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Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: a systematic review and meta-analysis

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

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

  1. 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

  2. Accessed HFEA (2018) HFEA fertility treatment in 2016: trends and figures. https://www.hfea.gov.uk. Accessed Mar 2018

  3. 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

    Article  PubMed  Google Scholar 

  4. 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

    Article  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  PubMed  Google Scholar 

  7. Revel A (2012) Defective endometrial receptivity. Fertil Steril 97(5):1028–1032. https://doi.org/10.1016/j.fertnstert.2012.03.039

    Article  PubMed  Google Scholar 

  8. 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

    Article  PubMed  Google Scholar 

  9. 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

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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

    Article  Google Scholar 

  11. 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

    Article  CAS  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  Google Scholar 

  14. 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

    Article  CAS  Google Scholar 

  15. 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

    Article  Google Scholar 

  16. 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

    Google Scholar 

  17. 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

    Google Scholar 

  18. 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

    Article  Google Scholar 

  19. 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

    Article  Google Scholar 

  20. 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

    Article  Google Scholar 

  21. 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

    Article  Google Scholar 

  22. 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

    Article  Google Scholar 

  23. 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

    Article  Google Scholar 

  24. Nan Y (2014) Research of intrauterine administration of peripherl blood mononuclear cells (PBMCs)’s improvement on embryonic implantation. Doctorate thesis, WuHan University

  25. 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

    Article  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  Google Scholar 

  31. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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

    Article  CAS  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  Google Scholar 

  35. 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

    Article  CAS  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  Google Scholar 

  38. Lessey BA (2011) Assessment of endometrial receptivity. Fertil Steril 96(3):522–529. https://doi.org/10.1016/j.fertnstert.2011.07.1095

    Article  CAS  PubMed  Google Scholar 

  39. 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

  40. 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

    Article  CAS  Google Scholar 

  41. 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

    Article  Google Scholar 

  42. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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

    Article  CAS  Google Scholar 

  44. 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

    Article  CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  Google Scholar 

  46. 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

    Article  CAS  Google Scholar 

  47. 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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

There was no funding received for the creation and completion of this work.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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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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Correspondence to Xuehong Zhang.

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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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