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. 2025 Aug 21;87:103442. doi: 10.1016/j.eclinm.2025.103442

Therapeutic efficacy of Cyclosporine A in recurrent spontaneous abortion: a meta-analysis and network meta-analysis incorporating Chinese and English language studies

Xianyang Hu a,c, Xixi Huang a,c, Tingxuan Yin a,c, Hailin Yu a, Lu Liu a,∗∗, Meirong Du b,∗
PMCID: PMC12396494  PMID: 40896468

Summary

Background

Recurrent spontaneous abortion (RSA) poses a significant clinical challenge for childbearing women. Cyclosporine A (CsA), first introduced by our group for RSA treatment, has gained wide clinical application in China, yet remains underutilized internationally. With this systematic review, we aimed to systematically evaluate the efficacy and safety of CsA based therapy in the management of RSA.

Methods

PubMed, Embase, Web of Science, Cochrane library, CNKI, VIP, and Wanfang databases were searched from inception to July 12, 2025. Eligible studies in English and Chinese language, involved patients with RSA and assessed CsA's effects on pregnancy outcomes were included. Risk of bias was evaluated using appropriate tools based on study design. Pooled odds ratios (ORs) were calculated via meta-analysis. Publication bias was evaluated with funnel plots. Subgroup and network meta-analysis (NMA) were conducted to assess robustness and compare relative efficacy. Primary outcomes included miscarriage rate and live birth rate as reported in clinical pregnancy outcomes. This study was registered with PROSPERO (CRD42024541367).

Findings

A total of 29 clinical studies (n = 3556 RSA patients) were included, with 22 comparing CsA-treated vs non-CsA-treated groups. The majority of studies were conducted in a Chinese population (28 = China, and 1 = Iran) as CsA therapy for RSA has not received approval outside of China. CsA therapy was associated with a lower miscarriage rate (OR, 0.37 [95% CI, 0.25–0.56]), higher live birth rate (OR, 37 2.44 [95% CI, 1.59–3.74]), and higher ongoing pregnancy rate (OR, 2.59 [95% CI, 1.54–38 4.37]). NMA revealed that CsA combined with conventional treatment, and immunotherapy (P-score: 0.147–0.275) had superior effects on miscarriage reduction compared to monotherapy (P41 score: 0.619–0.792). CsA-based combinations also remained superior to monotherapies (P-score: 0.704–0.791 vs 0.27–0.305). However, for live birth rate, the combination of conventional treatment and immunotherapy showed the greatest efficacy (P-score: 0.892).

Interpretation

This meta-analysis demonstrates the potential benefits of CsA therapy for pregnancy outcomes in RSA patients, particularly when combined with other therapeutic interventions. These findings require further multi-center prospective testing at an international level.

Funding

This study was supported by the National Natural Science Foundation of China (NSFC), the National Key R&D Program of China, the Shanghai Municipal Health and Family Planning Commission, and the Shanghai Sailing Program.

Keywords: Recurrent spontaneous abortion, Cyclosporine A, Meta-analysis, Network meta-analysis

Research in context.

Evidence before this study

Recurrent spontaneous abortion (RSA), defined as two or more consecutive pregnancy losses, affects 1–3% of women of reproductive age and remains unexplained in nearly half of all cases. Immune dysregulation is increasingly recognized as a major contributing factor. Various therapeutic strategies including anticoagulants, hormonal support and immunomodulators, have been evaluated, but clinical evidence remains inconclusive. Although several Chinese studies report favorable outcomes with Cyclosporine A (CsA), a literature search conducted through Chinese and English databases (up to February 2025) showed no prior systematic review has comprehensively assessed its efficacy and safety.

Added value of this study

This study presents the first systematic review, pairwise meta-analysis, and network meta-analysis (NMA) synthesizing evidence from both Chinese and English language studies to evaluate the therapeutic efficacy and safety of CsA-based treatments for RSA. By analyzing 29 studies comprising over 3500 patients, studies correlated CsA with reduced miscarriage rates and improved live birth outcomes. The therapeutic benefit was particularly evident when CsA is administered in combination with other therapies.

Implications of all the available evidence

Our findings support CsA as a promising therapeutic option for women with high-risk RSA, particularly those unresponsive to conventional treatments. The current evidence base is strengthened by the inclusion of a large number of Chinese studies, however heterogeneity in study design, patient selection, and outcome reporting limits generalizability. There is a critical need for large-scale, multicenter, randomized controlled trials with standardized treatment protocols and long-term follow-up to confirm these findings.

Introduction

Recurrent Spontaneous Abortion (RSA) is defined as the loss of two or more pregnancies in the same couple by both European Society of Human Reproduction and Embryology (ESHRE)1,2 and American Society for Reproductive Medicine (ASRM).3 The exact prevalence of RSA is hard to estimate, but most studies report that it affects 1–3% childbearing women.1,4 RSA can result from various reasons, including chromosomal abnormalities, abnormal anatomy, endometrial dysfunction.5 However, despite extensive research, the etiology remains unknown in up to 50–75% of cases, with maternal–fetal immune dysregulation recognized as a key contributing factor.3,6,7 RSA not only compromises women's reproductive health but also has a profound impact on their mental8 and cardiovascular health,9 underscoring the need for effective treatments.

Management of RSA remains a major clinical challenge. Although various therapeutic strategies have been proposed, including anticoagulants, hormonal therapies and immunomodulatory agents the efficacy of these interventions remains controversial. Given the complex and often multifactorial nature of RSA, novel therapeutic approaches are urgently needed to improve outcomes of affected women.

In this context, our group identified CsA, a well-known immunosuppressant drug traditionally used to prevent organ rejection post-transplantation,10 as a promising candidate for RSA treatment.11, 12, 13, 14 This hypothesis stems from the similarities between fetus as a semi-allograft and organ transplanted,15 where immune tolerance mechanisms play a crucial role. CsA exerts immunosuppressive effects primarily by inhibiting T-cell proliferation and activation, while also modulating the function of various immune cells.14,16,17 Our previous studies demonstrated that CsA not only exerts immunosuppressive effects but also enhances trophoblast function18, 19, 20, 21, 22, 23, 24, 25 and promotes maternal–fetal immune tolerance.13,15,26 Importantly, we confirmed that CsA induces coordinated cellular crosstalk at the maternal–fetal interface, involving trophoblasts, decidual stromal cells,20 and immune cells. CsA has also been shown to improve embryo adhesion and facilitate early implantation, further supporting its therapeutic potential in RSA.27

Building on these findings, we conducted a prospective cohort study involving nearly 1000 women with RSA, which demonstrated that short-term CsA administration during early pregnancy improved maternal outcomes. The effectiveness of CsA appeared comparable to that of conventional treatment and did not increase the risk of maternal complications or fetal congenital anomalies.12

In recent years, CsA has been increasingly investigated as a potential therapy for RSA, largely driven by our pioneering work. Its clinical application has gained wide recognition in China.28 However, its use in Western countries remains limited.

