Abstract
Purpose
Recurrent implantation failure (RIF) is a common cause of disappointment and a big challenge after assisted reproduction technology treatments. The objective of this study was to evaluate the existing literature to explore whether peripheral blood mononuclear cells’ (PBMCs) instillation could improve pregnancy outcomes among patients with RIF.
Methods
We conducted a comprehensive search including PubMed, EMBASE, Cochrane library and various databases in China. Three randomized controlled trials (RCTs) and three non-randomized controlled trials (non-RCTs) were included. We included subgroup and sensitivity analyses using Stata 12.0.
Results
The results of the three RCTs showed that PBMC improved outcomes in all patients compared with placebo or no-treatment [clinical pregnancy rate (CPR): odds ratio (OR) 2.45, 95% confidence interval (CI) 1.53–3.91; implantation rate (IR): OR 2.46, 95% CI 1.48–4.09; live birth rate (LBR): OR 2.43, 95% CI 1.32–4.49]. However, the results of the three non-RCTs indicated that there were no statistically significant differences in the outcomes and that the heterogeneity was higher (I2 > 0%). Subgroup analysis further suggested that PBMCs treatment significantly increased the CPR, IR and LBR in the three or more implantation failure subgroups (CPR: OR 2.83, 95% CI 1.29–6.22; IR: OR 3.74, 95% CI 1.71–8.19; LBR: OR 3.03, 95% CI 1.15–7.98).
Conclusions
Among patients with three or more implantation failures, this treatment improved IR, LBR, and CPR compared to that in controls, due to the limited data available, PBMCs’ intrauterine instillation should only be used in the context of clinical trials.
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References
Accessed CAR (2011) Canadian ART Register (CARTR) latest annual figures. https://www.cfas.ca/index.php?option=com_content&view=article&id=1129%. Accessed Mar 2018
Accessed HFEA (2018) HFEA fertility treatment in 2016: trends and figures. https://www.hfea.gov.uk. Accessed Mar 2018
Kushnir VA, Vidali A, Barad DH, Gleicher N (2013) The status of public reporting of clinical outcomes in assisted reproductive technology. Fertil Steril 100(3):736–741. https://doi.org/10.1016/j.fertnstert.2013.05.012
Zeyneloglu HB, Onalan G (2014) Remedies for recurrent implantation failure. Semin Reprod Med 32(4):297–305. https://doi.org/10.1055/s-0034-1375182
Thornhill AR, deDie-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN, Sermon KD, Wilton L (2005) ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)’. Hum Reprod 20(1):35–48. https://doi.org/10.1093/humrep/deh579
Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ (2014) What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod Biomed Online 28(4):409–423. https://doi.org/10.1016/j.rbmo.2013.12.006
Revel A (2012) Defective endometrial receptivity. Fertil Steril 97(5):1028–1032. https://doi.org/10.1016/j.fertnstert.2012.03.039
Blesa D, Ruiz-Alonso M, Simon C (2014) Clinical management of endometrial receptivity. Semin Reprod Med 32(5):410–413. https://doi.org/10.1055/s-0034-1376360
Teh WT, McBain J, Rogers P (2016) What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet 33(11):1419–1430. https://doi.org/10.1007/s10815-016-0773-6
Egawa H, Fujiwara H, Hirano T, Nakayama T, Higuchi T, Tatsumi K, Mori T, Fujii S (2002) Peripheral blood mononuclear cells in early pregnancy promote invasion of human choriocarcinoma cell line, BeWo cells. Hum Reprod (Oxf, Engl) 17(2):473–480
Kosaka K, Fujiwara H, Tatsumi K, Yoshioka S, Higuchi T, Sato Y, Nakayama T, Fujii S (2003) Human peripheral blood mononuclear cells enhance cell–cell interaction between human endometrial epithelial cells and BeWo-cell spheroids. Hum Reprod (Oxf, Engl) 18(1):19–25
Yu N, Zhang B, Xu M, Wang S, Liu R, Wu J, Yang J, Feng L (2016) Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG improves the implantation and pregnancy rates in patients with repeated implantation failure: a prospective randomized study. Am J Reprod Immunol 76(3):212–216. https://doi.org/10.1111/aji.12542
Madkour A, Bouamoud N, Louanjli N, Kaarouch I, Copin H, Benkhalifa M, Sefrioui O (2016) Intrauterine insemination of cultured peripheral blood mononuclear cells prior to embryo transfer improves clinical outcome for patients with repeated implantation failures. Zygote (Cambridge, England) 24(1):58–69. https://doi.org/10.1017/S0967199414000719
