Journal of Reproductive Immunology: Review Article

Journal of Reproductive Immunology 137 (2020) 103077
Contents lists available at ScienceDirect
Journal of Reproductive Immunology

journal homepage: www.elsevier.com/locate/jri
Review article
Efficacy of intrauterine administration of autologous peripheral blood T

mononuclear cells on the pregnancy outcomes in patients with recurrent
implantation failure: A systematic review and meta-analysis
Zahra Pourmoghadama,c,e, Samaneh Abdolmohammadi-Vahida,e, Fariba Pashazadehd,
leili Aghebati-Malekid, Freshteh Ansaric, Mehdi Yousefib,e,*
a
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
b
Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
c
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
d
Research Center for Evidence-Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
e
Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
ARTICLE INFO ABSTRACT
Keywords: One in every nine couples suffers from implantation defects and pregnancy failures. In spite of many con-
Peripheral blood mononuclear cell tributions that ART has given to infertility treatment, there are many reports of the failure of ART. Therefore,
Recurrent implantation failure scientists suggested many complementary therapies for use besides ART to improve the quality of infertility
Meta-analysis treatments. Intrauterine PBMC-therapy is one of these complementary therapies that were used before IVF.
Studies that examined PBMC treatment in women with at least three IVF/ET failure were included in this review.
These studies involved RCT and quasi-experimental (non-randomized experimental) studies. A three-step search
strategy was used for published and unpublished clinical trials written in English and Persian. No time limitation
was set for studies. Study selection according to the inclusion criteria and methodological quality assessment and
data extraction were done by two independent reviewers, which result in five studies being included (two RCTs
and three quasi-experimental studies). Finally, all of these article extracted data were pooled in a statistical
meta-analysis. Findings demonstrated that implantation, pregnancy and live birth rate were statistically in-
creased and the miscarriage rate was significantly decreased in the PBMC-treated group than that non-treated
group. In conclusion, based on the evidence, PBMCs can be an effective therapeutic approach in women with at
least three IVF/ET failure and lacking initial inflammation that is essential for implantation.
1. Introduction a morphologically low-quality embryo can reduce the implantation