Although most studies reported favorable outcomes with CsA,12,16,28, 29, 30 others have yielded inconsistent results and this approach has not been widely adopted into clinical practice or guidelines due to a lack of strong evidence from high-quality studies. To date, no systematic review has comprehensively compared the efficacy of CsA-based therapies with non-CsA treatments for RSA. Moreover, no network meta-analysis (NMA) has been conducted to integrate findings across studies, limiting the ability to draw definitive conclusions regarding the relative efficacy of different interventions. To address this gap, we conducted a meta-analysis and NMA incorporating both Chinese and international studies, considering the widespread use of CsA in China. This study represents the first comprehensive synthesis of evidence on CsA for RSA management and aims to provide a clearer understanding of its therapeutic potential.

Methods

This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines31 and registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42024541367).

Search strategy and selection criteria

Our initial search strategy involved a systematic search of three major English-language electronic databases (PubMed, Embase, and Web of Science) and three Chinese-language databases (China National Knowledge Infrastructure [CNKI], Wanfang Digital Journals [Wanfang], and VIP Information Database [VIP]) from their inception to July 12, 2025. Detailed search strategies for each database were provided in Supplementary Table S1. Both Medical Subject Headings (MeSH) and free-text keywords were used, tailored to the indexing system of each database. In addition, the Cochrane library was manually searched to ensure no eligible trials were missed. Details of these records and inclusion decisions are provided in Supplementary Table S2.

The inclusion criteria were as follows: (1) clinical studies investigating oral CsA for the treatment of RSA; (2) studies reporting relevant pregnancy outcomes, including but not limited to miscarriage rate, ongoing pregnancy rate, live birth rate, preterm birth rate, hypertension in pregnancy, and other adverse events; (3) studies with quantitative data on the number of outcome events and the total sample size.

The exclusion criteria included the following: (1) non-peer-reviewed sources, such as theses or dissertations; (2) articles without original human clinical data, such as reviews, systematic reviews, letters, conference abstracts, editorials, and expert consensus statements; (3) non-clinical studies, including those based on animal models or cellular experiments; (4) studies of RSA with identified etiologies; (5) studies not directly related to oral CsA for the treatment of RSA; (6) studies lacking clinical outcome or presenting these data unclearly.

The study selection process consisted of the following steps: Firstly, all records retrieved from the literature search were imported into EndNote version 21 (Clarivate Analytics) for deduplication. Secondly, the remaining articles were imported into Covidence for screening. Two reviewers (Xianyang Hu and Xixi Huang) independently screened the titles and abstracts to identify potentially eligible studies followed by full-text reviews. Finally, the reviewers cross-checked the included studies to ensure consistency and completeness. Any discrepancies were discussed and resolved by a third reviewer (Tingxuan Yin).

Ethics

Ethics approval is not required for systematic review and meta-analysis.

Data extraction

Two reviewers (Xianyang Hu and Xixi Huang) independently extracted data from the included studies using a standardized extraction form. Information extracted included: author, year of publication, published language, country, study design, patient characteristics (including RSA, unexplained RSA [URSA], and RSA with elevated uterine natural killer [uNK] cells), number of participants in the intervention and control groups, experimental period, intervention details, control group details, mean age of participants in each group, number of miscarriages in each group, and clinical outcomes. Clinical outcomes included miscarriage rate, live birth rate, ongoing pregnancy rate, preterm birth rate, hypertension in pregnancy rate, and other adverse events rate, with detailed data on the number of events and total sample size. Xianyang Hu and Xixi Huang cross-checked their extracted data, and any discrepancies were resolved through discussion.

Risk of bias assessment

The risk of bias in the selected RCTs was assessed using the Cochrane risk of bias (Cochrane RoB) tool within RevMan 5 software.32 RevMan 5 was also used to visualize the risk of bias assessments. For Controlled clinical trials (CCTs), single-arm studies and retrospective studies, other tools were employed to comprehensively assess the risk of bias. Specifically, the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool33 was used for CCT, the Methodological Index for Non-Randomized Studies (MINORS)34 was used for single-arm studies, while the Newcastle–Ottawa Scale (NOS)35 was used for retrospective studies.

Meta-analysis

Our initial meta-analysis focused on six clinical outcomes: miscarriage, live birth, ongoing pregnancy, preterm birth, hypertension in pregnancy, and other adverse events. As all outcomes were binary, odds ratios (ORs) with 95% confidence intervals (CIs)36 and P values were calculated to compare outcomes between the CsA-treated and non-CsA-treated groups. ORs were chosen as the primary effect size measure to ensure consistency across diverse study designs, including non-randomized and retrospective studies.

Heterogeneity was assessed using the I2 statistic and Cochran's Q test, with a significance threshold of I2 > 50% or P < 0.10. Regardless of the degree of heterogeneity, all meta-analysis were conducted using a random-effects model to account for potential between-study variability and enhance the generalizability of the results. Forest plots were generated to depict the contribution of each individual study to the meta-analytic result. Subgroup analyses for the primary outcomes (miscarriage rate and live birth rate) were conducted based on patient characteristics (including RSA, URSA, and RSA with elevated uNK) and the number of previous abortions. Publication bias was assessed using funnel plots, with Egger's and Begg's tests performed for outcomes with more than 10 studies. For outcomes with suspected publication bias, we further applied the trim-and-fill method to evaluate the potential impact of missing studies on the pooled estimates.

Network meta-analysis

A Bayesian network meta-analysis (NMA)37 was further performed to evaluate the effects of various treatments on two primary outcomes: miscarriage rate and live birth rate. A connected treatment network was generated using a circular layout, with node size proportional to the number of included studies per treatment and edge thickness reflecting the number of direct comparisons. Treatment effects were estimated as ORs with corresponding 95% CIs. All interventions were initially compared to the no-treatment group. A Random effects model was fitted. The unrelated means method was applied to address potential inconsistency between direct and indirect comparisons, with subsequent visualization using the netsplit and netheat functions. Pairwise comparisons of all interventions were conducted and summarized. Ranking interventions based on their effectiveness is a key advantage of NMA. We used both the P-score and the Surface Under the Cumulative Ranking Curve (SUCRA) to assess the likelihood of each intervention being the best treatment. The ranking results were visualized using bar plots and rankgrams.

