using Ficoll separation and then cultured for 72h. Two days prior to embryo transfer, 0.4 ml of cultured PBMCs were transferred into the patient’s uterus) 122 35.21 ± 4.84 - - Control 128 34.55 ± 5.03 - - Wang 2019 Prospective randomized-controlled trial Failure of implantation in at least 4 consecutive IVF attempts, in which 1 embryos of high-grade quality are transferred in each cycle hCG (The hCG+G2 fluid was prepared on the day of embryo transfer, and 40 µL of which was injected at an intrauterine site at 3 minutes before embryo transfer) 69 31.35±3.18 22.3±3.25 - Control (the G2 fluid was prepared on the day of embryo transfer, and 40 µL of which was injected at an intrauterine site at 3 minutes before embryo transfer) 68 31.7±3.56 22.7±3.61 - Al-Zebeidi 2020 Randomised controlled trial a history of three or more RIF undergoing ICSI cycles Intralipid (received intralipid 20% 100 ml diluted in 500 ml normal saline for infusion therapy on the day of embryo transfer (ET) and repeated dose was administered on the day of the pregnancy test) 71 35.32 ± 4.23 28.30 ± 4.66 - Control (underwent the standard ICSI cycle without intralipid infusion therapy) 71 35.21 ± 4.77 28.30 ± 4.66 - Huang 2020 Prospective randomized single-blind study more than two failed implantations (each time containing at least one high-quality embryo intrauterine GCSF (administered a 1-ml uterine infusion of recombinant human G-CSF (150 mg, 1ml) through an intrauterine insemination catheter.) 52 32.09±4.21 21.24±2.29 Control (an intrauterine infusion of physiological saline before embryo transfer) 52 32.07±4.36 21.51±2.90 Kalem 2020 Prospective randomized controlled trial the failure to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles to a woman under the age of 40 years intrauterine GCSF (received G-CSF once a day on hCG day, before hCG injection. The procedure involved the administration of 30 mIU of Leucostim (G-CSF 30mIU/mL) through slow infusion into the endometrial cavity using a soft embryo transfer catheter) 82 34.61 ± 4.77 25.92 ± 4.44 - Control (normal saline of 1 mL was infused into the endometrial cavity of patients in the same way as the study group) 75 34.92 ± 5.60 24.94 ± 4.92 - Pourmoghadam 2020 Double-blind randomized control trial at least three previous failures of IVF/ET therapy PBMC (PBMCs (15–20×106 cells) were suspended in 500 µl PBS and was gently administered to the uterine cavity two days before ET using an embryo transfer catheter) 50 33.42 ± 3.1 26.94 ± 2.13 - Control (500µl PBS was administered into the uterine cavity) 50 34.64 ± 3.0 28.53 ± 2.84 - Salehpour 2020 Randomised controlled trial patients who failed to conceive after 3 or more embryo transfers with high-quality embryos and candidates for frozenthawed embryo transfer (FET) PRP (Intrauterine infusion of PRP was carried out 48 h before embryo transfer under ultrasound guidance) 49 35.73 ± 3.49 25.61 ± 3.13 1.9 ± 0.8 Control (standard treatment) 48 34.95 ± 4.23 25.46 ± 2.68 1.7 ± 0.6 Zamaniyan 2021 Randomised controlled trial women who unsuccessful to be pregnant after three or more high-quality embryo transfers undergoing frozen-thawed embryo transfer PRP (Intrauterine infusion of platelet-rich plasma was performed 48 h before embryo transfer) 55 33.88 ± 6.32 26.49 ± 4.53 - Control 43 33.13 ± 5.00 25.03 ± 3.66 - In Figure 3, the network of eligible comparisons is shown for each outcome. There is no closed loop between interventions, which suggests that all these pairwise comparisons are indirect. Therefore, statistical analysis is performed directly under the consistency model. Figure 4 reveals the results of the CPR network meta-analysis. PBMC, PRP, SC-GCSF and hCG administration can significantly increase CPR when compared to the control group (PBMC: OR = 2.44; 95% CI, 1.67-3.57; PRP: OR = 2.70; 95% CI, 1.41-5.26; SC-GCSF: OR = 2.78; 95% CI, 1.35-5.88; hCG: OR = 2.44; 95% CI, 1.20-4.98). Besides, PBMC, PRP and SC-GCSF can also significantly improve CPR compared to LMWH (PBMC: OR = 2.15; 95% CI, 1.21-3.83; PRP: OR = 2.38; 95% CI, 1.08-5.24; SC-GCSF: OR = 2.46; 95% CI, 1.05-5.72). Nine studies reported data on LBR. The network meta-analysis outcomes implied that the administration of PBMC and PRP had a higher LBR in comparison with the control group (PBMC: OR = 2.86; 95% CI, 1.64-5.00; PRP: OR = 5.26; 95% CI, 2.00-14.29) (Figure 5). The effect of PRP on LBR was significantly better than IU-GCSF (OR = 3.81; 95% CI, 1.22-11.86), LMWH (OR = 4.38; 95% CI, 1.50-12.90) and Intralipid (OR = 3.85; 95% CI, 1.03-14.29), and the efficacy of PBMC for LBR was also significantly better than that of LMWH (OR = 2.35; 95% CI, 1.14-4.85). We conducted a network meta-analysis on nine studies that reported on IR. The results showed that IU-GCSF, PBMC, PRP, SC-GCSF and hCG were significantly associated with higher IR compared to the control (IU-GCSF: OR = 3.57; 95% CI, 1.16-11.1; PBMC: OR =2.56; 95% CI, 1.28-5.26; PRP: OR = 3.23; 95% CI, 1.43-7.69; SC-GCSF: OR = 2.86; 95% CI, 1.30-6.25; hCG: OR = 1.86; 95% CI, 1.05-3.28) (Figure 6). Furthermore, PRP significantly improved IR compared with LMWH (OR = 2.81; 95% CI, 1.07-7.4). The I 2 values were 37.4% for CPR, 16.1% for LBR and 50.8% for IR (Figure S1-3). In Figure 7, the comparison-adjusted funnel plots of the network meta-analysis of each outcome suggested no publication bias. The ranking probability of SUCRA for each treatment included in the network was shown in Table 2. In terms of CPR, SC-GCSF was the most effective therapy (78.9%), whereas LMWH was the least effective therapy (18.3%). As far as LBR is concerned, PRP is the most effective treatment (94.8%), and LMWH is the worst (29.4%). In addition, in terms of IR, the most effective treatment is IU-GCSF (77.6%), and the least effective is LMWH (16.2%). Table 2. SUCRA of CPR, LBR and IR Treatment CPR LBR IR IU-GCSF 37.1 39.5 77.6 LMWH 18.3 29.4 16.2 PBMC 73.1 78 63.4 PRP 77.9 94.8 75.9 SC-GCSF 78.9 60.4 68.1 control 7 11 5.1 hCG 71.4 43.7 intralipid 36.3 36.9 Discussion Given the fact that the pregnancy rate has increased year by year due to the development of assisted reproductive technology, but there are still a number of patients suffering from RIF [ 29 – 31 ]. Uterine abnormalities, spermatic factor anomalies, genetic, hormonal, and metabolic pathologies, acquired thrombophilia, and autoimmune disorders are all possible causes of RIF [ 32 ]. However, RIF remains unexplained in approximately 30% of instances, and the reasons underlying this unexplained infertility are not fully understood [ 33 ]. It has been reported that immune factors are crucial in the process of embryo implantation, thus immunotherapies can improve the pregnancy outcome of some patients with RIF [ 33 ]. Recently, there have been many studies on the pathogenesis of RIF immune factors and immunotherapeutic methods, but there are differences in efficacy due to the different mechanisms of action of different preparations. Therefore, this study evaluated the efficacy of immunotherapies in improving the CPR and LBR of RIF patients through network meta-analysis. According to the outcomes of treated RIF patients, it was found that PBMC and PRP are effective in boosting CPR and LBR. In comparison to the