chance of a good quality embryo (El-Danasouri et al., 2016). The im-
Infertility means not being able to conceive after having regular plantation process comprises two main components; a healthy embryo
unprotected intercourse for more than one year (Pourmoghadam et al., with implantation potential and a receptive endometrium enabling
2018). In the Europe and United States of America (USA), one in every implantation. A cross-talk between the embryo and the endometrium
nine couples suffers from implantation defects and pregnancy failures. and the balance between the embryo, endometrium, and immune
Most of the pregnancy failures happen during the embryo implantation system interactions are essential for successful implantation and pla-
period (Teklenburg et al., 2010), the majority of these losses represent cement in the proper location (Salamonsen et al., 2016; Fox et al.,
elimination of embryos with karyotype abnormalities, so before any 2016). Hence, any abnormalities in the endometrium, embryo, hor-
diagnosis or treatment, it is necessary to ensure the health and quality monal profile, and even the mother's immune system can result in
of the embryo (Ouyang et al., 2016). It is demonstrated that transferring implantation failure (Achache and Revel, 2006; Fukui et al., 2011).
Abbreviation: ART, assisted reproductive technologies; CD, cluster of differentiation; ET, embryo transfer; hCG, human chorionic gonadotropin; IVF, in vitro
fertilization; IVIg, intra-venous immunoglobulin; IL, interleukin; JBI, Joanna Briggs institute; OR, odd ratio; PBMC, peripheral blood mononuclear cell; PRISMA,
preferred reporting items for systematic reviews and meta-analyses; RIF, recurrent implantation failure; RCT, randomized controlled trials; Th-1, T helper 1; Th-2, T
helper 2; TNF, tumor necrosis factor; uNK cell, uterine natural killer cell
⁎
Corresponding author.
E-mail address: Yousefime@tbzmed.ac.ir (M. Yousefi).
https://doi.org/10.1016/j.jri.2019.103077
Received 3 July 2019; Received in revised form 29 September 2019; Accepted 20 December 2019
0165-0378/ © 2019 Elsevier B.V. All rights reserved.
Downloaded for SIMS SRM Institutes of Medical Science (librarian@simshospitals.com) at SRM Institutes for Medical Science Vadapalani from ClinicalKey.com by Elsevier on August 28,
2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
Z. Pourmoghadam, et al. Journal of Reproductive Immunology 137 (2020) 103077
RIF is determined as a failure of the implantation after at least three 1.2.2. Intervention
IVF attempts, in which 1–2 high-quality embryos in each IVF cycle are Studies that evaluated the intrauterine administration of the auto-
transferred (Shufaro and Schenker, 2011). Accordingly, the treatment logous PBMC prior to embryo transfer were included.
of RIF should be carried out by detection of the disorders and ab-
normalities and treating those that lead to implantation failure 1.2.3. Comparator
(Margalioth et al., 2006; Shufaro and Schenker, 2011). Implantation is The comparator group was RIF women undergoing no treatments
similar to an open wound that requires a potent inflammatory response (non-PBMC treated women).
to initially allow the embryo to adhere. During this period, the blas-
tocyst should pass through the uterine epithelium for implantation and 1.2.4. Outcomes
damage the endometrial tissue to invade, and then convert to an anti- The outcomes were implantation rate measured by ultrasonography
inflammatory response which involved suppression of local immune via embryo sac observation, pregnancy rate measured by pregnancy test
activity and control the invasion of the embryo (Mor et al., 2011). The (β-hCG) and controlled by ultrasound and, live birth rate and mis-
presence of semen in the uterus before implantation causes the invasion carriage rate.
and accumulation of T lymphocytes and macrophages around uterine
epithelium, these immune cells are thought to play a key role in the 1.2.5. Types of studies
implantation process that involves inflammatory factors essential for This systematic review considered both experimental and quasi-
implantation initiation (Song et al., 2016; Azad et al., 2017). Then, uNK experimental study designs including RCTs and non-RCTs.
cells, as the most represented immune cells at the time of implantation,
are recruited and accumulate in the site of inflammation. They are re- 2. Methods
cruited by sex hormones and IL-11 and IL-15 cytokines released from
the uterus (Parham, 2004; Becknell and Caligiuri, 2005; Ashkar et al., The proposed systematic review was conducted in accordance with
2003). It was shown that uNKs play an important role in pregnancy the JBI methodology for systematic reviews of the effectiveness of
success and then maybe IVF process (Shreeve and Moffett, 2019; evidence (Godfrey and Harrison, 2010). This review title has been re-
PrabhuDas et al., 2015), and recently, several studies have revealed that gistered in JBI and its protocol has been registered on Prospero data-
immune cells located in implantation site are effectively involved in base with registration number CRD42018116525.
embryo implantation that confirms the above report (Lea and Sandra,
2007; Yoshinaga, 2008; Fujiwara et al., 2009; Nakayama et al., 2002; 2.1. Search strategy
PrabhuDas et al., 2015). In other words, initially, the presence of
lymphocytes shifts the immunological responses to the Th-1 response The search strategy aimed to find both published and unpublished
and their cytokines profile (McMaster et al., 1992; Sanford et al., 1992). studies. A three-step search strategy was exerted in this review. An
Subsequently, the domination of Th-2 responses and their cytokines initial limited search of the MEDLINE database (via PubMed) was un-
suppresses inflammation caused by the previous response, so that dertaken followed by analysis of the text words included in the title and
pregnancy can continue successfully (Chaouat et al., 2007; Challis abstract and the index terms used to describe the articles. A second