Statistics

All statistical analyses were conducted using R, version 4.3.3 on the RStudio platform, version 2024.12.1 + 563. The following R packages were used for meta-analysis and NMA: ‘meta’ version 8.0.2, ‘metafor’ version 4.6.0, ‘dmetar’ version 0.1.0, ‘netmeta’ version 3.2.0. All statistical tests were two-sided, and the threshold for significance was set at P < 0.05.

Role of the funding source

The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Description of the studies

A total of 1346 studies were initially identified, including 199 studies from Chinese and 1147 from English databases. In the Chinese databases, 78 duplicate records were removed, and 53 records, including theses (n = 41), conference papers (n = 11), and studies without relevant outcomes (n = 1), were excluded. Title and abstract screening removed 15 articles, including expert consensus (n = 1), reviews (n = 11), systematic reviews (n = 3), and case reports (n = 3). Full-text articles were screened further and additional 23 studies were excluded due to non-clinical trial design (n = 16), experience summaries (n = 1), or lack of direct relevance to CsA or RSA (n = 6). Of the remaining 27 studies, 4 were excluded for lack of available clinical results, resulting in 23 eligible studies from Chinese databases. From the English databases, 812 ineligible or duplicate records were removed. During title and abstract screening, 320 articles were excluded for not being related to CsA or RSA (n = 224) or not being clinical trials (n = 93). Following full-text review, 8 studies were excluded due to focus on recurrent implantation failure (RIF) rather than RSA (n = 5), non-English publication (n = 2), or non-oral administration (n = 1). One additional study was excluded for being a study protocol without available outcome data. Finally, 6 eligible studies were included from the English databases (Fig. 1). The study selection process is illustrated in Fig. 1.

Fig. 1.

Fig. 1

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Flow diagram for the selection of eligible studies.

In total, 3556 patients with RSA across 29 studies were included, comprising 19 RCTs, 7 CCTs, 2 single-arm studies, and 1 retrospective cohort study.12,16,28, 29, 30,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 Basic study characteristics are summarized in Supplementary Table S3. Most of the included studies were conducted in China, all using oral CsA administration during early pregnancy. Publication years ranged from 2015 to 2025. Sample sizes across studies ranged from 26 to 908 participants. Patients were aged between 20 and 35 years, with a history of 2–6 miscarriages. Regarding patient characteristics, 19 studies focused on strictly defined URSA, 7 included patients with generalized RSA, and 3 specifically enrolled RSA patients with elevated uNK. Treatment regimens included CsA, traditional Chinese medicine (TCM), conventional treatment, and immunotherapy.

Among the eligible studies, 22 that provided direct comparisons of clinical outcomes between patients receiving CsA-containing regimens and those receiving regimens without CsA were included in the pairwise meta-analysis. The effectiveness outcomes assessed included miscarriage rate (19 studies, 2569 patients), live birth rate (14 studies, 1859 patients), and ongoing pregnancy rate (11 studies, 1789 patients). The safety outcomes covered preterm birth (5 studies, 1218 patients), hypertension in pregnancy rate (3 studies, 1176 patients) and other adverse events rate (9 studies, 1734 patients). The NMA further examined miscarriage rate and live birth rate, with detailed categorization of interventions, including CsA-based combinations, monotherapies, and no treatment.

Risk of bias assessment

Among the 19 RCTs assessed using the Cochrane RoB tool, none were rated as high risk of bias. Most domains were classified as low risk, indicating a generally robust methodological quality (Supplementary Table S4 and Supplementary Figure S1A). For the 7 CCTs evaluated using the ROBINS-I tool (Supplementary Table S5), 5 studies had no domains rated as high risk of bias and were considered to have a low or moderate overall risk. One study had high risk in a single domain and was assessed as having a moderate overall risk. These findings suggest generally acceptable quality among the CCTs included. Two single-arm studies were assessed using the MINORS criteria (Supplementary Table S6) and scored 11 and 12 out of 16, suggesting acceptable methodological quality for non-comparative studies. The retrospective cohort study achieved a score of 7 out of 9 on the NOS (Supplementary Table S7), indicating high methodological quality. Overall, the included studies demonstrated generally low to moderate risk of bias, supporting the credibility of the synthesized evidence.

Efficacy and safety of CsA in treating RSA

Evidence from pairwise meta-analysis comparing treatment regimens with and without CsA suggested that the inclusion of CsA was significantly associated with a decreased risk of miscarriage (OR, 0.37 [95% CI, 0.25–0.56], I2 = 55.8%) and an increased likelihood of live birth (OR, 2.44 [95% CI, 1.59–3.74], I2 = 53.8%) and ongoing pregnancy (OR, 2.59 [95% CI, 1.54–4.37], I2 = 69.8%), without increasing hypertension in pregnancy (OR, 0.27 [95% CI, 0.10–0.72], I2 = 0), other adverse events (RR, 0.81 [95% CI, 0.52–1.27], I2 = 20.4%), and preterm birth (OR, 0.91 [95% CI, 0.52–1.56], I2 = 24.1%) (Fig. 2).

Fig. 2.

Fig. 2

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Association of Cyclosporine A (CsA) with Pregnancy Outcomes. A: Miscarriage rate, B: Live birth rate, C: Ongoing pregnancy rate, D: Hypertension in pregnancy, E: Other adverse events, F: Preterm birth rate. The squares represent odds ratios (OR) for each study, with the size of the square proportional to the study's weight in the meta-analysis. Horizontal lines show the 95% confidence interval (CI). The diamond at the bottom represents the pooled OR with its 95% CI. ES, effect size; SE, standard error.

Subgroup analyses based on patient characteristics and miscarriage history revealed important differences in treatment effects (Fig. 3). CsA therapy was associated with a significantly reduced miscarriage rate and increased live birth rate in both RSA (miscarriage rate: OR, 0.18 [95% CI, 0.08–0.40], I2 = 0; live birth rate: OR, 60.9 [95% CI, 2.15–17.28]) and strictly defined URSA populations (miscarriage rate: OR, 0.35 [95% CI, 0.20–0.61], I2 = 55.8%; live birth rate: OR, 2.74 [95% CI, 1.46–5.15, I2 = 53.8%]). In contrast, among patients with RSA and elevated uNK cell levels, CsA therapy was not significantly associated with a reduction in miscarriage rate (OR, 0.57 [95% CI, 0.30–1.07], I2 = 19.1%), although a modest but statistically significant improvement in live birth rate was observed (OR, 1.79 [95% CI, 1.02–3.14], I2 = 18.3%) (Fig. 3A and C).

Fig. 3.