Makrigiannakis A, Benkhalifa M, Vrekoussis T, Mahjub S, Kalantaridou SN, Gurgan T (2015) Repeated implantation failure: a new potential treatment option. Eur J Clin Investig 45(4):380–384. https://doi.org/10.1111/eci.12417
Stamenov G, Parvanov D, Vasileva M, Nikolova K, Chaushev T (2017) Successful treatment with autologous human peripheral blood mononuclear cells in three women with displaced window of implantation. J Assist Reprod Genet 34(10):1398. https://doi.org/10.1007/s10815-017-1055-7
Chen LN, Quan S, Li H, Chen SM, Zhang WQ, Luo C, Song YL, Xing FQ (2011) Frozen embryo transfer combined with intrauterine administration of autologous peripheral blood mononuclear cells for repeated implantation failure: report of 3 cases. J South Med Univ 31(4):724–726
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ Br Med J 343(7829):889–893
Stang A (2010) Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605
Yanghong L, Jing Z, Lian L, Xiaobo S (2017) Effect of intrauterine administration of autologous peripheral blood mononuclear cells on pregnancy outcomes in patients with recurrent implantation failure and the related mechanism. Chin J Reprod Contracep 37(7):539–544. https://doi.org/10.3760/cma.j.issn.2096-2716.2017.07.004
Sudoma I, Goncharova Y, Masliy Y (2011) Comparison of intrauterine autologous peripheral blood mononuclear cells administration, intravenous immunoglobulin and combination of two methods in the management of multiple ART failures. Am J Reprod Immunol 65:32–33. https://doi.org/10.1111/j.1600-0897.2011.01013.x
Makrigiannakis A (2011) New approaches in treating recurrent implantation failures. Reprod Biomed Online 22:S105. https://doi.org/10.1016/S1472-6483(11)60045-X
Kremenska Y, Masliy Y, Goncharova Y, Kremenskoy M, Veselovskyy V, Zukin V, Sudoma I (2010) Cytokines and hormone receptors gene expression in peripheral blood mononuclear cells of women with multiple implantation failures in ART cycles. Hum Reprod 25:i219–i220. https://doi.org/10.1093/humrep/de.25.s1.242
Sefrioui O, Madkour A, Louanjli N, Ahbbas L, Aboulmaouahib S, Nait Ouhmane F (2014) Immunotherapy of patients with repeated implantation failures in randomized controlled design and its impact on luteal progesterone synthesis. Hum Reprod 29:i127–i128. https://doi.org/10.1093/humrep/29.Supplement_1.1
Nan Y (2014) Research of intrauterine administration of peripherl blood mononuclear cells (PBMCs)’s improvement on embryonic implantation. Doctorate thesis, WuHan University
Sudoma I, Mykytenko D, Goncharova Y, Masliy Y, Kremens'ka Y, Dons'koy B, Pylyp L (2011) Molecular-genetic and immunological features of peripheral blood mononuclear cells (PBMCs) and their correlation with the success of intrauterine administration of autologous PBMCs and intravenous immunoglobulin (IVIG) in patients with multiple unsuccessful ART programs. J Reprod Immunol 90(2):179–180. https://doi.org/10.1016/j.jri.2011.06.090
Ginsburg ES, Xiao L, Gargiulo AR, Kung FT, Politch JA, Schust DJ, Hill JA (2005) T-helper 2 and 3 type immunity to trophoblast in successful in vitro fertilization-embryo transfer. Fertil Steril 83(6):1659–1664. https://doi.org/10.1016/j.fertnstert.2004.12.038
Yoshioka S, Fujiwara H, Nakayama T, Kosaka K, Mori T, Fujii S (2006) Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF-embryo transfer. Hum Reprod 21(12):3290–3294. https://doi.org/10.1093/humrep/del312
Li S, Wang J, Cheng Y, Zhou D, Yin T, Xu W, Yu N, Yang J (2017) Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol 119:15–22. https://doi.org/10.1016/j.jri.2016.11.006
Okitsu O, Kiyokawa M, Oda T, Miyake K, Sato Y, Fujiwara H (2011) Intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol 92(1–2):82–87. https://doi.org/10.1016/j.jri.2011.07.001
Qi L, Ruochun L, Xian C, Cuicui L, Lianhui D, Chungyu H (2013) Effect of intrauterine administration of peripheral blood mononuclear cell on the pregnancy outcome of patients with recurrent implantation failure. J Reprod Med 22(12):922–926. https://doi.org/10.3969/j.issn.1004-3845.2013.12.006
Mor G, Cardenas I, Abrahams V, Guller S (2011) Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 1221:80–87. https://doi.org/10.1111/j.1749-6632.2010.05938.x