control group, PBMC, PRP, SC-GCSF and hCG treatment significantly increased CPR and IR, and PBMC and PRP were significantly related with greater LBR. Previous research has demonstrated that RIF patients can benefit with immunotherapies, but there are still no direct or indirect comparisons of the efficacy of different immunotherapies [ 12 , 34 – 37 ]. This study evaluated the efficacy of five immunotherapies through a network meta-analysis system, and found that SC-GCSF is the best in improving CPR, while IU-GCSF is the best in improving IR. Our results confirmed the conclusions of Zhao et al., and Xie et al. Zhao et al. showed that the administration of G-CSF may have a favorable clinical effect on pregnancy outcomes. In addition, the best way to administer G-CSF may be the subcutaneous injection [ 38 ]. Xie et al. found that intrauterine perfusion of G-CSF could significantly improve IR compared with control group [ 39 ]. G-CSF, as a glycoprotein, belongs to the growth factor family. It has been discovered to regulate the growth of the endometrium and involve in the occurrence of early endometriosis [ 40 ]. G-CSF has been shown to promote endometrial stem cells, mobilize bone marrow stem cells, and enhance endometrial development [ 41 ]. However, there is still controversy about the ideal route of G-CSF administration, and the reasons for the difference between the two administration effects have not yet been fully clarified. Therefore, more and higher-quality studies are needed to clarify these phenomena. For LBR, PRP has the best efficacy among the five immunotherapies. We also discovered that PRP had a significantly better effect on LBR than IU-G-CSF, LMWH, and Intralipid. Moreover, PRP can also increase the CPR and IR of RIF patients compared with the control group. PRP is made up of a high concentration of autologous platelets, normally 5-7 times greater compared to the platelet concentration in peripheral blood, which was collected by centrifuging peripheral whole blood [ 42 ]. PRP contains a variety of growth factors and cytokines, which may help regulate endometrial cell migration, attachment, proliferation, differentiation and neovascularization, thereby having a beneficial effect on endometrial receptivity [ 43 , 44 ]. Amable et al. shows that compared with whole blood plasma or platelet-poor plasma, the levels of 12 proteins (including six growth factors, three anti-inflammatory cytokines and three pro-inflammatory cytokines) in activated PRP are increased [ 45 ]. These cytokines and growth factors may boost the endometrium receptivity. Besides, a mouse experiment showed that autologous PRP intrauterine infusion accelerated and enhanced the regeneration of impaired endometrium and reduced endometrial fibrosis [ 46 ]. Owing to the limitation of the quantity of the studies, currently there is no meta-analysis to analyze the effect of PRP on LBR, so additional high-standard studies are required to verify the benefits of PRP on LBR. Intrauterine infusion of PBMC is also a good choice for RIF patients. PBMC is mainly composed of T lymphocytes, B lymphocytes and monocytes [ 47 ]. It has been reported that PBMC is able to regulate a variety of cytokines production, and also promote the spread and invasion of blastocysts to the endometrium and the in vitro receptivity of the endometrium [ 36 ]. The results of a recent RCT indicate that PBMC is an effective treatment strategy for RIF-related infertility [ 22 ]. Besides, consistent with the results of our research, Maleki-Hajiagha et al. found that PBMC can increase the CPR and LBR of RIF patients [ 11 ]. This study uncovered that PBMC can significantly increase the CPR, LBR and IR of RIF patients in contrast to the control group. The implantation promotion effect of PBMC can be explained by a variety of mechanisms. It is reported that PBMC can regulate the production of several cytokines, such as IL-1α, IL-1β, TNF-α, and promote the spread and invasion of blastocysts to the endometrium and the receptivity of the endometrium in vitro [ 48 ]. In addition, in vivo studies have shown that the administration of PBMC can promote implantation and clinical pregnancy rates, and may optimize the in vitro fertilization results of patients with multiple failures of in vitro fertilization/ICSI [ 21 , 49 ]. Although our research shows that its clinical effects are positive, adverse reactions should also be considered, which requires further research to evaluate. While, limitations are existed in our study. Firstly, the number of selected studies is relatively small, and there is only one RCT on hCG. Secondly, the included studies may be biased, and undermined hypercoagulative and immunological abnormalities are not investigated and intervened appropriately. Thirdly, few studies reported the adverse events of interventions within the qualified studies, so it is lacking of the safety evaluation on different drugs in RIF treatment. Finally, there are differences in the dose of the same drug in different studies, but because of the restricted sample size, it is unfeasible to further divide the subgroups for analysis. Conclusions This network meta-analysis showed that PBMC, PRP, SC-GCSF and hCG administration can significantly increase CPR and IR compared to the control group. Furthermore, PBMC and PRP had a higher LBR compared with the control group. Based on our findings, among the different available immunotherapeutic medications, PBMC and PRP may provide the best therapeutic efficac y . 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Mekinian A, Cohen J, Alijotas-Reig J, Carbillon L, Nicaise-Roland P, Kayem G et al : Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation? Am J Reprod Immunol 2016, 76:8–28. Kolanska K, Bendifallah S, Cohen J, Placais L, Selleret L, Johanet C et al : Unexplained recurrent implantation failures: Predictive factors of pregnancy and therapeutic management from a French multicentre study. J Reprod Immunol 2021, 145:103313. Potdar N, Gelbaya TA, Konje JC, Nardo LG: Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis. Hum Reprod Update 2013, 19:674–684. Pourmoghadam Z, Abdolmohammadi-Vahid S, Pashazadeh F, Aghebati-Maleki L, Ansari F, Yousefi M: Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis. J Reprod Immunol 2020, 137:103077. 