Fig. 3

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Subgroup Analysis of Cyclosporine A (CsA) with Miscarriage and Live Birth Rate. A: Subgroup analysis of miscarriage rate by patient definitions, B: Subgroup analysis of miscarriage rate by number of miscarriages, C: Subgroup analysis of live birth rate by patient definitions, D: Subgroup analysis of live birth rate by number of miscarriages. The squares represent odds ratios (OR) for each study, with the size of the square proportional to the study's weight. Horizontal lines indicate the 95% CI, and the diamond at the bottom shows the pooled RR with its 95% CI. ES, effect size; SE, standard error.

When stratified by miscarriage history, no significant benefit of CsA therapy was observed in studies enrolling patients with ≤3 previous miscarriages (miscarriage rate: OR, 0.61 [95% CI, 0.31–1.20], I2 = 63.7%; live birth rate: OR, 1.25 [95% CI, 0.72–2.17], I2 = 30.7%). In contrast, CsA was significantly associated with improved pregnancy outcomes in populations with 3–4 previous miscarriages (miscarriage rate: OR, 0.35 [95% CI, 0.20–0.60], I2 = 0; live birth rate: OR, 2.96 [95% CI, 1.67–5.23], I2 = 0) and >4 previous miscarriages (miscarriage rate: OR, 0.25 [95% CI, 0.15–0.42], I2 = 0; live birth rate: OR, 3.87 [95% CI, 2.32–6.45], I2 = 0) (Fig. 3B and D).

To assess potential publication bias, we performed both visual inspection of funnel plots (Supplementary Figure S1B) and statistical tests for each outcome (Supplementary Table S8). No evidence of publication bias was detected for hypertension in pregnancy rate, preterm birth rate, or other adverse events rate. However, for miscarriage rate, live birth rate, and ongoing pregnancy rate, funnel plots showed noticeable asymmetry, and Egger's test indicated possible publication bias, although Begg's test results were not statistically significant (Supplementary Table S8).

We further conducted a trim-and-fill sensitivity analysis for the three outcomes with suspected bias. The results identified several potentially missing studies, but the adjusted pooled estimates remained statistically significant and directionally consistent with the original findings (Supplementary Figure S3A and B), suggesting that the conclusions were robust despite the potential for publication bias.

Efficacy of CsA-based treatments for RSA

To further evaluate the comparative effectiveness of various CsA-based treatment strategies for RSA, we conducted a NMA focusing on miscarriage and live birth rate, including a broad range of interventions and their combination (Fig. 4A and B). When compared with no treatment, nearly all interventions demonstrated a significantly reduced miscarriage rate (Fig. 4C) (OR: 0.04–0.017) and increased live birth rate (Fig. 4D) (OR: 5.57–27.27).

Fig. 4.

Fig. 4

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Network Meta-Analysis of Cyclosporine A (CsA)-Based Treatments for Live Birth and Miscarriage Rate. A: Network of treatments for miscarriage rate, B: Network of treatments for live birth rate. The size of each node is proportional to the number of studies, and the width of the edges represents the number of comparisons. C: Forest plot for miscarriage rate comparing the efficacy of various treatments against n treatment, D: Forest plot for live birth rate comparing the efficacy of various treatments against n treatment. The odds ratios (OR) with 95% confidence intervals (CI) are shown for each comparison using the random effects model. E: Miscarriage rate ranking based on P-scores, (F) Live birth rate ranking by P-scores. G: Rank probability plots for miscarriage rate, H: Rank probability plots for live birth rate. It shows the distribution of ranks for each treatment strategy across different comparisons.

Treatment rankings based on P-scores reinforced these findings. For miscarriage rate, CsA + immunotherapy + conventional treatment (P-score = 0.147), CsA + conventional treatment (P-score = 0.155) and CsA + immunotherapy (P-score = 0.275) ranked lowest followed by other treatment regiments (P-score: 0.307–0.792), indicating a strong association with miscarriage reduction (Fig. 4E). For live birth rate, the combination of immunotherapy and conventional treatment ranked highest (P-score = 0.891), closely followed by CsA + immunotherapy (P-score = 0.791), CsA + immunotherapy + conventional treatment (P-score = 0.747) and CsA + conventional treatment (P-score: 0.704) (Fig. 4F). Probability curves (Fig. 4G and H) showed the ranking probabilities of each treatment across outcomes.

Results from the netsplit and netheat analyses did not suggest major inconsistency (Supplementary Figure S2), and all pairwise comparisons were summarized accordingly, providing a comprehensive overview of the comparative efficacy landscape (Supplementary Tables S9–S10).

Notably, although some included studies involved TCM, these treatment arms were excluded from the primary NMA due to the heterogeneous and often compound nature of TCM formulations, which pose challenges to standardization and interpretation in a comparative framework. However, given the widespread clinical application of TCM in China for RSA management, exploratory analyses including TCM-related regimens were conducted (Supplementary Figure S4), offering additional insight while not influencing the core comparative conclusions.

Discussion

To our knowledge, this is the first comprehensive meta-analysis and NMA evaluating CsA-based therapies for RSA. Our findings indicate that CsA treatment is associated with improved pregnancy outcomes, including reduced miscarriage rate and increased live birth rate. Notably, combination therapies involving CsA demonstrated superior clinical efficacy compared to monotherapy. CsA also appeared to be well tolerated, with no major safety concerns noted in the included studies. These results offer new therapeutic insights for RSA management and underscore the potential of CsA as an additional treatment option for patients with limited success from conventional treatment.

CsA treatment was particularly effective in patients with three or more miscarriages, whereas those with fewer miscarriages did not appear to benefit significantly. Patients with URSA responded better to CsA than the broader RSA population, though both groups showed notable improvement. However, no clear advantage was observed in cases of RSA with elevated uNK. These findings suggest that RSA has yet to be stratified into well-defined clinical subtypes, and future research incorporating immunological profiling may help identify those most likely to benefit from CsA therapy.

Previous studies have broadly examined immunotherapy for RSA,60 but none evaluated the therapeutic potential of CsA. Our group was the first to propose CsA for RSA management, demonstrating its dual role in promoting trophoblast function and enhancing maternal–fetal immune tolerance.12,14 We further confirmed that CsA modulated immune responses and supported implantation-related processes, providing mechanistic evidence for its clinical benefits. We also found that CsA modulated maternal–fetal immune responses by inducing coordinated crosstalk among trophoblasts, decidual stromal cells, and immune cells,13,20,24, 25, 26, 27 providing mechanistic evidence for its clinical benefits. These insights, together with the favorable outcomes shown in this systematic review and NMA, support the potential of CsA as a targeted therapy in select RSA populations.

