- Academic Editor
Background: A major challenge in reproductive medicine is repeated implantation failure (RIF). Possible benefits of platelet-rich plasma (PRP) for pregnancy outcomes are still uncertain, and more evidence is required to properly evaluate this. The current meta-analysis was therefore carried out to assess the impact of intrauterine PRP infusion on pregnancy outcomes in women with RIF. Methods: Various databases (Web of Science, PubMed, Cochrane Library, Embase) were screened for English-language papers that investigated the effect of PRP treatment on pregnancy outcomes in RIF women who underwent in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). This effect was analyzed in both frozen-thawed and fresh cycles. These studies involved randomized controlled trial (RCT) and quasi-experimental (non-randomized experimental) studies, but excluded case-control, case series, self-control, cross-sectional studies. The Newcastle-Ottawa Scale was employed to determine study quality. Risk ratios (RRs) were calculated for dichotomous outcome variables, and weighted mean difference (WMD) with 95% confidence interval (95% CI) for continuous outcome variables. These were performed under fixed- or random-effect models. Results: This meta-analysis evaluated 15 articles from the literature. Improved pregnancy outcomes were observed in RIF women who received PRP, including higher rates of implantation, clinical pregnancy and live birth compared to control patients. Conclusions: The results of this study indicate that PRP could be a useful treatment strategy for RIF patients and those with a thin endometrium. Additional large RCTs are required to identify the subpopulation of women who could derive the maximum benefit from PRP.
Assisted reproductive technology (ART) including in vitro fertilization
(IVF) and intracytoplasmic sperm injection (ICSI) have proven to be effective
options for infertile couples. Although ART has resulted in major clinical and
scientific progress, repeated implantation failure (RIF) remains an emotionally
and physically challenging problem for infertile couples and clinicians. The
definition of RIF varies, but typically it means failure to achieve clinical
pregnancy after transfer of
Platelet-rich plasma (PRP) is concentrated PRP protein derived from whole blood
and with a 4–5-fold higher concentration of platelets compared to normal [2].
The alpha granules in platelets contain a mixture of proteins that become
bioactive in PRP. Intrauterine PRP infusion of PRP is reported to enhance
endometrial growth and improve embryo acceptance. Platelet granules are known to
contain various factors including interleukin 8 (IL-8), transforming growth
factor-
In this systematic review and meta-analysis, we therefore evaluated whether intrauterine PRP infusion improves clinical pregnancy outcomes in RIF patients.
The present systematic review was carried out as recommended by the Cochrane guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [9]. Databases used in this search were: Cochrane Library, MEDLINE, PubMed, Web of Science, Google Scholar, and Embase. Articles published in English from the beginning of the database to January 2023 were identified with the following search terms as words in the title or abstract: “In Vitro Fertilization” or “IVF” or “Intracytoplasmic sperm injection” or “ICSI” or “Embryo transfer” and “Platelet-rich plasma” or “Platelet rich plasma” or “PRP” and “Repeated Implantation Failure” or “Recurrent implantation failure” or “RIF”. In addition, references from candidate articles and reviews were manually searched for further relevant reports.
Selected articles reported one or more of these outcomes: rate of clinical pregnancy, rate of live birth, rate of miscarriage, rate of chemical pregnancy, and endometrial thickness. Randomized controlled trials (RCTs) as well as quasi-experimental studies were assessed. After searching the database by keywords, two authors (TTM and YP) separately checked the abstract of studies. Extraction of data was carried out independently by two authors (TTM and YP) using full-text copies of relevant papers.
Studies were included in our review if they fulfilled the following criteria: (1) the study was a RCT, quasi-experimental and cohort study in which medically confirmed pregnancy outcomes were the endpoints; (2) the intervention was IU infusion of PRP around the time of embryo transfer; (3) the population were diagnosed as having had an RIF; (4) the control group was any other active intervention, no intervention or placebo. Studies were excluded if those were case-control, case series, self-control, cross-sectional. Also, we excluded studies if we were unable to obtain adequate details of the study methodology or results.