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. Zhang L, Xu WH, Fu XH, Huang QX, Guo XY, Zhang L et al : Therapeutic role of granulocyte colony-stimulating factor (G-CSF) for infertile women under in vitro fertilization and embryo transfer (IVF-ET) treatment: a meta-analysis. Arch Gynecol Obstet 2018, 298:861–871. Zhao J, Xu B, Xie S, Zhang Q, Li YP: Whether G-CSF administration has beneficial effect on the outcome after assisted reproductive technology? A systematic review and meta-analysis. Reprod Biol Endocrinol 2016, 14:62. Xie Y, Zhang T, Tian Z, Zhang J, Wang W, Zhang H et al : Efficacy of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) for Infertile women with thin endometrium: A systematic review and meta-analysis. Am J Reprod Immunol 2017, 78. Jensen JR, Witz CA, Schenken RS, Tekmal RR: A potential role for colony-stimulating factor 1 in the genesis of the early endometriotic lesion. Fertil Steril 2010, 93:251–256. Xu B, Zhang Q, Hao J, Xu D, Li Y: Two protocols to treat thin endometrium with granulocyte colony-stimulating factor during frozen embryo transfer cycles. Reprod Biomed Online 2015, 30:349–358. Alves R, Grimalt R: A Review of Platelet-Rich Plasma: History, Biology, Mechanism of Action, and Classification. Skin Appendage Disord 2018, 4:18–24. Magdi Y, El-Damen A, Fathi AM, Abdelaziz AM, Abd-Elfatah Youssef M, Abd-Allah AA et al : Revisiting the management of recurrent implantation failure through freeze-all policy. Fertil Steril 2017, 108:72–77. Chang Y, Li J, Chen Y, Wei L, Yang X, Shi Y et al : Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. Int J Clin Exp Med 2015, 8:1286–1290. Amable PR, Carias RB, Teixeira MV, da Cruz Pacheco I, Correa do Amaral RJ, Granjeiro JM et al : Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors. Stem Cell Res Ther 2013, 4:67. Jang HY, Myoung SM, Choe JM, Kim T, Cheon YP, Kim YM et al : Effects of Autologous Platelet-Rich Plasma on Regeneration of Damaged Endometrium in Female Rats. Yonsei Med J 2017, 58:1195–1203. Chaudhary N, Que Nguyen TN, Maguire A, Wynne C, Meade AD: Comparison of sample preparation methodologies towards optimisation of Raman spectroscopy for peripheral blood mononuclear cells. Anal Methods 2021, 13:1019–1032. Yu N, Yan W, Yin T, Wang Y, Guo Y, Zhou D et al : HCG-Activated Human Peripheral Blood Mononuclear Cells (PBMC) Promote Trophoblast Cell Invasion. PLoS One 2015, 10:e0125589. Li S, Wang J, Cheng Y, Zhou D, Yin T, Xu W et al : Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. Journal of Reproductive Immunology 2017, 119:15–22. Additional Declarations No competing interests reported. Supplementary Files FigureS1.tif FigureS2.tif FigureS3.tif Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 01 Jun, 2022 Reviews received at journal 13 Apr, 2022 Reviewers agreed at journal 13 Apr, 2022 Reviewers invited by journal 13 Apr, 2022 Editor assigned by journal 13 Apr, 2022 Editor invited by journal 02 Feb, 2022 Submission checks completed at journal 02 Feb, 2022 First submitted to journal 18 Jan, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-1270989\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":81035756,\"identity\":\"0e9de51d-4b6d-44ed-b9c5-828428375fdc\",\"order_by\":0,\"name\":\"Mengqi Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Kapok Zhucheng medical clinic\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mengqi\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":81035758,\"identity\":\"4c1a8d1c-b41e-4cc9-a004-512c8dd009d1\",\"order_by\":1,\"name\":\"Yuan Yuan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Kapok Zhucheng medical clinic\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuan\",\"middleName\":\"\",\"lastName\":\"Yuan\",\"suffix\":\"\"},{\"id\":81035760,\"identity\":\"fefbfde1-64a5-4905-839e-bdff8fa77440\",\"order_by\":2,\"name\":\"Yan Qiao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Kapok Zhucheng medical clinic\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yan\",\"middleName\":\"\",\"lastName\":\"Qiao\",\"suffix\":\"\"},{\"id\":81035761,\"identity\":\"acfafa69-7c5e-4c31-a864-0d1658125496\",\"order_by\":3,\"name\":\"Xi Sui\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shenzhen Kapok Health Medical Co., Ltd. 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21:04:35\",\"extension\":\"tif\",\"order_by\":12,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":106464,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"FigureS3.tif\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1270989/v1/2af9beafe60ac057b2ce2307.tif\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"The effectiveness of immunotherapies for patients with repeated implantation failure: a systematic review and network meta-analysis\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eRepeated implantation failure (RIF) is unable to achieve a clinical pregnancy after multiple cycles of fertilization \\u003cem\\u003ein vitro\\u003c/em\\u003e and cumulative transfer of multiple high-quality embryos in patients undergoing assisted reproductive techniques [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Due to the complexity of the causes of RIF and the high diversity of patients, different academic organizations and researchers have attempted to propose clear diagnostic criteria, but no consensus has been generated to date. The current widely-used definition of RIF by Coughlan et al. is that, for a woman under the age of 40 years, the unsuccessful clinical pregnancy after at least 4 good-quality embryos transfer within minimum three fresh or frozen cycles[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Implantation is a very complicated process and there are plenty of factors that contribute to RIF, either maternal or embryonic origin. The embryo, as a homozygous hemizygous antigen, is subject to a variety of factors for its successful implantation [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. After embryo transferred into uterus cavity, the endometrium must be receptive for the embryo synchronizedly and the maternal immune system must tolerate the continued presence of the paternal alloantigen during the pregnancy [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. In the absence of common factors as uterine abnormalities, hormonal or metabolic disorders, infections, immunological factors, thrombophilias as well as severe male factors, abnormal immunological response could result in a defected maternal-fetal immunotolerance and impaired endometrium receptivity. In order to restore the underlying immunological imbalance, some immunotherapies have been introduced to enhance clinical outcomes in women with unexplained RIF. [\\u003cspan additionalcitationids=\\\"CR7\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe immunotherapeut\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003eic\\u003c/span\\u003e agents mainly are low-molecular-weight heparin (LMWH), intravenous immunoglobulin (IVIG), intrauterine human chorionic gonadotropin (hCG), subcutaneous (SC) or intrauterine (IU) infusion of granulocyte colony stimulating factor (GCSF), peripheral blood mononuclear cells (PBMCs), and intrauterine autologous platelet-rich plasma (PRP) [\\u003cspan additionalcitationids=\\\"CR10 CR11\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. However, there is much conflicting evidence and the comparable effectiveness of these immunotherapies in the setting of RIF is unrevealed.\\u003c/p\\u003e \\u003cp\\u003eTherefore, our study uses a network meta-analysis to compare the effectiveness of the most widely used immunotherapies for RIF treatment, in order to provide an evidence basis for clinical application.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSearch strategy\\u003c/h2\\u003e \\u003cp\\u003ePublications are determined by searching the Pubmed, Embase and web of science databases. The search date is from the establishment of the database till August 2021, and the search language was limited to English. The following terms were applied for this search: repeated implantation failure, recurrent implantation failure, intravenous immunoglobulin, PBMC, G-CSF, IVIG, PRP, Intralipid, Glucocorticoid, hCG, LMWH and Aspirin.