Kalu E, Bhaskaran S, Thum MY, Vishwanatha R, Croucher C, Sherriff E, Ford B, Bansal AS (2008) Serial estimation of Th1:th2 cytokines profile in women undergoing in-vitro fertilization-embryo transfer. Am J Reprod Immunol (New York, NY: 1989) 59(3):206–211. https://doi.org/10.1111/j.1600-0897.2007.00565.x
Kwak-Kim JYH, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, Beer AE, Gilman-Sachs A (2003) Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod 18(4):767–773. https://doi.org/10.1093/humrep/deg156
Yin B, Zeng Y (2017) Functional properties of peripheral CD8(+) T cells in patients with repeated implantation failure. Am J Reprod Immunol 78(2):Suppl A. https://doi.org/10.1111/aji.12704
Saito S, Nakashima A, Shima T, Ito M (2010) Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol (New York, NY: 1989) 63(6):601–610. https://doi.org/10.1111/j.1600-0897.2010.00852.x
Hammer A (2011) Immunological regulation of trophoblast invasion. J Reprod Immunol 90(1):21–28. https://doi.org/10.1016/j.jri.2011.05.001
Hashii K, Fujiwara H, Yoshioka S, Kataoka N, Yamada S, Hirano T, Mori T, Fujii S, Maeda M (1998) Peripheral blood mononuclear cells stimulate progesterone production by luteal cells derived from pregnant and non-pregnant women: possible involvement of interleukin-4 and interleukin-10 in corpus luteum function and differentiation. Hum Reprod 13(2):2738–2744
Lessey BA (2011) Assessment of endometrial receptivity. Fertil Steril 96(3):522–529. https://doi.org/10.1016/j.fertnstert.2011.07.1095
Guo Y (2017) Effects of human PBMC on endometrial receptivity-related makers and embyro implantation in patients with repeated implantation failures. Master thesis, Zhengzhou University
Yu N, Yang J, Guo Y, Fang J, Yin T, Luo J, Li X, Li W, Zhao Q, Zou Y, Xu W (2014) Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves endometrial receptivity in mice with embryonic implantation dysfunction. Am J Reprod Immunol (New York, NY: 1989) 71(1):24–33. https://doi.org/10.1111/aji.12150
Fujiwara H, Ideta A, Araki Y, Takao Y, Sato Y, Tsunoda N, Aoyagi Y, Konishi I (2009) Immune system cooperatively supports endocrine system-primed embryo implantation. J Mamm Ova Res 26:122–128
Yu N, Yan W, Yin T, Wang Y, Guo Y, Zhou D, Xu M, Ding J, Yang J (2015) HCG-activated human peripheral blood mononuclear cells (PBMC) promote trophoblast cell invasion. PLoS ONE 10(6):e0125589. https://doi.org/10.1371/journal.pone.0125589
Benkhalifa M, Zayani Y, Bach V, Copin H, Feki M, Benkhalifa M, Allal-Elasmi M (2018) Does the dysregulation of matrix metalloproteinases contribute to recurrent implantation failure? Expert Rev Proteom 15(4):311–323. https://doi.org/10.1080/14789450.2018.1464915
Brownbill P, McKeeman GC, Brockelsby JC, Crocker IP, Sibley CP (2007) Vasoactive and permeability effects of vascular endothelial growth factor-165 in the term in vitro dually perfused human placental lobule. Endocrinology 148(10):4734–4744. https://doi.org/10.1210/en.2007-0180
Crocker IP, Strachan BK, Lash GE, Cooper S, Warren AY, Baker PN (2001) Vascular endothelial growth factor but not placental growth factor promotes trophoblast syncytialization in vitro. J Soc Gynecol Investig 8(6):341–346
Su MT, Tsai PY, Tsai HL, Chen YC, Kuo PL (2017) miR-346 and miR-582-3p-regulated EG-VEGF expression and trophoblast invasion via matrix metalloproteinases 2 and 9. Biofactors (Oxford, England) 43(2):210–219. https://doi.org/10.1002/biof.1325
Nakayama T, Fujiwara H, Maeda M, Inoue T, Yoshioka S, Mori T, Fujii S (2002) Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: HCG enhances the effects of PBMC. Hum Reprod 17(1):207–212. https://doi.org/10.1093/humrep/17.1.207
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YW, LFL, and XHZ conceived and designed the study. YW, LFL, and XY analysed the data. YW and LL wrote the “Introduction and Discussion”. YW and PJY wrote the “Materials and methods” and “Results”. KHY and XHZ provided significant advice for the manuscript. YW and XY were primarily responsible for writing and modifying the draft.
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Wu, Y., Li, L., Liu, L. et al. Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: a systematic review and meta-analysis. Arch Gynecol Obstet 300, 1445–1459 (2019). https://doi.org/10.1007/s00404-019-05275-w
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DOI: https://doi.org/10.1007/s00404-019-05275-w