et al., 2009; Mor, 2008; Mor et al., 2011). Additionally, it has been search, using all identified keywords and index terms, was undertaken
demonstrated that in some RIF cases, there is no initial inflammation on July 2018 throughout the following databases: MEDLINE (via
necessary for successful implantation (Nakayama et al., 2002; Yoshioka PubMed), the Cochrane library (CENTRAL), Embase, and Irandoc, SID
et al., 2006; Madkour et al., 2016). and Magiran (for Persian articles). The search for unpublished studies
Hence, immunological therapy with PBMCs would be effective for and gray literature included Proquest (for dissertation),
embryo implantation by providing essential initial inflammation (Yu Clinicaltrials.gov, WHO, Greylit.org, nyam.org and google scholar.
et al., 2014). PBMCs mainly consist of monocytes, T and B lymphocytes Finally, for the third search step, the reference lists of all reports and
in mammalian species. According to various studies, PBMCs induce the articles selected for critical appraisal were searched for additional
production of several cytokines in humans, such as IL-1α, IL-1β, and studies. Clinical trials written in English and Persian were considered
TNF-α that they can have a positive effect on the endometrium and for inclusion in this review but animal studies were excluded. There was
endometrial receptivity. Besides, PBMCs initiate and control the inva- no limitation on publication date or publication status. The full search
sion for hemochorial placentation establishment as well as regulate strategy for Embase is provided in Appendix A.
immune responses for the embryo implantation (Fujiwara, 2009;
Fujiwara et al., 2016). Therefore, since PBMCs can provide a suitable 2.2. Study selection
condition for embryo implantation as well as the fact that there has not
yet been a systematic review article published in this field, we decided Following the systematic literature search, all identified citations
to examine the results obtained from articles that investigated the effect were loaded into Endnote X8 software (https://endnote.com/) and
of the intrauterine administration of activated autologous PBMCs on duplicates were removed. Titles and abstracts were then screened by
pregnancy outcomes (implantation, pregnancy, live birth and mis- two independent reviewers to assess according to the inclusion/exclu-
carriage rates) in women with RIF. sion criteria for the review. The full text of the potentially eligible
studies was retrieved and assessed in detail by two independent re-
1.1. Review question viewers. Full-text studies that did not meet the inclusion criteria were
excluded and the reasons for their exclusion are provided in Appendix
The question of this review was if the intrauterine administration of B. Any disagreements that arose between the reviewers were resolved
autologous PBMC affects implantation, pregnancy, live birth, and mis- through discussion, or with a third reviewer. The results of the search
carriage rates in patients with RIF. are fully included in the final report and presented in PRISMA flow
diagram (Moher et al., 2009).
1.2. Inclusion criteria
2.3. Assessment of methodological quality
1.2.1. Participants
This review considered studies that evaluated women between Eligible studies were critically appraised by two independent re-
30–45 years old who experienced at least three implantation failures viewers using standardized critical appraisal instruments from the JBI
and underwent the intrauterine PBMC-therapy. for experimental and quasi-experimental studies (Peters et al., 2015).
2
Any disagreements that arose between the reviewers were resolved the systematic review.
through discussion, or with a third reviewer. The reviewers attempted
to contact the authors of the studies for missing information and un-
clear data, but no success was achieved. 3.3. Characteristics of the included studies
2.4. Data extraction A total of five studies were included in the meta-analysis (Tables C1
and C2 in Appendix C). Of these, two were conducted in China (Yu
After methodological quality assessment, data were extracted from et al., 2016; Li et al., 2017), two in Japan (Okitsu et al., 2011; Yoshioka
studies included in the review by two independent reviewers, using a et al., 2006) and one in France (Madkour et al., 2016). These studies
JBI modified extraction tool. The extracted data included specific de- were published between 2006 and 2017. Included studies assessed
tails about the interventions (the number of PBMCs, and the type and women in different groups based on the number of IVF/ET failure.
dose of its activator), populations (number of participants in both in- Women with at least three IVF/ET failures, according to the prevailing
tervention and control groups), study methods and outcomes relevant RIF definition, pooled into the meta-analysis, others will be narratively
to the study question, and specific objectives (pregnancy outcomes). expressed in this part. Intervention and control groups were similar at
Any disagreement that arose between the reviewers were resolved baseline in all studies. Three studies used cultured PBMCs (Madkour
through discussion, or with a third reviewer. Authors of papers were et al., 2016; Li et al., 2017; Yu et al., 2016), and one of them exerted
contacted to request missing or additional data and we omitted those fresh PBMCs (Okitsu et al., 2011) and the other one, utilized a mixture
studies that their data were not clear to us. of fresh and cultured PBMCs (Yoshioka et al., 2006). All studies eval-
uated implantation and pregnancy rates. Except for one (Madkour
2.5. Data synthesis et al., 2016), the other articles reported live birth rate (Yu et al., 2016;
Yoshioka et al., 2006; Li et al., 2017; Okitsu et al., 2011) and only two
Data were, where possible, pooled with statistical meta-analysis papers assessed miscarriage rate (Madkour et al., 2016; Yu et al., 2016).
using Revman 5.2. Effect sizes were expressed as odds ratio (OR, for Yu et al. (Yu et al., 2016) examined all four outcomes in women with