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSelection criteria\\u003c/h2\\u003e \\u003cp\\u003eStrict literature inclusion and exclusion criteria were established. The selected documents must be qualified as follows: (1) These studies are randomized controlled trials; (2) The study participants had two or more episodes of implantation failure; (3) The experimental group was treated with immunotherapy, and the control group was given with the standard care/placebo/no immunotherapy; (4) The study includes at least one outcome (clinical pregnancy rate (CPR), live birth rate (LBR) and implantation rate (IR)).\\u003c/p\\u003e \\u003cp\\u003eResearch was excluded as any of the following conditions: (1) The data is incomplete or cannot be used for statistical analysis; (2) Non-authoritative documents such as reviews, letters, conference abstracts, and reviews.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData extraction\\u003c/h2\\u003e \\u003cp\\u003eTwo authors independently derived the relevant data from the qualified literature, additionally, the extracted content included: the first author of the literature, publication year, research type, total number of people included, age, RIF inclusion criteria and outcome indicators, etc. The Cochrane quality evaluation system was utilized to access the quality of the involved randomized control trials. If the opinions of the two authors disagree, the third author will make the judgment.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eThe Stata 14.0 was used to accomplish the network meta-analysis under the consistency model. The odds ratio (OR) was analyzed for dichotomous outcomes with 95% CI. A paired meta-analysis was performed using a fixed-effects model based on the main results. I\\u003csup\\u003e2\\u003c/sup\\u003e is used to assess heterogeneity, and I\\u003csup\\u003e2\\u003c/sup\\u003e \\u0026ge; 50% indicates statistical heterogeneity. The surface under the cumulative ranking (SUCRA) is to evaluate the likelihood that each intervention is the most beneficial or safest treatment. A greater SUCRA value means the higher treatment efficacy. A comparison-correction funnel chart was used to assess publication bias.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eOverall, 3350 documents were identified according to the searching criteria. 901 duplicate articles were eliminated, and 2379 literatures were eliminated after the title and abstract examining. The remaining 70 publications\\u0026rsquo; full text was read, and 16 RCTs meeting the requirements were finally included (Figure 1).\\u003c/p\\u003e \\u003cp\\u003eA total of 16 RCTs including 2008 participants were included [\\u003cspan additionalcitationids=\\\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. Among them, 3 are LMWH, 6 are GCSF, 4 are PBMC, one is hCG, one is intralipid, and 2 are PRP. Since studies of Glucocorticoid and IVIG do not meet the selection criteria, n\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003eo\\u003c/span\\u003e study was included here. The age of the sample population is between 30.51 and 37.8. Table \\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e demonstrates the baseline characteristics of the involved studies. Next, Figure 2 indicates the assessment of these selected studies\\u0026rsquo; quality using the Cochrane risk of bias tool.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eBaseline characteristics of included studies\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"8\\\"\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003estudy\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eStudy design\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRIF criteria\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInvention\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNo. of patients\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eAge (Year)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eBMI (kg/m2)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNo. of transferred embryos (mean)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eUrman 2009\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomized open-labeled pilot trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eThree or more previously failed fresh embryo transfer cycles\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLMWH (administered LMWH at a dose of 1 mg/kg/day starting on the day after oocyte retrieval)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.0\\u0026plusmn;5.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.6\\u0026plusmn;0.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (received no medication besides progesterone gel on the day after oocyte retrieval)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.8\\u0026plusmn;5.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.6\\u0026plusmn;0.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBerker 2011\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective, quasi-randomized, controlled study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eat least two consecutive failed cycles of intracytoplasmic\\u003c/p\\u003e \\u003cp\\u003esperm injection and embryo transfer (ICSI-ET)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLMWH (administered LMWH at a standard dose of 40 mg/0.4 mL per day starting on the day of oocyte retrieval)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e104\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.3\\u0026plusmn;4.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.4\\u0026plusmn;0.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e103\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.2\\u0026plusmn;5.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.5\\u0026plusmn;0.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAleyasin 2016\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized openlabel controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eFailure of implantation in at least three consecutive IVF attempts, in which three embryos of high-grade quality are transferred in each cycle\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003esubcutaneous GCSF (A single dose of 300 \\u0026micro;g G-CSF administered subcutaneously 1 h before the embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e33.5\\u0026plusmn;4.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.3 \\u0026plusmn; 0.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (did not receive any additional treatment before the embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e32.4\\u0026plusmn;5.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.5 \\u0026plusmn; 0.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDavari-Tanha 2016\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomized double blind placebo control trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ethree times implantation failure when there was history of transferring at least four good quality embryos without uterine or thrombophilic factors.