Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: a systematic review and meta-analysis

It has been proposed that intrauterine administration of peripheral blood mononuclear cells (PBMCs) modulates maternal immune response through a cascade of cytokines, chemokines and growth factors to favor implantation. We conducted a meta-analysis to verify the effect of intrauterine PBMC administration on the outcome of embryo transfer in women with recurrent implantation failure (RIF). All relevant trials published in PubMed, Web of Science and Cochrane library databases were searched. Two randomized controlled trials and three cohort studies (1173 patients in total) matched the inclusion criteria. No differences in live birth rates were seen between the PBMC-treated patients and controls (OR: 1.65, 95% CI: 0.84–3.25; p = 0.14; I2: 66.3%). The clinical pregnancy rate was significantly higher in women who received intrauterine PBMCs before embryo transfer compared with those who did not (OR: 1.65, 95% CI: 1.30–2.10; p = 0.001, heterogeneity; I2: 60.6%). Subgroup analyses revealed a significant increase in clinical pregnancy rates with the administration of PBMCs in women with ≥3 previous failures compared with controls (OR: 2.69, 95% CI: 1.53–4.72; p = 0.001, I2: 38.3%). In summary, the data did not demonstrate an association between the administration of PBMCs into the uterine cavity before fresh or frozen-thawed embryo transfer and live birth rates in women with RIF. Whether intrauterine PBMC administration significantly changes live birth and miscarriage rates requires further investigation.


TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. Page 1, the title defines the study as a systematic review and meta-analysis.

Structured summary
2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
Page 1, first paragraph provides a structured summary of the study. Systematic review registration number is not available.

Rationale
3 Describe the rationale for the review in the context of what is already known.
Page 1, paragraphs 2-3; Page 2, paragraph 1 provides the rationale for the review and scientific background Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
Page 2, paragraph 2 defines the objective of the study

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Page 5, paragraph 5 and page 6, paragraphs 1-2 define the review protocol. Systematic review registration number is not available.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
Page 6, paragraph 3 defines the eligibility criteria. Detailed criteria based on PICOS format are presented in Supplementary Table S1 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
Page 5, paragraph 5 and page 6, paragraph 1 describe information sources Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Page 5, paragraph 5 and page 6, paragraphs 1-2 describe the search strategy Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the metaanalysis).
Page 6, paragraph 3; Figure 1; and Supplementary Table 1 describe study selection and eligibility criteria Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
Page 6, paragraphs 5-6; subheading data extraction and quality assessment Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe the methods used for assessing the risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Page 7, paragraph 1; Supplementary 16 Describe the methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression); if done, indicate which were pre-specified. -

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
Page 2, paragraph 4 describes study selection, and Figure 1 presents the flow diagram

Study characteristics
18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Summary of evidence
24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
Page 3, the first paragraph of Discussion Limitations 25 Discuss limitations of study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
Page 4, paragraphs 1-2 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.