NMA is a well-established method for synthesizing evidence,37 expanding on traditional pairwise meta-analysis by connecting multiple interventions across studies within a broader network. Our NMA highlighted the advantages of CsA-combination approaches to RSA treatment. Combining CsA with conventional treatment, and immunotherapy showed a significant reduction in miscarriage rate compared to monotherapy with conventional agent, immunotherapy or CsA alone. While conventional treatment combined with immunotherapy proved most effective for live birth rate, CsA combination therapies remained highly effective in increasing live birth rate.

Considering that RSA is a highly heterogeneous condition with over 50% of cases having an unclear etiology, and no one universally effective treatment method for all patients with RSA, our decade-long basic research, clinical experience, and public health expertise, along with the findings of this study, strongly recommend future studies to explore CsA-based combination therapies for these high-risk groups, offering a crucial option when other standard therapeutic approaches have failed. Moreover, two key aspects of RSA pathophysiology, genetic risk and autoimmune risk, should be considered. CsA may be more effective in cases with autoimmune dysregulation, while its benefit in patients with abnormal genetic changes, such as gene mutation, deletion, amplification, or chromosomal translocation, remain useless. Additionally, CsA has been shown to regulate the biological behavior of trophoblast cells, improve trophoblast function, and promote placental development, further broadening its potential clinical applicability in RSA treatment.18, 19, 20, 21, 22, 23, 24, 25

Despite these promising findings, it is important to note that CsA has not been approved for RSA treatment by either the ASRM or the ESHRE.1, 2, 3 And the comparison studies included in this study have not received endorsement from these societies. In addition, several treatments included in CsA-based therapy, such as steroids, lymphocyte immunotherapy (LIT) and intravenous immunoglobulin (IVIG), remain controversial, with no consensus on optimal dosage, timing, treatment duration or patient selection. These therapies are not currently recommended or even opposed by ASRM or ESHRE guidelines.1, 2, 3

This study has several limitations. First, given that the majority of included studies originated from China, regional bias may exist, and caution is warranted when generalizing findings to broader populations. The conclusions should be interpreted as hypothesis-generating, pending validation in international, multicenter trials. Second, substantial heterogeneity was observed in some outcomes. Although subgroup analyses were performed, residual heterogeneity may persist. Third, publication bias cannot be fully excluded, as studies with positive results are more likely to be published. Nevertheless, trim-and-fill analyses showed that the adjusted estimates remained robust and consistent with the original findings. The therapeutic efficacy of CsA has also been consistently recognized in clinical practice over the past decade. Fourth, a considerable proportion of studies were non-RCTs. Despite the use of validated tools (ROBINS-I, MINORS, and NOS) for quality appraisal, inherent biases may remain. Fifth, although subgroup analyses were performed to explore heterogeneity and improve the comparability of results, differences in patient stratification across studies may still introduce bias. This limitation highlights the need for future trials with more consistent patient classification and standardized reporting. In addition, while adverse events were reported in most studies, inconsistent definitions and assessments, along with limited long-term safety data, highlight the need for standardized reporting and extended follow-up. Regarding the NMA, its interpretation should be cautious due to limited direct head-to-head comparisons and small sample sizes for some treatments. Despite these limitations, the analysis offers a broad perspective on how CsA compares to other therapies. We consider these findings exploratory and hypothesis-generating, emphasizing the need for future well-designed randomized trials to confirm these results.

In conclusion, RSA and its severe complications remain a significant global challenge to reproductive health, with few effective treatment options currently available. No country has successfully reversed the rising burden of RSA worldwide. CsA, proposed and applied clinically for pregnancy maintenance by our group, offers a promising therapeutic avenue. This meta-analysis and NMA provide the first comprehensive comparison between CsA-based and non-CsA-based therapies for RSA. Our findings indicate that CsA can improve pregnancy outcomes, particularly in reducing miscarriage rate and increasing live birth rate. The benefits were especially notable for patients with three or more previous miscarriages and those with URSA. We also found that combining CsA with other therapies further improves therapeutic efficacy. These results have important research, clinical, and public health implications, offering renewed hope for women with RSA. To promote broader recognition and application of CsA, high-quality, multicenter trials with standardized assessment and long-term follow-up are urgently needed to guide clinical practice and policy.

Contributors

MD, LL and XYH designed the study. XYH, XXH, and TY extracted and checked the data. XYH prepared the first draft. XYH managed and analyzed the data, while HLY, LL and MD reviewed the analyses and validated the results. XYH, XXH, TY had access to and verified the underlying data. XYH, XXH, TY, HY, LL and MD revised the paper. All authors read and approved the final manuscript.

Data sharing statement

The data used in this study were derived from previously published studies and are publicly available.

Declaration of interests

The authors declare no conflicts of interest relevant to this article.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC) (grants U23A20405, 82271713, and 81630036 to Meirong Du; grant 82101706 to Lu Liu), the National Key R&D Program of China (grant 2021YFE0206500 to Meirong Du), the Shanghai Municipal Health and Family Planning Commission (grant 20204Y0403 to Lu Liu), and the Shanghai Sailing Program (grant 21YF1403700 to Lu Liu). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. We thank the Medical Science Data Center of Fudan University for supporting the platform for data analysis. We acknowledge the use of ChatGPT-4o (https://openai.com/zh-Hans-CN/chatgpt/overview/) and DeepSeek-R1 (https://www.deepseek.com/) for language polishing in this manuscript.

Footnotes

Appendix A

Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2025.103442.

Contributor Information

Lu Liu, Email: liulu11n@163.com.

Meirong Du, Email: mrdu@fudan.edu.cn, mrdu@tongji.edu.cn.

Appendix A. Supplementary data

Supplementary Figure S1

Risk of Bias Plots and Publication Bias Plots. A: Risk of bias plots for selected cluster RCT articles, B: Funnel plot of the included studies.

mmc1.pdf (1.3MB, pdf)
Supplementary Figure S2

Inconsistency Assessment in Network Meta-Analysis for Miscarriage and Live Birth Rate. A: Forest plot showing direct and indirect evidence comparisons for miscarriage rate, B: Forest plot showing direct and indirect evidence comparisons for live birth rate, C: Netsplit analysis for miscarriage rate, D: Netsplit analysis for live birth rate. Larger gray squares in the rows indicate higher study weight, and redder colors represent greater consistency. OR: odds ratios, CI: confidence intervals.

mmc2.pdf (463.6KB, pdf)
Supplementary Figure S3

Funnel and Forest Plots with Trim-and-Fill Adjustment for Publication Bias. A: Funnel plots for miscarriage rate, live birth rate and ongoing pregnancy rate using the trim-and-fill method. Blue dots represent observed studies; black dots indicate imputed (filled) studies. B: Corresponding forest plots showing original and adjusted odds ratios (ORs) after trim-and-fill correction.