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eintrauterine GCSF (At the time of oocyte retrieval one ml of G-CSF (300 \\u0026micro;g/ml) was administered by a Trans cervical Cook catheter for embryo transfer slowly into uterine cavity)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e40\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.5 \\u0026plusmn; 4.32\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e25.2 \\u0026plusmn; 1.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (a catheter pass through the cervix without any injection)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.4 \\u0026plusmn; 4.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e24.8 \\u0026plusmn; 1.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEftekhar 2016\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003etwo or more episodes of implantation failure\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eintrauterine GCSF (received uterine infusion of 300 \\u0026micro;g (0.5ml) recombinant human GCSF (300 \\u0026micro;g) by the use of IUI catheter after ovarian puncture under general anesthesia)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e32.55 \\u0026plusmn; 4.61\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.11 \\u0026plusmn; 0.77\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (the standard treatment)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.75 \\u0026plusmn; 5.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2.35 \\u0026plusmn; 0.71\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMadkour 2016\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eat least two previous failures of implantation after IVF/intra-cytoplasmic spermatozoa injection (ICSI) (mean = 3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePBMC (Intrauterine administration of PBMC prior to fresh embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.74 \\u0026plusmn; 4.17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.44 \\u0026plusmn; 3.86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eYu 2016\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ePatients who had not experienced successful pregnancy despite three or more IVF-ET sessions\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePBMC (intrauterine administration of autologous PBMC activated by HCG in vitro before ET)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e93\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.08\\u0026plusmn;3.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (undergoing ET without a previous intrauterine administration of autologous PBMC)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e105\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.22\\u0026plusmn;5.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eArefi 2018\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ethe history of more than two previous IVF/Intracytoplasmic sperm injection-embryo transfer (ET) failures despite transfer of at least two good-quality embryos in each attempt.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003esubcutaneous GCSF (receive 300 \\u0026micro;g (0.5 ml) recombinant human G-CSF subcutaneously which was injected 30 min before blastocyst embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e32\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.53 \\u0026plusmn; 5.50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e3.31 \\u0026plusmn; 0.85\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.05 \\u0026plusmn; 6.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e3.20 \\u0026plusmn; 0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNobijari 2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ea history of at least one RIF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePBMC (a blood sample was collected 5 days before the scheduled frozenthawed embryo transfer; PBMCs were isolated using Ficoll separation and then cultured for 72h. Two days prior to embryo transfer, 0.4 ml of cultured PBMCs were transferred into the patient\\u0026rsquo;s uterus)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e122\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.21 \\u0026plusmn; 4.84\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e128\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.55 \\u0026plusmn; 5.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eWang 2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized-controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eFailure of implantation in at least 4 consecutive IVF attempts, in which 1 embryos of high-grade quality are transferred in each cycle\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ehCG (The hCG+G2 fluid was prepared on the day of embryo transfer, and 40 \\u0026micro;L of which was injected at an intrauterine site at 3 minutes before embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e69\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.35\\u0026plusmn;3.18\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e22.3\\u0026plusmn;3.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (the G2 fluid was prepared on the day of embryo transfer, and 40 \\u0026micro;L of which was injected at an intrauterine site at 3 minutes before embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e68\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.7\\u0026plusmn;3.56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e22.7\\u0026plusmn;3.61\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAl-Zebeidi 2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ea history of three or more RIF undergoing ICSI cycles\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIntralipid (received intralipid 20% 100 ml diluted in 500 ml normal saline for infusion therapy on the day of embryo transfer (ET) and repeated dose was administered on the day of the pregnancy test)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.32 \\u0026plusmn; 4.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e28.30 \\u0026plusmn; 4.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (underwent the standard ICSI cycle without intralipid infusion therapy)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.21 \\u0026plusmn; 4.77\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e28.30 \\u0026plusmn; 4.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHuang 2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized single-blind study\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003emore than two failed implantations (each time containing at least one high-quality embryo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eintrauterine GCSF (administered a 1-ml uterine infusion of recombinant human G-CSF (150 mg, 1ml) through an intrauterine insemination catheter.)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e32.09\\u0026plusmn;4.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003e21.24\\u0026plusmn;2.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (an intrauterine infusion of physiological saline before embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e32.07\\u0026plusmn;4.