categorical data, such as implantation rate, pregnancy rate, live birth three or more repeated IVF failures. They showed that implantation,
rate, and miscarriage rate), and their 95 % confidence intervals (95 % pregnancy, and live birth rates were significantly increased compared
CI) were calculated for analysis. Heterogeneity was assessed statisti- with the control group after treatment with PBMCs that were cultured
cally using the standard chi-squared and I2 tests. Statistical analyses 24 h in the presence of hCG. However, there were no significant dif-
were performed using a fixed-effects model (Tufanaru et al., 2015). ferences in the miscarriage rate between the two groups. Okitsu et al.
Sensitivity analyses were conducted to test decisions made regarding. reported their data in three groups based on the number of IVF failure:
Because there were less than 10 studies included in this meta-analysis, a one or more, one or two, three or more. High implantation and preg-
funnel plot was not generated to assess the publication bias. nancy rates were observed in patients with three or more IVF failures
after fresh PBMCs insemination. There was no significant difference in
3. Results the live birth rate in any groups. A mixture of fresh and cultured PBMCs
(for 48 h in the presence of hCG) was transferred into the uterine cavity
3.1. Study inclusion of women with four or more IVF failures in a study by Yoshioka et al.
They showed a significant increase in pregnancy, implantation, and live
Based on inclusion criteria, 234 studies from electronic databases birth rates in PBMC-treated group in comparison to the control group.
and 62 studies from hand search were found. After removing the du- Li et al. examined the effect of cultured PBMCs (24 h in the presence of
plications, 170 studies remained and were selected for the title eva- hCG) in women with one, two, three, and more than four IVF failures.
luation, of which 29 studies that seemed to be related, remained for There were no significant differences in implantation, pregnancy, and
abstract assessment. Finally, only 13 studies were selected to be re- live birth rate between the intervention and control groups in women
viewed for their full text. Since five studies (Kremenska et al., 2010; with one and three IVF failures. However, significant differences were
Sudoma et al., 2009; Chakravarty et al., 2018; Sudoma et al., 2011a, b) observed in implantation and pregnancy rates in women with two im-
were just presented in an abstract format (conference paper) and no plantation failures. When their analysis was limited to the patients with
sufficient data available about study details in those abstracts, re- four or more implantation failures, significant differences were detected
viewers decided to exclude them from further analysis in this section. in all their evaluated groups. Madkour et al. evaluated implantation,
Reviewers tried to contact with authors by email to request for their pregnancy, and miscarriage rates in women with at least two and at
article full-text but they did not succeed. In addition, one study least three IVF failures. They showed that in women with at least three
(Sefrioui et al., 2014) was presented as a poster format. It was omitted IVF failures, implantation and pregnancy rates were significantly in-
from further analysis, not only for insufficient details but also because creased in the intervention group than the control group and the mis-
of exact similarity with a previously selected article. Two other studies carriage rate was significantly decreased in the PBMC-treated women.
(Makrigiannakis et al., 2019, 2015) could not be included in our sys- Similar results were observed in women with at least two implantation
tematic review because they did not match our inclusion criteria. These failures, but the miscarriage rate was not significantly different between
eight excluded studies are listed in Appendix B with their exclusion the intervention and control groups.
reasons. The other five articles (Yu et al., 2016; Madkour et al., 2016;
Yoshioka et al., 2006; Okitsu et al., 2011; Li et al., 2017) that met the
inclusion criteria were included in the systematic review and finally, all 3.4. Review findings
of them were assessed in the meta-analysis. Fig. 1 is the flowchart de-
monstrating the studies selection and inclusion process. The results from five studies were pooled via meta-analysis to es-
timate the overall effects of the intrauterine PBMC-therapy on im-
3.2. Methodological quality plantation rate, pregnancy rate, live birth rate, and miscarriage rate.
Those result that could not be meta-analyzed, were narratively dis-
Articles that met the inclusion criteria reporting on RCTs and non- cussed. All studies used ultrasonography and β-hCG test as methods to
randomized experimental studies were appraised in terms of quality detect pregnancy outcomes.
using standard JBI SUMARI critical appraisal tools (Peters et al., 2015).
Tables 1 and 2 indicate the evaluation results of the studies included in
3
Fig. 1. Study selection and inclusion process. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Moher D et al. 2009.
3.5. Implantation rate 3.6. Pregnancy rate
3.5.1. Implantation rate in quasi-experimental studies 3.6.1. The pregnancy rate in quasi-experimental studies
In quasi-experimental studies, the results of the meta-analysis The results of the meta-analysis showed that there was a statistically
showed that there was a statistically significant difference in the im- significant difference in the pregnancy rate between the PBMC-treated
plantation rate between the intervention and control groups (OR = and non-treated groups (OR = 2.03; 95 % CI = 1.22, 3.36; P = 0.006).
1.59; 95 % CI = 1.04, 2.42; P = 0.03). There was also a significant There was a 28 % heterogeneity between these studies (I2 = 28 %;
heterogeneity among these studies (I2 = 70 %; Fig. 2). Fig. 4).
3.5.2. Implantation rate in RCTs 3.6.2. The pregnancy rate in RCTs