RevMan 5.3 (Cochrane Collaboration, Oxford, UK) was used to assess bias. These were deemed low, unclear risk, or high bias according to the following: allocation concealment, random sequence generation, blinding, selective reporting, incomplete outcome data, and other types of bias. The quality of cohort studies was evaluated with the Newcastle–Ottawa scaling system. A specific judgment was also made with regard to the following: study group selection, group comparability, and measurement of exposures and outcomes. Table 1 (Ref. [6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]) lists the studies evaluated in this review.
No. | Author, Year | Study type | Country | Study period | Age (years) | Blinded | No. of patients | Embryo stage | Blood volume (mL) | Comparison | Outcomes |
1 | Allahveisi et al., 2020 [11] | RCT | Iran | 2018–2019 | not given | 50 | blastocyst | 35 | PRP/Control | CPR, IR, ET | |
2 | Dawood et al., 2022 [12] | RCT | Egypt | 2018.12–2021.10 | 20–35 | open label | 104 | blastocyst | 15 | PRP/Control | CPR, IR, BCPR, ET |
3 | Ershadi et al., 2022 [13] | RCT | Iran | since 2019 | not given | 85 | cleavage embryo | 8 | PRP/Control | CPR, BCPR, IR, SAR, ET | |
4 | Nazari et al., 2020 [14] | RCT | Iran | 2016–2017 | not given | not given | 138 | blastocyst | 8.5 | PRP/Control | CPR, BCPR |
5 | Nazari et al., 2022 [6] | RCT | Iran | 2018–2020 | 18–38 | not given | 418 | blastocyst | 8.5 | PRP/Control | BCPR, CPR, LBR, SAR, ET |
6 | Obidniak et al., 2017 [8] | RCT | Russia | not given | 28–39 | open label | 90 | not given | not given | PRP/Control | CPR, IR |
7 | Safdarian et al., 2022 [15] | RCT | Iran | 2017.10–2020.4 | 20–40 | not given | 120 | blastocyst | 8.5 | PRP/Control | CPR, BCPR, IR, LBR, OGR |
8 | Zamaniyan et al., 2021 [16] | RCT | Iran | 2016.2–2019.1 | 20–40 | blind | 120 | blastocyst | 17.5 | PRP/Control | CPR, OGR, SAR |
9 | Zargar et al., 2021 [17] | RCT | Iran | not given | single blind | 80 | cleavage embryo | 8.5 | PRP/Control | CPR, BCPR, LBR, SAR | |
10 | Coksuer et al., 2019 [18] | retrospective cohort | Turkey | 2014.1–2017.1 | 21–39 | not given | 273 | blastocyst | 8 | PRP/Control | CPR, BCPR, SAR |
11 | Mehrafza et al., 2019 [19] | retrospective cohort | Iran | 2016–2017 | not given | not given | 123 | both | 8.5 | PRP/GCSF | CPR, IR, BCPR, |
12 | Tehraninejad et al., 2021 [20] | Non-RCT | Iran | 2016–2018 | not given | 85 | blastocyst | 10 | PRP/Control | CPR, BCPR, OGR | |
13 | Noushin et al., 2021 [10] | prospective cohort | UK | 2019.5–2020.5 | not given | 318 | cleavage embryo | 10 | PRP/Control | CPR, BCPR, LBR, SAR | |
14 | Xu et al., 2022 [21] | retrospective cohort | China | 2019.1–2021.1 | 23–40 | not given | 410 | both | 20 | PRP/Control | CPR, IR, BCPR, LBR, SAR, ET |
15 | Yuan et al., 2022 [22] | retrospective cohort | China | 2019–2021 | 25–40 | not given | 64 | cleavage embryo | 8.5 | PRP/Control | CPR, IR |
RCT, randomized controlled trial; PRP, platelet-rich plasma; CPR, clinical pregnancy rate; IR, implantation rate; ET, endometrial thickness; BCPR, biochemical pregnancy rate; SAR, sponteneous abortion rate; LBR, live birth rate; OGR, ongoing pregnancy rate; GCSF, granulocyte colony stimulating factor.