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003e21.51\\u0026plusmn;2.90\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKalem 2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eProspective randomized controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ethe failure to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles to a woman under the age of 40 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eintrauterine GCSF (received G-CSF once a day on hCG day, before hCG injection. The procedure involved the administration of 30 mIU of Leucostim (G-CSF 30mIU/mL) through slow infusion into the endometrial cavity using a soft embryo transfer catheter)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.61 \\u0026plusmn; 4.77\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e25.92 \\u0026plusmn; 4.44\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (normal saline of 1 mL was infused into the endometrial cavity of patients in the same way as the study group)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.92 \\u0026plusmn; 5.60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e24.94 \\u0026plusmn; 4.92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePourmoghadam 2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eDouble-blind randomized control trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eat least three previous failures of IVF/ET therapy\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePBMC (PBMCs (15\\u0026ndash;20\\u0026times;106 cells) were suspended in 500 \\u0026micro;l PBS and was gently administered to the uterine cavity two days before ET using an embryo transfer catheter)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e33.42 \\u0026plusmn; 3.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e26.94 \\u0026plusmn; 2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (500\\u0026micro;l PBS was administered into the uterine cavity)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.64 \\u0026plusmn; 3.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e28.53 \\u0026plusmn; 2.84\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSalehpour 2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003epatients who failed to conceive after 3 or more embryo transfers with high-quality embryos and candidates for frozenthawed embryo transfer (FET)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePRP (Intrauterine infusion of PRP was carried out 48 h before embryo transfer under ultrasound guidance)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e49\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35.73 \\u0026plusmn; 3.49\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e25.61 \\u0026plusmn; 3.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1.9 \\u0026plusmn; 0.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl (standard treatment)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34.95 \\u0026plusmn; 4.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e25.46 \\u0026plusmn; 2.68\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1.7 \\u0026plusmn; 0.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eZamaniyan 2021\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomised controlled trial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ewomen who unsuccessful to be pregnant after three or more high-quality embryo transfers undergoing frozen-thawed embryo transfer\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePRP (Intrauterine infusion of platelet-rich plasma was performed 48 h before embryo transfer)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e55\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e33.88 \\u0026plusmn; 6.32\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e26.49 \\u0026plusmn; 4.53\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e43\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e33.13 \\u0026plusmn; 5.00\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e25.03 \\u0026plusmn; 3.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eIn Figure 3, the network of eligible comparisons is shown for each outcome. There is no closed loop between interventions, which suggests that all these pairwise comparisons are indirect. Therefore, statistical analysis is performed directly under the consistency model.\\u003c/p\\u003e \\u003cp\\u003eFigure 4 reveals the results of the CPR network meta-analysis. PBMC, PRP, SC-GCSF and hCG administration can significantly increase CPR when compared to the control group (PBMC: OR = 2.44; 95% CI, 1.67-3.57; PRP: OR = 2.70; 95% CI, 1.41-5.26; SC-GCSF: OR = 2.78; 95% CI, 1.35-5.88; hCG: OR = 2.44; 95% CI, 1.20-4.98). Besides, PBMC, PRP and SC-GCSF can also significantly improve CPR compared to LMWH (PBMC: OR = 2.15; 95% CI, 1.21-3.83; PRP: OR = 2.38; 95% CI, 1.08-5.24; SC-GCSF: OR = 2.46; 95% CI, 1.05-5.72).\\u003c/p\\u003e \\u003cp\\u003eNine studies reported data on LBR. The network meta-analysis outcomes implied that the administration of PBMC and PRP had a higher LBR in comparison with the control group (PBMC: OR = 2.86; 95% CI, 1.64-5.00; PRP: OR = 5.26; 95% CI, 2.00-14.29) (Figure 5). The effect of PRP on LBR was significantly better than IU-GCSF (OR = 3.81; 95% CI, 1.22-11.86), LMWH (OR = 4.38; 95% CI, 1.50-12.90) and Intralipid (OR = 3.85; 95% CI, 1.03-14.29), and the efficacy of PBMC for LBR was also significantly better than that of LMWH (OR = 2.35; 95% CI, 1.14-4.85).\\u003c/p\\u003e \\u003cp\\u003eWe conducted a network meta-analysis on nine studies that reported on IR. The results showed that IU-GCSF, PBMC, PRP, SC-GCSF and hCG were significantly associated with higher IR compared to the control (IU-GCSF: OR = 3.57; 95% CI, 1.16-11.1; PBMC: OR =2.56; 95% CI, 1.28-5.26; PRP: OR = 3.23; 95% CI, 1.43-7.69; SC-GCSF: OR = 2.86; 95% CI, 1.30-6.25; hCG: OR = 1.86; 95% CI, 1.05-3.28) (Figure 6). Furthermore, PRP significantly improved IR compared with LMWH (OR = 2.81; 95% CI, 1.07-7.4).\\u003c/p\\u003e \\u003cp\\u003eThe I\\u003csup\\u003e2\\u003c/sup\\u003e values were 37.4% for CPR, 16.1% for LBR and 50.8% for IR (Figure S1-3). In Figure 7, the comparison-adjusted funnel plots of the network meta-analysis of each outcome suggested no publication bias.\\u003c/p\\u003e \\u003cp\\u003eThe ranking probability of SUCRA for each treatment included in the network was shown in Table 2. In terms of CPR, SC-GCSF was the most effective therapy (78.9%), whereas LMWH was the least effective therapy (18.3%). As far as LBR is concerned, PRP is the most effective treatment (94.8%), and LMWH is the worst (29.4%). In addition, in terms of IR, the most effective treatment is IU-GCSF (77.6%), and the least effective is LMWH (16.2%).\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2. SUCRA of CPR, LBR and IR\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003eTreatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003eCPR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003eLBR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003eIR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003eIU-GCSF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e37.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e39.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e77.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003eLMWH\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e18.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e29.