In RCTs, the results of the meta-analysis showed that there was a The results of the meta-analysis showed that there was a statistically
statistically significant difference in the implantation rate between the significant difference in the pregnancy rate between the PBMC-treated
intervention and control groups (OR = 2.47; 95 % CI = 1.31, 4.67; P = and non-treated groups (OR = 3.57; 95 % CI = 1.99, 6.40;
0.005). Interestingly, there was no heterogeneity among these studies P < 0.0001). There was no heterogeneity between these studies (I2 = 0
(I2 = 0 %; Fig. 3). %; Fig. 5).
Table 1
Critical appraisal results of Randomized Controlled Trial studies.
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13
Yu et al. (2016) U U Y U U U Y Y N Y Y Y Y
Madkour et al. (2016) U U Y U U U Y Y Y Y Y Y Y
Total % 0 0 100 0 0 0 100 100 50 100 100 100 100
Y = Yes, N = No, U = Unclear; JBI critical appraisal checklist for randomized controlled trials: Q1= Was true randomization used for assignment of participants to
treatment groups?; Q2 = Was allocation to treatment groups concealed?; Q3= Were treatment groups similar at baseline?; Q4= Were participants blind to
treatment assignment?; Q5= Were those delivering treatment blind to treatment assignment?; Q6= Were outcome assessors blind to treatment assignment?; Q7=
Were treatment groups treated identically other than the intervention of interest?; Q8= Was follow-up complete, and if not, were strategies to address incomplete
follow-up utilized?; Q9= Were participants analyzed in the groups to which they were randomized?; Q10= Were outcomes measured in the same way for treatment
groups?; Q11= Were outcomes measured in a reliable way?; Q12= Was appropriate statistical analysis used?; Q13= Was the trial design appropriate, and any
deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?
4
Table 2 3.8. Miscarriage rate