Data was analyzed using RevMan 5.3 (Cochrane Collaboration, Oxford, UK). PRP
treatment effects on the outcomes were evaluated using pooled risk ratios (RRs)
with 95% confidence interval (95% CI). In the absence of heterogeneity, RRs were estimated with the
Mantel–Haenszel fixed effects model. Otherwise, a random effects model was used.
The heterogeneity between studies was assessed statistically with Cochran’s
Q-test, with I
In all, 240 potentially relevant articles were found in the databases using the search strategy. Following removal of duplicates, the 168 remaining studies underwent title evaluation, leaving 81 possibly relevant studies for further assessment of the abstract. One study was presented in abstract form only (conference paper) and was excluded from the analysis because it contained insufficient data. Six papers were non-compliant for the inclusion criteria. Nine papers were case series, case reports, and single-arm research. One study was excluded because the control patients were patients from the first time of embryo transfer, rather than RIF. Three studies were excluded because the control group were self-control. One study was excluded because the researcher had published another study which included patients from the same institute at the same time duration. Finally, 15 articles meeting the inclusion criteria were further evaluated. A flowchart of the study selection and inclusion processes is shown below (Fig. 1).
Study selection. RIF, repeated implantation failure.
Table 1 lists the major details for the 15 studies evaluated in this review. These were published between 2017 and 2022. Nine of the papers reported RCTs and 6 were cohort studies. Overall, the 15 studies included 2478 women aged between 20–41 years. All women in the PRP and control patients were RIF. Sample size for each study ranged from 50 to 418 women. The volume of peripheral blood for the preparation of PRP ranged from 8 mL to 35 mL. Embryo transfer was “cleavage stage” in 4 studies, “blastocyst stage” in 8 studies, both cleavage and blastocyst stages in two studies, and in one study the stage was not given. One study compared PRP administered to the sub-endometrial (SE-PRP) or endometrial surface (intrauterine, IU-PRP) with the control group. This found there was no advantage of SE-PRP compared to the less invasive IU-PRP. SE-PRP cannot be administered during the index cycle of FET preparation because it is invasive and risks damaging the growing endometrium [10]. Twelve studies transferred the embryo only in frozen-thawed cycles, two in fresh condition [8, 22], and one in both fresh and frozen condition [17]. One study compared PRP administration with that of granulocyte colony stimulating factor (GCSF) [19], whereas all others used untreated controls. The risk of bias for nine RCTs is shown in Fig. 2. The quality of the six cohort studies was assessed using the Newcastle-Ottawa Scale (NOS). Four cohort studies scored 7, and two cohort studies scored 8. The quality of the literature was high.
Summary of risk of bias for randomized controlled trials.
Meta-analysis of results from 14 studies was carried out to estimate the impact
of PRP on the rate of clinical pregnancy [6, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. When considering
only the 8 RCTs [6, 8, 11, 13, 14, 15, 16, 17], a significant improvement in pregnancy was
seen for PRP patients compared to control patients (risk ratios (RR) = 2.02, 95% CI:
1.56–2.61, p
Forest plot showing risk ratios (RRs) and 95% confidence interval (95% CI) for clinical pregnancy in RCT and non-RCT studies. M-H, Mantel-Haenszel.
Forest plot showing RRs and 95% confidence interval (95% CI) for clinical pregnancy. M-H, Mantel-Haenszel.
Four papers reported the rate of live birth [6, 11, 17, 21]. These included 811
RIF women, of whom 399 were PRP patients and 412 were control patients. A
random-effects model (Fig. 5) revealed no significant difference in the live
birth rate between the two patient groups (RR = 2.62, 95% CI: 0.87–7.92,
p = 0.09). Moreover, an I
Forest plot showing individual and combined effect size estimates and 95% CI in studies reporting rate of live birth in RIF patients.
Four papers reported the rate of implantation [15, 19, 21, 22]. As shown in Fig. 6, a highly significant difference was found between PRP and control patients (RR
= 1.79, 95% CI: 1.39–2.29, p
Forest plot showing individual and combined effect size estimates and 95% CI in studies assessing rate of implantation in RIF patients.
Seven studies reported the spontaneous abortion rate [6, 10, 13, 16, 18, 21]. As
shown in Fig. 7, a significant difference in spontaneous abortion was found
between PRP and control patients (RR = 0.51, 95% CI: 0.30–0.81;
I
Forest plot showing individual and combined effect size estimates and 95% CI in studies assessing spontaneous abortion in RIF women.