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e16.2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003ePBMC\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e73.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e78\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e63.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003ePRP\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e77.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e94.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e75.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003eSC-GCSF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e78.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e60.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e68.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003econtrol\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e11\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e5.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003ehCG\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e71.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e43.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"29.537366548042705%\\\"\\u003e\\n \\u003cp\\u003eintralipid\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e36.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e36.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"23.487544483985765%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eGiven the fact that the pregnancy rate has increased year by year due to the development of assisted reproductive technology, but there are still a number of patients suffering from RIF [\\u003cspan additionalcitationids=\\\"CR30\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. Uterine abnormalities, spermatic factor anomalies, genetic, hormonal, and metabolic pathologies, acquired thrombophilia, and autoimmune disorders are all possible causes of RIF [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. However, RIF remains unexplained in approximately 30% of instances, and the reasons underlying this unexplained infertility are not fully understood [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. It has been reported that immune factors are crucial in the process of embryo implantation, thus immunotherapies can improve the pregnancy outcome of some patients with RIF [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. Recently, there have been many studies on the pathogenesis of RIF immune factors and immunotherapeutic methods, but there are differences in efficacy due to the different mechanisms of action of different preparations. Therefore, this study evaluated the efficacy of immunotherapies in improving the CPR and LBR of RIF patients through network meta-analysis. According to the outcomes of treated RIF patients, it was found that PBMC and PRP are effective in boosting CPR and LBR. In comparison to the control group, PBMC, PRP, SC-GCSF and hCG treatment significantly increased CPR and IR, and PBMC and PRP were significantly related with greater LBR.\\u003c/p\\u003e \\u003cp\\u003ePrevious research has demonstrated that RIF patients can benefit with immunotherapies, but there are still no direct or indirect comparisons of the efficacy of different immunotherapies [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR35 CR36\\\" citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]. This study evaluated the efficacy of five immunotherapies through a network meta-analysis system, and found that SC-GCSF is the best in improving CPR, while IU-GCSF is the best in improving IR. Our results confirmed the conclusions of Zhao et al., and Xie et al. Zhao et al. showed that the administration of G-CSF may have a favorable clinical effect on pregnancy outcomes. In addition, the best way to administer G-CSF may be the subcutaneous injection [\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e]. Xie et al. found that intrauterine perfusion of G-CSF could significantly improve IR compared with control group [\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e]. G-CSF, as a glycoprotein, belongs to the growth factor family. It has been discovered to regulate the growth of the endometrium and involve in the occurrence of early endometriosis [\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e]. G-CSF has been shown to promote endometrial stem cells, mobilize bone marrow stem cells, and enhance endometrial development [\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e]. However, there is still controversy about the ideal route of G-CSF administration, and the reasons for the difference between the two administration effects have not yet been fully clarified. Therefore, more and higher-quality studies are needed to clarify these phenomena.\\u003c/p\\u003e \\u003cp\\u003eFor LBR, PRP has the best efficacy among the five immunotherapies. We also discovered that PRP had a significantly better effect on LBR than IU-G-CSF, LMWH, and Intralipid. Moreover, PRP can also increase the CPR and IR of RIF patients compared with the control group. PRP is made up of a high concentration of autologous platelets, normally 5-7 times greater compared to the platelet concentration in peripheral blood, which was collected by centrifuging peripheral whole blood [\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e]. PRP contains a variety of growth factors and cytokines, which may help regulate endometrial cell migration, attachment, proliferation, differentiation and neovascularization, thereby having a beneficial effect on endometrial receptivity [\\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]. Amable et al. shows that compared with whole blood plasma or platelet-poor plasma, the levels of 12 proteins (including six growth factors, three anti-inflammatory cytokines and three pro-inflammatory cytokines) in activated PRP are increased [\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e]. These cytokines and growth factors may boost the endometrium receptivity. Besides, a mouse experiment showed that autologous PRP intrauterine infusion accelerated and enhanced the regeneration of impaired endometrium and reduced endometrial fibrosis [\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e]. Owing to the limitation of the quantity of the studies, currently there is no meta-analysis to analyze the effect of PRP on LBR, so additional high-standard studies are required to verify the benefits of PRP on LBR.