mmc3.pdf (458.4KB, pdf)
Supplementary Figure S4

Exploratory Network Meta-Analysis of Cyclosporine A (CsA)-Based Treatments Involving Traditional Chinese Medicine (TCM) for Recurrent Spontaneous Abortion Management. (A) Forest plot for live birth rate comparing efficacy of various treatment regimens incorporating TCM. (B) Forest plot for miscarriage rate comparing treatment effects of TCM-containing regimens.

mmc4.pdf (226.5KB, pdf)
Supplementary Tables
mmc5.docx (55.4KB, docx)

References

  • 1.Bender Atik R., Christiansen O.B., Elson J., et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2) doi: 10.1093/hropen/hoy004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cavalcante M.B., Sampaio O.G.M., Câmara F.E.A., Barini R. ESHRE guideline update 2022: new perspectives in the management of couples with recurrent pregnancy loss. Am J Reprod Immunol. 2023;90(2) doi: 10.1111/aji.13739. [DOI] [PubMed] [Google Scholar]
  • 3.Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–1111. doi: 10.1016/j.fertnstert.2012.06.048. [DOI] [PubMed] [Google Scholar]
  • 4.Quenby S., Gallos I.D., Dhillon-Smith R.K., et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658–1667. doi: 10.1016/s0140-6736(21)00682-6. [DOI] [PubMed] [Google Scholar]
  • 5.Dimitriadis E., Menkhorst E., Saito S., Kutteh W.H., Brosens J.J. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6(1):98. doi: 10.1038/s41572-020-00228-z. [DOI] [PubMed] [Google Scholar]
  • 6.Alijotas-Reig J., Garrido-Gimenez C. Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv. 2013;68(6):445–466. doi: 10.1097/OGX.0b013e31828aca19. [DOI] [PubMed] [Google Scholar]
  • 7.Yu H., Hu X., Huang X., et al. Causal relationship between circulating immune cells and recurrent spontaneous abortion: a bidirectional mendelian randomization study. Am J Reprod Immunol. 2024;91(6) doi: 10.1111/aji.13888. [DOI] [PubMed] [Google Scholar]
  • 8.Steinberg J.R., Laursen T.M., Adler N.E., Gasse C., Agerbo E., Munk-Olsen T. Examining the association of antidepressant prescriptions with first abortion and first childbirth. JAMA Psychiatry. 2018;75(8):828–834. doi: 10.1001/jamapsychiatry.2018.0849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Agarwala A., Michos E.D., Samad Z., Ballantyne C.M., Virani S.S. The use of sex-specific factors in the assessment of women's cardiovascular risk. Circulation. 2020;141(7):592–599. doi: 10.1161/circulationaha.119.043429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Conrad M., Angeli J.P., Vandenabeele P., Stockwell B.R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016;15(5):348–366. doi: 10.1038/nrd.2015.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Yan F., Li D., Sun X., et al. [Effect of cyclosporin A on the growth of human first trimester cytotrophoblasts in vitro] Zhonghua Fu Chan Ke Za Zhi. 2002;37(2):74–76. [PubMed] [Google Scholar]
  • 12.Du M.-R., Li M.-Q., Zhou W.-J., Li D.-J. Short-term cyclosporin A treatment improves pregnancy outcomes in patients with unexplained pregnancy loss: a prospective, open-label, observational study. Clin Transl Discov. 2022;2(4):e135. doi: 10.1002/ctd2.135. [DOI] [Google Scholar]
  • 13.Du M.R., Dong L., Zhou W.H., Yan F.T., Li D.J. Cyclosporin a improves pregnancy outcome by promoting functions of trophoblasts and inducing maternal tolerance to the allogeneic fetus in abortion-prone matings in the mouse. Biol Reprod. 2007;76(5):906–914. doi: 10.1095/biolreprod.106.056648. [DOI] [PubMed] [Google Scholar]
  • 14.Du M.R., Zhou W.H., Yan F.T., et al. Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells. Hum Reprod. 2007;22(9):2528–2537. doi: 10.1093/humrep/dem222. [DOI] [PubMed] [Google Scholar]
  • 15.Hirsch A.J., Roberts V.H.J., Grigsby P.L., et al. Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Commun. 2018;9(1):263. doi: 10.1038/s41467-017-02499-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Azizi R., Ahmadi M., Danaii S., et al. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio. J Cell Physiol. 2019;234(10):19039–19047. doi: 10.1002/jcp.28543. [DOI] [PubMed] [Google Scholar]
  • 17.Zhou W.H., Dong L., Du M.R., Zhu X.Y., Li D.J. Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4. Reproduction. 2008;135(3):385–395. doi: 10.1530/rep-07-0063. [DOI] [PubMed] [Google Scholar]
  • 18.Tang C., Pan J., Li H., et al. Cyclosporin A protects trophoblasts from H(2)O(2)-induced oxidative injury via FAK-src pathway. Biochem Biophys Res Commun. 2019;518(3):423–429. doi: 10.1016/j.bbrc.2019.07.118. [DOI] [PubMed] [Google Scholar]
  • 19.Zhao H.B., Tang C.L., Hou Y.L., et al. CXCL12/CXCR4 axis triggers the activation of EGF receptor and ERK signaling pathway in CsA-induced proliferation of human trophoblast cells. PLoS One. 2012;7(7) doi: 10.1371/journal.pone.0038375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Meng Y.H., Shao J., Li H., et al. CsA improves the trophoblasts invasiveness through strengthening the cross-talk of trophoblasts and decidual stromal cells mediated by CXCL12 and CD82 in early pregnancy. Int J Clin Exp Pathol. 2012;5(4):299–307. [PMC free article] [PubMed] [Google Scholar]
  • 21.Zhao H.B., Wang C., Li R.X., et al. E-cadherin, as a negative regulator of invasive behavior of human trophoblast cells, is down-regulated by Cyclosporin A via epidermal growth factor/extracellular signal-regulated protein kinase signaling pathway. Biol Reprod. 2010;83(3):370–376. doi: 10.1095/biolreprod.110.083402. [DOI] [PubMed] [Google Scholar]
  • 22.Du M.R., Zhou W.H., Dong L., et al. Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated AP1 and Ca2+/calcineurin/NFAT signaling pathways. Biol Reprod. 2008;78(6):1102–1110. doi: 10.1095/biolreprod.107.063503. [DOI] [PubMed] [Google Scholar]
  • 23.Zhou W.H., Du M.R., Dong L., et al. Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway. Hum Reprod. 2007;22(10):2743–2750. doi: 10.1093/humrep/dem097. [DOI] [PubMed] [Google Scholar]
  • 24.Wang S.-C., Yu M., Li Y.-H., et al. Cyclosporin A promotes proliferating cell nuclear antigen expression a nd migration of human cytotrophoblast cells via the mitgen-activated p rotein kinase-3/1-mediated nuclear factor-κB signaling pathways. Int J Clin Exp Pathol. 2013;(10):1999–2010. [PMC free article] [PubMed] [Google Scholar]
  • 25.Tang C.L., Zhao H.B., Li M.Q., Du M.R., Meng Y.H., Li D.J. Focal adhesion kinase signaling is necessary for the Cyclosporin A-enhanced migration and invasion of human trophoblast cells. Placenta. 2012;33(9):704–711. doi: 10.1016/j.placenta.2012.06.007. [DOI] [PubMed] [Google Scholar]
  • 26.Piao H.L., Wang S.C., Tao Y., et al. Cyclosporine A enhances Th2 bias at the maternal-fetal interface in early human pregnancy with aid of the interaction between maternal and fetal cells. PLoS One. 2012;7(9) doi: 10.1371/journal.pone.0045275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Huang Y.H., Ma Y.L., Ma L., et al. Cyclosporine A improves adhesion and invasion of mouse preimplantation embryos via upregulating integrin β3 and matrix metalloproteinase-9. Int J Clin Exp Pathol. 2014;7(4):1379–1388. [PMC free article] [PubMed] [Google Scholar]
  • 28.Ling Y., Huang Y., Chen C., Mao J., Zhang H. Low dose Cyclosporin A treatment increases live birth rate of unexplained recurrent abortion - initial cohort study. Clin Exp Obstet Gynecol. 2017;44(2):230–235. [PubMed] [Google Scholar]
  • 29.Fu J.H. Analysis of the use of cyclosporin A to treat refractory immune recurrent spontaneous abortion. Clin Exp Obstet Gynecol. 2015;42(6):739–742. [PubMed] [Google Scholar]
  • 30.Zhang Z.M., Zhang N., Wang X.F. Prognostic model on pregnancy outcomes for women with recurrent spontaneous abortions treated with cyclosporin A: a single-institution experience. Clinics. 2024;79 doi: 10.1016/j.clinsp.2024.100349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–269. doi: 10.7326/0003-4819-151-4-200908180-00135. w64. [DOI] [PubMed] [Google Scholar]