Six studies reported changes to endometrial thickness after PRP treatment [11, 13, 16, 17, 21, 23]. These included a total of 506 cases and 512 controls. As
shown in Fig. 8, endometrial thickness in RIF patients treated with PRP was
greater than in the controls (standardized mean difference (SMD): 0.39, 95% CI:
–0.23 to 1.1; p = 0.22, I
Forest plot showing individual and combined effect size estimates and 95% CI in studies reporting standardized mean differences for endometrial thickness in RIF patients. SD, standard deviation; IV, Inverse-Variance Weighted.
This systematic review assessed studies of PRP intervention aimed at improving pregnancy outcomes in RIF women. Our evaluation revealed significantly higher rates of implantation, clinical pregnancy, implantation, and endometrial thickness in women who received intrauterine PRP administration versus controls. Endometrial thickness was also improved by PRP treatment. Positive effects of PRP therapy were reported in almost all studies included in this meta-analysis, including higher rates of clinical pregnancy and live birth, and lower rates of implantation failure and miscarriage. This study also updates earlier systematic reviews with larger sizes [24, 25, 26, 27]. The increased rates of live births and biochemical, clinical and ongoing pregnancies found in the present analysis of PRP-treated RIF women concurs with the findings of the previous reviews. RCTs are usually considered to be more convincing than cohort ones owing to the former’s objectivity. Involving studies that included nine RCTs and six cohort studies also made this meta-analysis more objective and convincing after subgroup analysis. Two studies involved some participants undergoing a fresh embryo transfer [8, 22], and one study involved both fresh and frozen-thawed transfer [17]. Therefore, we did not extract them from the statistics to conduct a subgroup analysis.
The statistical measure of homogeneity, was low across all pregnancy endpoints, which suggests consistent effects throughout the studies. The first meta-analysis reported by Maleki-Hajiagha et al. [27] in 2020 found that IU-PRP increased the rate of clinical pregnancy in the FET cycle, thereby supporting current observations. The meta-analysis by Maleki-Hajiagha et al. [27] included 3 RCTs and 4 cohort studies, with significant heterogeneity observed between the studies. As another previous meta-analysis [24, 25] also proved that the IU-PRP has a positive effect on the pregnancy results for RIF patients, additional large RCTs on the regular use of PRP in RIF women are warranted in order to provide more conclusive results. More carefully designed studies are also required to confirm the impact of IU-PRP in RIF patients.
Platelet-rich plasma is a platelet concentrate obtained by centrifugation. PRP
is an inexpensive way to deliver high concentrations of VEGF, TGF-
Several limitations should be considered in the present meta-analysis. Firstly, most of the studies were from only a few countries and ethnic groups, thus making it difficult to generalize the findings. Strengths of the meta-analysis include the homogeneity of pooled indices across studies, as well as the robustness to sensitivity and subgroup analysis, as included studies from different embryo transfer cycles and embryo types. First, only a limited number of relevant studies with high-quality evidence, which included studies (n = 14) and the fact that only 8 RCT compared PRP with placebo, were available for analysis. Although we conducted comprehensive and time-consuming literature searches to identify all relevant studies, we cannot exclude the possibility that publication bias might have affected our results.
Our systematic review and meta-analysis suggest that intrauterine administration of autologous PRP treatment can improve implantation, clinical pregnancy, and live birth in RIF patients. But, comprehensive data regarding complications, and adverse pregnancy outcomes was not available, so, we are not able to provide conclusive results. Further large, multicenter RCTs with a double-blind design are required to accurately ascertain the effectiveness of PRP in these patients.
All data points generated or analyzed during this study are included in this article and there are no further underlying data necessary to reproduce the results.
TTM and YP Performed the literature search and performed the extraction of data. TTM performed the risk of bias assessment. YP performed the statistical analysis. Both authors contributed to the writing of the manuscript. Both authors have read and agreed to the published version of the manuscript.
Not applicable.
We would like to express our thanks to everyone who helped us in the process of writing this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.
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