\\u003c/p\\u003e \\u003cp\\u003eIntrauterine infusion of PBMC is also a good choice for RIF patients. PBMC is mainly composed of T lymphocytes, B lymphocytes and monocytes [\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e]. It has been reported that PBMC is able to regulate a variety of cytokines production, and also promote the spread and invasion of blastocysts to the endometrium and the \\u003cem\\u003ein vitro\\u003c/em\\u003e receptivity of the endometrium [\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]. The results of a recent RCT indicate that PBMC is an effective treatment strategy for RIF-related infertility [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. Besides, consistent with the results of our research, Maleki-Hajiagha et al. found that PBMC can increase the CPR and LBR of RIF patients [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. This study uncovered that PBMC can significantly increase the CPR, LBR and IR of RIF patients in contrast to the control group. The implantation promotion effect of PBMC can be explained by a variety of mechanisms. It is reported that PBMC can regulate the production of several cytokines, such as IL-1α, IL-1β, TNF-α, and promote the spread and invasion of blastocysts to the endometrium and the receptivity of the endometrium \\u003cem\\u003ein vitro\\u003c/em\\u003e [\\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e]. In addition, \\u003cem\\u003ein vivo\\u003c/em\\u003e studies have shown that the administration of PBMC can promote implantation and clinical pregnancy rates, and may optimize the \\u003cem\\u003ein vitro\\u003c/em\\u003e fertilization results of patients with multiple failures of \\u003cem\\u003ein vitro\\u003c/em\\u003e fertilization/ICSI [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e]. Although our research shows that its clinical effects are positive, adverse reactions should also be considered, which requires further research to evaluate.\\u003c/p\\u003e \\u003cp\\u003eWhile, limitations are existed in our study. Firstly, the number of selected studies is relatively small, and there is only one RCT on hCG. Secondly, the included studies may be biased, and undermined hypercoagulative and immunological abnormalities are not investigated and intervened appropriately. Thirdly, few studies reported the adverse events of interventions within the qualified studies, so it is lacking of the safety evaluation on different drugs in RIF treatment. Finally, there are differences in the dose of the same drug in different studies, but because of the restricted sample size, it is unfeasible to further divide the subgroups for analysis.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eThis network meta-analysis showed that PBMC, PRP, SC-GCSF and hCG administration can significantly increase CPR and IR compared to the control group. Furthermore, PBMC and PRP had a higher LBR compared with the control group. Based on our findings, among the different available immunotherapeutic medications, PBMC and PRP may provide the best therapeutic efficac\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003ey\\u003c/span\\u003e. More top-quality RCTs are necessitated in the future to verify the trustworthiness of the conclusions drawn in this research due to the restricted number of RCTs.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAuthors have no conflict of interests to declare\\u003c/strong\\u003e\\u003cstrong\\u003e.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNo fund supported this research, which is a meta-analysis.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cbr\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eBashiri A, Halper KI, Orvieto R: Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. 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Anal Methods 2021, 13:1019\\u0026ndash;1032.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYu N, Yan W, Yin T, Wang Y, Guo Y, Zhou D \\u003cem\\u003eet al\\u003c/em\\u003e: HCG-Activated Human Peripheral Blood Mononuclear Cells (PBMC) Promote Trophoblast Cell Invasion. PLoS One 2015, 10:e0125589.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLi S, Wang J, Cheng Y, Zhou D, Yin T, Xu W \\u003cem\\u003eet al\\u003c/em\\u003e: Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. Journal of Reproductive Immunology 2017, 119:15\\u0026ndash;22.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"repeated implantation failure, immunotherapies, network meta-analysis, pregnancy outcome\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-1270989/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-1270989/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cem\\u003eBackground: \\u003c/em\\u003eThis study compared clinical pregnancy outcomes of repeated implantation failure (RIF) patients treated with immunotherapies using a network meta-analysis.\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eMethods:\\u0026nbsp;\\u003c/em\\u003ePublications are determined by searching the Pubmed, Embase and web of science databases. The search date is from the establishment of the database till August 2021. The outcomes were clinical pregnancy rate (CPR), live birth rate (LBR) and implantation rate (IR). The Cochrane bias risk assessment tool was applied to evaluate the quality of the study, and Stata 14.0 was used for the network meta-analysis.\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eResults:\\u003c/em\\u003e A total of 16 RCTs including 2008 participants were included. The network meta-analysis results show that PBMC, PRP and SC-GCSF can significantly improve CPR compared with LMWH (PBMC: OR = 2.15; 95% CI, 1.21-3.83; PRP: OR = 2.38; 95% CI, 1.08-5.24; SC-GCSF: OR = 2.46; 95% CI, 1.05-5.72). The LBR of PRP was significantly higher than IU-GCSF (OR = 3.81; 95% CI, 1.22-11.86), LMWH (OR = 4.38; 95% CI, 1.50-12.90) and Intralipid (OR = 3.85; 95% CI, 1.03-14.29), and the LBR of PBMC was also significantly better than that of LMWH (OR = 2.35; 95% CI, 1.14-4.85). Furthermore, PRP treatment significantly improved IR compared with LMWH treatment (OR = 2.81; 95% CI, 1.07-7.4).\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eDiscussion: \\u003c/em\\u003eBased on the limited evidence from existing RCTs, PBMC and PRP seem to be the best therapeutic options for RIF patients. However, due to research quantity restrictions, more top-quality researches are required in the future to obtain additional high-level evidence.\\u003c/p\\u003e\",\"manuscriptTitle\":\"The effectiveness of immunotherapies for patients with repeated implantation failure: a systematic review and network meta-analysis\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2022-02-04 21:04:33\",\"doi\":\"10.21203/rs.3.rs-1270989/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Major revision\",\"date\":\"2022-06-01T07:08:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2022-04-13T20:36:11+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"dae305a3-b0c4-4774-84dc-b7ae3705161c\",\"date\":\"2022-04-13T20:11:04+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2022-04-13T07:36:52+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2022-04-13T07:13:53+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2022-02-02T16:29:28+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2022-02-02T16:25:23+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2022-01-18T06:03:16+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"c0ae1027-63ff-4f26-9f4a-dba0cde4b9da\",\"owner\":[],\"postedDate\":\"February 4th, 2022\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2022-09-21T11:44:26+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2022-02-04 21:04:33\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-1270989\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-1270989\",\"identity\":\"rs-1270989\",\"version\":[\"v1\"]},\"buildId\":\"B-jG_2CBjPDmsCi4Wdhf-\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}