Critical appraisal results of eligible Quasi-Experimental (non-randomized ex-
perimental) studies. Only RCTs reported the miscarriage rate.
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9
3.8.1. Miscarriage rate in RCTs
Okitsu et al. (2011) Y Y Y Y NA Y Y U Y The meta-analysis of two included studies in these groups showed a
Yoshioka et al. (2006) Y Y Y Y NA Y Y U Y
statistically significant decrease in the intervention group compared with
Li et al. (2017) Y Y Y Y NA Y Y Y Y
Total % 100 100 100 100 0 100 100 33 100 the control group (OR = 0.42; 95 %CI = 0.23, 0.77; P = 0.005). There
was significant heterogeneity between the studies (I2 = 80 %; Fig. 7)
Y= Yes, N= No, U= Unclear; JBI critical appraisal checklist for randomized
controlled trials: Q1= Is it clear in the study what is the ‘cause’ and what is the 4. Discussion
‘effect’ (i.e. there is no confusion about which variable comes first)?; Q2 =
Were the participants included in any comparisons similar?; Q3= Were the In the current systematic review, we evaluated the studies in which
participants included in any comparisons receiving similar treatment/care,
PBMC was prescribed for RIF women in order to improve pregnancy out-
other than the exposure or intervention of interest?; Q4= Was there a control
comes. To the best of our knowledge, this article is the first systematic re-
group?; Q5= Was there multiple measurements of the outcome/conditions
both pre and post the intervention/exposure?; Q6= Was follow-up complete, view that focuses on this subject and it revealed that intrauterine adminis-
and if not, was follow-up adequately reported and strategies to deal with loss to tration of autologous PBMCs can affect positively the pregnancy outcomes.
follow-up employed?; Q7= Were the outcomes of participants included in any According to previous studies PBMC-therapy has not been beneficial for
comparisons measured in the same way?; Q8= Were outcomes measured in a women with one or two implantation failure (Li et al., 2017; Okitsu et al.,
reliable way?; Q9= Was appropriate statistical analysis used? 2011; Gultomruk et al., 2014), so in this review, we compared the effects of
intrauterine PBMC-therapy in women with at least three IVF/ET failures on
3.7. Live birth rate pregnancy outcomes, including implantation rate, pregnancy rate, live birth
rate and miscarriage rate or we performed the meta-analysis just on the data
3.7.1. The live birth rate in quasi-experimental studies extracted from these subgroups. We conducted a widespread literature
The live birth rate in quasi-experimental studies was significantly search according to the latest guidelines for conducting and reporting sys-
increased in the RIF women treated with PBMCs compared to the tematic reviews and among studies written in English and Persian. In this
control group (OR = 1.80; 95 % CI = 1.05, 3.10; P = 0.03). study, we analyzed the studies in two subgroups according to their study
Interestingly, there was no heterogeneity among these studies (I2 = 0 design; randomized control trial and non-randomized control trial. Yoshika
%; Fig. 6). for the first time, based on the idea that PBMC regulates the cross-talk be-
tween endometrium and embryo used PBMC to increase pregnancy out-
comes in women with RIF (Yoshioka et al., 2006). Although the exact ef-
3.7.2. Live birth rate in RCTs fects of PBMC are not known but some suggestions are mentioned bellow:
Among RCTs, only Yu et al. (Yu et al., 2016) reported live birth rate, PBMC can facilitate embryo attachment and invasion through increasing
so it could not be evaluated by meta-analysis. According to this study, endometrial differentiation (Yu et al., 2015). PBMC induces the desirable
live birth rate was significantly increased in the RIF women treated inflammatory condition in implantation site (Madkour et al., 2016). Pro-
with PBMCs compared to the control group (17.11 % and 7.04 %, re- tease released by PBMC changes the function and structure of surface mo-
spectively). lecules on endometrial epithelial cells (Fujiwara et al., 2016), PBMC create a
guided pathway for attachment and invasion of the embryo through its
movement toward the stromal tissue of endometrium (Fujiwara et al.,
Fig. 2. Forrest plot for the effect of PBMC-therapy on implantation rate in Quasi-experimental studies. (CI: Confidence Interval, PBMC: Peripheral Blood
Mononuclear Cell).
Fig. 3. Forrest plot for the effect of PBMC-therapy on implantation rate in Randomized Controlled Trial (RCT) studies. (CI: Confidence Interval, PBMC: Peripheral
Blood Mononuclear Cell).
5
Fig. 4. Forrest plot for the effect of PBMC-therapy on pregnancy rate in Quasi-experimental studies. (CI: Confidence Interval, PBMC: Peripheral Blood Mononuclear
Cell).
Fig. 5. Forrest plot for the effect of PBMC-therapy on pregnancy rate in Randomized Controlled Trial (RCT) studies. (CI: Confidence Interval, PBMC: Peripheral
Fig. 6. Forrest plot for the effect of PBMC-therapy on live birth rate in Quasi-experimental studies. (CI: Confidence Interval, PBMC: Peripheral Blood Mononuclear
Cell).
2009). The function of PBMCs promoted when cultured at the presence of PBMC was co-cultured with other hormones such as CHR (Makrigiannakis
HCG (Nakayama et al., 2002). PBMC function regulated by sugar side chain et al., 2015, 2019) and HMG (Madkour et al., 2016).
receptors of HCG (Kosaka et al., 2002), PBMCs stimulating to produce After duplication removing and methodological quality assessment
chemo-attractant factors and so the enhancement of BeWo cell invasion is only 5 related studies remained and included in our review. All included
another effect of HCG (Egawa et al., 2002). Murine blastocyst attachment studies that examined implantation and pregnancy rates showed positive
improved by HCG-activated PBMCs (Nakayama et al., 2002). In addition to effects of this treatment on women with at least three IVF/ET failures. The
increasing inflammatory condition suitable for embryo implantation, HCG- live birth rate was evaluated in all of the studies except than one of them