  • 32.Aychiluhm S.B., Mondal U.K., Isaac V., Ross A.G., Ahmed K.Y. Interventions for childhood central obesity: a systematic review and meta-analysis. JAMA Netw Open. 2025;8(4) doi: 10.1001/jamanetworkopen.2025.4331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Soneji S., Barrington-Trimis J.L., Wills T.A., et al. Association between initial use of e-Cigarettes and subsequent cigarette smoking among adolescents and young adults: a systematic review and meta-analysis. JAMA Pediatr. 2017;171(8):788–797. doi: 10.1001/jamapediatrics.2017.1488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Friedant A.J., Handorf E.A., Su S., Scott W.J. Minimally invasive versus open thymectomy for thymic malignancies: systematic review and meta-analysis. J Thorac Oncol. 2016;11(1):30–38. doi: 10.1016/j.jtho.2015.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Willems R.P.J., van Dijk K., Ket J.C.F., Vandenbroucke-Grauls C. Evaluation of the association between gastric acid suppression and risk of intestinal colonization with multidrug-resistant microorganisms: a systematic review and meta-analysis. JAMA Intern Med. 2020;180(4):561–571. doi: 10.1001/jamainternmed.2020.0009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Karmali K.N., Lloyd-Jones D.M., Berendsen M.A., et al. Drugs for primary prevention of atherosclerotic cardiovascular disease: an overview of systematic reviews. JAMA Cardiol. 2016;1(3):341–349. doi: 10.1001/jamacardio.2016.0218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Lopes R.D., Hong H., Harskamp R.E., et al. Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials. JAMA Cardiol. 2019;4(8):747–755. doi: 10.1001/jamacardio.2019.1880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Fu J.H., Zhu X.H., Sun H., Zhao L. Randomized controlled trial of Cyclosporin A for refractory immune recurrent spontaneous abortion. Chin J Pract Gynecol Obstet. 2016;32(5):441–445. [in Chinese] [Google Scholar]
  • 39.Chen Y., Yu Y.X. Efficacy analysis of combined Cyclosporin A treatment for refractory unexplained recurrent spontaneous abortion. J Clin Mil Med. 2017;45(10):1039–1041+1045. doi: 10.16680/j.1671-3826.2017.10.14. [in Chinese]. [DOI] [Google Scholar]
  • 40.Zhang L.P., Zhao J.D., Ma J.Q. Efficacy evaluation of Cyclosporin A combined with fat emulsion for recurrent spontaneous abortion. Trop Med J. 2018;18(12):1562–1565. [in Chinese] [Google Scholar]
  • 41.Guo N., Liu D., Wang T., Wang Y.X., Mi Y. Effect of dydrogesterone combined with Cyclosporin A on unexplained recurrent spontaneous abortion. Med Adv Biomed Res. 2019;19(15):2929–2932. doi: 10.13241/j.cnki.pmb.2019.15.029. [in Chinese]. [DOI] [Google Scholar]
  • 42.Ma T., Jin J., Wei Y., Zhang S.Y., Hu W.J. Cyclosporin A combined with lymphocyte therapy in URSA patients: effects on serum T cell subgroups, ACA, and pregnancy outcomes. Chin J Fam Plan. 2020;28(1):40–43. [in Chinese] [Google Scholar]
  • 43.Meng Z.Z., Wu P.Z., Wei H.L. Feasibility analysis of fat emulsion (or) cyclosporin replacement therapy combined with lymphocyte immunotherapy for unexplained recurrent spontaneous abortion. Maternal Child Health World. 2020;(17):3–4. [in Chinese] [Google Scholar]
  • 44.Tian H.J., Liang Y.F., Du M.R., Feng M.N. Analysis of the causes of 120 cases of recurrent spontaneous abortion and observation of the efficacy of cyclosporin A treatment. Chin J Doctors. 2020;22(6):926–928. doi: 10.3760/cma.j.cn431274-20200212-00125. [in Chinese]. [DOI] [Google Scholar]
  • 45.Chen L.L., Cui Y., Chen X.Y., Chen J., Zhu P. Feasibility analysis of cyclosporin combined with low molecular weight heparin calcium and shoutaiwan for unexplained recurrent spontaneous abortion. Prac Clin Med Trad Chin West Med. 2021;21(3):4–7. doi: 10.13638/j.issn.1671-4040.2021.03.002. [in Chinese]. [DOI] [Google Scholar]
  • 46.Cheng J., Li H.Y. Clinical efficacy of Cyclosporin A combined with chorionic gonadotropin treatment in unexplained recurrent spontaneous abortion patients. Med Clin Res. 2021;38(4):634–636. doi: 10.3969/j.issn.1671-7171.2021.04.047. [in Chinese]. [DOI] [Google Scholar]
  • 47.Qian Y.Q., Zhu X.L. Modified Bu Zhong Yi Qi Decoction combined with Cyclosporin A for recurrent spontaneous abortion with abnormal blocking antibodies: a clinical study. New Trad Chin Med. 2021;53(17):46–50. doi: 10.13457/j.cnki.jncm.2021.17.011. [in Chinese]. [DOI] [Google Scholar]
  • 48.Sun L.J., Liu L.X. Effects of Cyclosporin A combined with lymphocyte active immunotherapy on serum T cell subgroups, hormone levels, and ACA antibody levels in URSA patients. J Youjiang Med Univ Natl. 2021;43(1):56–59. [in Chinese] [Google Scholar]
  • 49.Liang B.Z., He R.L., Wang L. Efficacy observation of Cyclosporin A combined with immunoglobulin in the treatment of recurrent spontaneous abortion caused by elevated uNK cells. Physicians Online. 2022;12(11):15–17. doi: 10.3969/j.issn.2095-7165.2022.11.005. [in Chinese]. [DOI] [Google Scholar]
  • 50.Meng S. Clinical study on the combined treatment of dydrogesterone, Cyclosporin A, and Shoutaiwan for unexplained recurrent spontaneous abortion. Practical Gynecol Endocrinol Electron J. 2022;9(33) [in Chinese]. [Google Scholar]
  • 51.Qian Y.Q., Sun Y. Effects of an Tai Decoction combined with Cyclosporin A on immune balance and miscarriage rate in unexplained recurrent spontaneous abortion. Chin J Tradit Chin Med. 2022;40(4):219–222. doi: 10.13193/j.issn.1673-7717.2022.04.050. [in Chinese]. [DOI] [Google Scholar]
  • 52.Song S.H., Ouyang Q., Li Z.H., Li H.X., Zhou Z.L. Observation of the effect of dydrogesterone combined with Cyclosporin A on unexplained recurrent spontaneous abortion. Jiangxi Med J. 2022;57(9):1077–1078+1081. [in Chinese] [Google Scholar]
  • 53.Chen L.L., Cui Y., Chen X.Y., Zhu P. Feasibility analysis of Cyclosporin combined with low molecular weight heparin calcium for unexplained recurrent spontaneous abortion. Contemp Chin Med. 2023;30(32):85–89. [in Chinese] [Google Scholar]
  • 54.Ma M., Yao S.Y., Li Y.M. Effects of low molecular weight heparin combined with Cyclosporin A on unexplained recurrent spontaneous abortion, immune balance, and blood rheology. Chin J Fam Plan. 2023;31(1):153–158. [in Chinese] [Google Scholar]
  • 55.Wu X.Q., Wang S.Q., Liu W.P. Clinical study on Cyclosporin soft capsules combined with Zishen Yutaiwan for recurrent spontaneous abortion. Mod Diagnosis Treat. 2023;34(13):1919–1921. [in Chinese] [Google Scholar]
  • 56.Chen J., Che H.H., Zhang J. Efficacy of Cyclosporin A combined with dydrogesterone for unexplained recurrent spontaneous abortion and its effect on T lymphocyte subsets. J Clin Exp Med. 2024;23(15):1637–1641. [in Chinese]. [Google Scholar]
  • 57.Xu J.N., Dai Y.Z., Xing Y.H., Yang M.M. Effects of dalteparin sodium combined with Cyclosporin A on unexplained recurrent spontaneous abortion and immune microenvironment. Chin Prescr Drugs. 2024;22(3):122–125. [in Chinese] [Google Scholar]
  • 58.Zhao S.Y., Jin Q., Qiao Z.H., et al. Effects of Cyclosporin A on clinical outcomes, Th1/2/17 cytokines, and D-dimer in recurrent spontaneous abortion patients with elevated natural killer cells. J Chengdu Med Coll. 2024;19(2):253–257. [in Chinese] [Google Scholar]
  • 59.Zhen J. Analysis of the clinical value of Cyclosporin soft capsules combined with Zishen Yutaiwan for recurrent spontaneous abortion. Chin Sci Technol J Database Med. 2024;(9) [in Chinese]. [Google Scholar]
  • 60.Wang S.W., Zhong S.Y., Lou L.J., Hu Z.F., Sun H.Y., Zhu H.Y. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. 2016;33(6):720–736. doi: 10.1016/j.rbmo.2016.08.025. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figure S1