treated PBMC can subsequently provide a favorable tolerated condition for (Madkour et al., 2016) and reported that PBMC-therapy can significantly
semi-allograft embryo development (Schumacher et al., 2013). In the stu- increase the live birth rate in these women. Only one study assessed the
dies that we examined, in addition to HCG (Li et al., 2017; Yu et al., 2016), effect of this treatment on miscarriage rate (Madkour et al., 2016), and
Fig. 7. Forrest plot for the effect of PBMC-therapy on miscarriage rate in Randomized Controlled Trial (RCT) studies. (CI: Confidence Interval, PBMC: Peripheral
6
therefore, more studies are still required to provide definite and reliable treatment by offering free assisted reproductive services in order to
results. The heterogeneity between studies was determined by the I2 test evaluate the exact effects of this cell therapy. Moreover, to precisely
and was significantly high in meta-analysis results of implantation rate in evaluate the inflammatory manifestations, it is recommended to per-
quasi-experimental studies and miscarriage rate in RCTs (70 % and 80 % form endometrial sampling to study the inflammatory effects of these
respectively); hence, application and interpretation of these data need cells.
more caution. As we mentioned before, included studies also evaluated the
effect of PBMC-therapy in women with less than three IVF/ET failures but 5. Conclusions
there were no significant positive results in these groups of women.
Three studies in the abstract section reported a significant increase In conclusion, although the involved mechanisms of the therapeutic
in pregnancy rate after intrauterine PBMC-therapy (Motamedi et al., effects of these cells are not exactly understood, the results of this re-
2016; Kremenska et al., 2010; Chakravarty et al., 2018) but their data view and other studies discussed in the previous section confirm that
was not clear enough to be evaluated in the current systematic review. intrauterine administration of autologous PBMCs can improve the im-
Sudoma et al. assessed the effect of PBMCs in RIF women in different plantation, pregnancy, and live birth. More studies are still required to
studies published in the abstract. They showed that intrauterine ad- gain a clear conclusion of the effect of these therapies on miscarriage
ministration of the mixture of cultured and fresh PBMCs in women with rate and even on the other pregnancy outcomes.
a high prevalence of Th-2, significantly increased the implantation and
pregnancy rates than those women with the prevalence of Th-1 and 6. Recommendations for search
normal Th-1/ Th-2 ratio (Sudoma et al., 2009). Sudoma et al. also in
2011, in two different studies revealed that intrauterine application of In the current systematic review, one of our limitations was that we
PBMCs had significantly positive effects on pregnancy rate when failed to contact the author of abstract articles. It is suggested that fu-
combined with IVIg, which was administered on the day of embryo ture studies find a way to contact successfully to the authors of such
transfer (Sudoma et al., 2011a,b). Two studies by Makrigiannakis et al. studies. As the heterogeneity between studies was too high in some
did not match to our inclusion criteria because they used the data of the meta-analysis results between studies, maybe due to the difference in
previous null pregnancy of women as the control group. In one of them sample sizes, it is suggested that a further review be carried out in fu-
blastocyst stage (day 5) embryo and in another one cleavage stage (day ture after more original studies have been published in this field. In this
3) embryo was transferred after PBMC-therapy; both studies expressed way, by evaluating more studies and increasing the likelihood of sample
positive results on the pregnancy rate (44.44 % and 57.69 %, respec- size similarities, the heterogeneity will probably decrease. We re-
tively) in women with at least three IVF failures (Makrigiannakis et al., commended these future studies by subgrouping patients (cleavage
2015) (Makrigiannakis et al., 2019). Another positive effect of in- stage embryo versus blastocyst stage, freshly isolated PBMC versus co-
trauterine administration of autologous PBMC is that it may improve cultured PBMC, primary versus secondary infertility), determine pa-
the endometrial receptivity through increasing the total uNK cells po- tients who may benefit more from PBMC-therapy studies in order to
pulation (Penkova et al., 2018). indicate the best form of treatment with the most positive effect on
This study has some limitations. Firstly, we could not contact the pregnancy outcomes. Additionally, immunologic factors examination
authors of abstract articles, and secondly, the number of eligible studies before and after intervention can be effective in this regard.
was low. Although intrauterine injection of PBMCs has had positive
effects on pregnancy outcomes, more studies are recommended with Declaration of Competing Interest
focus on the women with more implantation failures (> three). Control
groups were women who had not received any treatment or interven- The authors declare no conflict of interest.
tion, on the other hand, endometrial trauma, as done by endometrial
scratch, increases implantation rates, so it could be the trauma of in- Acknowledgments
jecting cells into the uterine cavity that improved success rates. Thus,
there is no convincing evidence provided that PBMCs are required to be This review was conducted under the supervision of Research
infused into the uterine lumen to improve implantation rates. It is Center for Evidence-Based Medicine, in Tabriz University of Medical
suggested to encourage the susceptible women to received placebo Sciences without receiving any fund.
Appendix A. Search strategy
Embase Search conducted on July 2018.
No Query Result
#1 'recurrent implantation failure'/exp 79

#2 'recurrent implantation failure'/exp 2,308
#3 repeated AND implantation AND failure:ab,ti 1265
#4 'repeated implantation failure'/exp 61
#5 multiple AND implantation AND failure:ab,ti 2,473
#6 'mif':ab,ti 6,572
#7 rif:ab,ti 5,460
#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 16,909
#9 'peripheral blood mononuclear cell'/exp 57,029
#10 peripheral AND blood AND mononuclear AND cell:ab,ti 57,340
#11 'pbmc'/exp 57,029
#12 'pbmc':ab,ti 29,730
#13 'lymphocyte transfusion'/exp 1,152
#14 lymphocyte AND transfusion:ab,ti 4,419
#15 lymphocyte AND therapy:ab,ti 114,111
#16 lymphocyte AND insemination:ab,ti 114
#17 lymphocyte AND injection:ti,ab 25,319
7
#18 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 217,558
#19 #8 AND #18 449
#20 'pregnancy'/exp 726,897
#21 'pregnancy':ab,ti 467,737
#22 'implantation'/exp 129,937
#23 'implantation':ti,ab 221,387
#24 'miscarriage'/exp 39,130
#25 'miscarriage':ab,ti 15,827
#26 'live birth'/exp 26,920
#27 live AND birth:ti,ab 26,920
#28 #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 1,141,706
#29 #19 AND #28 111
Appendix B. Studies excluded on full text
Studies excluded on full text
1 Study (Kremenska et al., P-267 Cytokines and hormone receptors gene expression in peripheral blood mononuclear cells of women with multiple implantation failures
2010) in Art cycles.
Reason for exclusion Only abstract was available so we could not extract reliable data
2 Study (Makrigiannakis et al., Repeated implantation failure: a new potential treatment option.
2015)
Reason for exclusion It was not match to our inclusion criteria. Their control was the past null pregnancies of patients.
3 Study (Sefrioui et al., 2014) Immunotherapy of patients with repeated implantation failures in randomized controlled design and its impact on luteal progesterone
synthesis.
Reason for exclusion It was a poster and it is also similar to madkour et al. study
4 Study (Sudoma et al., 2009) Administration of intrauterine autologous peripheral blood mononuclear cells in patients with multiple implantation failures: Correlation with
peripheral blood Th1/Th2 ratio and PBMC cell gene expression
5 Study (Sudoma et al., 2011a) Comparison of intrauterine autologous peripheral blood mononuclear cells administration, intravenous immunoglobulin and combination of
two methods in the management of multiple ART failures
6 Study (Sudoma et al., Molecular-genetic and immunological features of peripheral blood mononuclear cells (PBMCs) and their correlation with the success of
2011b) intrauterine administration of autologous PBMCs and intravenous immunoglobulin (IVIG) in patients with multiple unsuccessful ART
programs
7 Study (Chakravarty et al., Intrauterine infusion of autologous peripheral blood mononuclear cells in frozen blastocyst transfer improves clinical outcome and
2018) metabolomic profile in repeated implantation failure-a pilot study
8 Study (Makrigiannakis et al., Intrauterine CRH-treated PBMC in repeated implantation failure
2019)
Reason for exclusion It was not match to our inclusion criteria. Their control was the past null pregnancies of patients.
Appendix C. Characteristics of included studies
Table C1
Characteristics of included studies.
Author Year Total number of Study design (Women Intervention Comparator (Women PBMCs Number of Reference
participants with…….. IVF-ET undergoing ET….) activator administered cells
failure)
1 Yoshioka et al 2006 n: 35 Four or more Intrauterine Without previous hCG 2 × 107 (Yoshioka
Study group: 17 administration of PBMC administration et al., 2006)
Control group:18 PBMCs
2 Okitsu et al 2011 n: 253 One or two Intrauterine Without previous 3 × 107 (Okitsu et al.,
Study group: 83 administration of PBMC administration 2011)
Control Three or more PBMCs
group:170
3 Madkour et al 2016 n: 54 At least two Intrauterine Without previous HMG- 1 × 107 (Madkour et al.,
Study group: 27 administration of PBMC administration Menoupur 2016)
Control group: 27 At least three PBMCs
4 Yu et al 2016 n: 240 Three or more Intrauterine Without previous hCG 1−2 × 107 (Yu et al.,
Study group: 93 administration of PBMC administration 2016)
Control PBMCs
group:105
5 Li et al 2017 n: 633 One Intrauterine Without previous hCG 1−2 × 107 (Li et al., 2017)
Study group: 294 administration of PBMC administration
Control Two PBMCs
group:339 Three
Four or more
PBMC: Peripheral Blood Mononuclear Cell, hCG: human Chorionic Gonadotropin, HMG: Human Menopausal Gonadotropin, IVF: In Vitro Fertilization, ET: Embryo
Transfer.
8
Table C2
Characteristics of included studies.
Author Year Out Comes
Number of IVF Implantation rate Pregnancy rate Live birth rate Miscarriage rate
failure
I C I C I C I C
1 Yoshioka et al 2006 Four or more 23.4 % 4.1 % 41.2 % 11.1 % 12.76 2.04 % – –
(11/47) (2/49) (7/17) (2/18) (6/47) (1/49)
2 Okitsu et al 2011 One or more 21.6 % (29/ 21.1 % (56/ 34.9 %(29/ 32.9 % (56/ 13.4 % (18/ 13.9 % (37/ – –
134) 266) 83) 170) 134) 266)
One or two 21 % (21/100) 24.8 % (50/ 32.8 % (21/ 37.3 % (50/ 14.0 % (14/ 16.3 % (33/ – –
202) 64) 134) 100) 202)
Three or more 25 % 9.38 % 42.1 % 16.7 % 12.5 % 6.3 % – –
(8/32) (6/64) (8/19) (6/36) (4/32) (4/64)
3 Madkour et al 2015 At least two 21.54 % 8.62 % 44.44 % 14.81 % – – 17 % 75 %
(14/65) (5/58) (12/27) (4/27) (5/27) (20/27)
At least three 35 % 14 % 70 % 24 % – – 14.29 % 75 %
(8/23) (5/37) (7/10) (4/17) (1/10) (13/17)
4 Yu et al 2016 Three or more 11.76 % 5.63 % 46.24 % 20.95 % 17.11 % 7.04 % 20.9 % 31.8 %
(22/187) (12/213) (43/93) (22/105) (32/187) (15/213) (19/93) (33/105)
5 Li et al 2016 One 29.35 % 32.33 % 43.75 % 41.23 % 19.57 % 18.10 % – –
(27.92) (75/233) (21.48) (47/114) (18/92) (42/233)
Two 35.98 % 27.74 % 48.15 % 42.18 % 17.29 % 16.78% – –
(77/214) (81/293) (52/108) (62/147) (37/214) (49/293)
Three 23.20 % 26.23 % 42.22 % 36.84 % 14.36 % 12.50 % – –
(42/181) (29/112) (38/90) (21/57) (26/181) (14/112)
Four or more 22 % 4.88 % 39.58 % 14.29 % 16 % 4.88 % – –
(22/100) (2/41) (19/48) (3/21) (16/100) (2/41)
I: intervention, C: control, IVF: In Vitro Fertilization.
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10

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Journal of Reproductive Immunology 137 (2020) 103077

Contents lists available at ScienceDirect

Journal of Reproductive Immunology

Efficacy of intrauterine administration of autologous peripheral blood T

ARTICLE INFO ABSTRACT

1. Introduction a morphologically low-quality embryo can reduce the implantation

3.5. Implantation rate 3.6. Pregnancy rate

3.5.2. Implantation rate in RCTs 3.6.2. The pregnancy rate in RCTs

Table 2 3.8. Miscarriage rate

Appendix A. Search strategy

Embase Search conducted on July 2018.

#1 'recurrent implantation failure'/exp 79

Appendix B. Studies excluded on full text

Studies excluded on full text

Appendix C. Characteristics of included studies

I: intervention, C: control, IVF: In Vitro Fertilization.

References Bahceci, M., 2014. Intrauterine administration of autologous mononuclear cells

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