Risk of Bias Plots and Publication Bias Plots. A: Risk of bias plots for selected cluster RCT articles, B: Funnel plot of the included studies.

mmc1.pdf (1.3MB, pdf)
Supplementary Figure S2

Inconsistency Assessment in Network Meta-Analysis for Miscarriage and Live Birth Rate. A: Forest plot showing direct and indirect evidence comparisons for miscarriage rate, B: Forest plot showing direct and indirect evidence comparisons for live birth rate, C: Netsplit analysis for miscarriage rate, D: Netsplit analysis for live birth rate. Larger gray squares in the rows indicate higher study weight, and redder colors represent greater consistency. OR: odds ratios, CI: confidence intervals.

mmc2.pdf (463.6KB, pdf)
Supplementary Figure S3

Funnel and Forest Plots with Trim-and-Fill Adjustment for Publication Bias. A: Funnel plots for miscarriage rate, live birth rate and ongoing pregnancy rate using the trim-and-fill method. Blue dots represent observed studies; black dots indicate imputed (filled) studies. B: Corresponding forest plots showing original and adjusted odds ratios (ORs) after trim-and-fill correction.

mmc3.pdf (458.4KB, pdf)
Supplementary Figure S4

Exploratory Network Meta-Analysis of Cyclosporine A (CsA)-Based Treatments Involving Traditional Chinese Medicine (TCM) for Recurrent Spontaneous Abortion Management. (A) Forest plot for live birth rate comparing efficacy of various treatment regimens incorporating TCM. (B) Forest plot for miscarriage rate comparing treatment effects of TCM-containing regimens.

mmc4.pdf (226.5KB, pdf)
Supplementary Tables
mmc5.docx (55.4KB, docx)

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