hCG-activated PBMC-therapy in RIF Patients

Recurrent Implantation Failure Clinical Trial

Official title:

Intrauterine Administration of Autologous hCG-activated Peripheral Blood Mononuclear Cells Improves Pregnancy Outcomes in Patients With Recurrent Implantation Failure; a Double-blind Randomized Control Trial Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03267797
• Other study ID #: SCARM-infertility-004
• Status: Completed
• Phase: N/A
• Start date: October 7, 2017
• Est. completion date: July 11, 2019

Study information

• Verified date: August 2019
• Source: SCARM Institute, Tabriz, Iran
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Despite the many research done in the field of infertility and in vitro fertilization (IVF), more than half of the embryos transmitted in the IVF and intracytoplasmic sperm injection (ICSI) do not implant successfully. Currently, pregnancy failure following at least three IVF/ET cycle, so that one or two high-quality embryos transmitted in each cycle is defined as recurrent implantation failure (RIF). Maternal and fetal factors can be a reason for implantation failure; maternal factors include endometrial receptivity, uterine anatomic abnormalities, and immunologic factors. Implantation failure with embryonic reasons includes genetic abnormalities and any factor that affects the implantation and growth of the embryo within the uterus. In recent years, the involvement of immune-related factors mainly natural killer cells (NK), dendritic cells (DCs), macrophages (MQ), regulatory T cells (Treg) and Th-1, in the endometrial differentiation and development and endometrial receptivity, as well as induction of immunological tolerance to the fetus, have been reported.

Description:

248 women with the history of implantation failure volunteered to receive PBMC-therapy. After immunologic consultation and doing flow cytometry analysis, 100 women with at least three IVF/ET failure who had low Th-17/Treg ratio in comparison with healthy control were enrolled in this study. These 100 patients divided randomly into two groups, 50 patients received PBMC and 50 patients as the control group received PBS. PBMCs were obtained from patients themselves five days before embryo transfer (ET) and were cultured with hCG for 48 hours. Frothy-eight hours later, PBMCs were then administered into the uterine cavity of that patient from the study group two days before ET. PBS was inseminated into the uterine cavity of the control group instead of PBMC. The concentration of inflammatory cytokines was examined in the supernatant of cultured PBMCs 2, 24 and 48 hour after incubation by ELISA. The pregnancy occurrence was confirmed 12 days after ET through positive pregnancy test (β-hCG test). The success of implantation and the occurrence of clinical pregnancy were evaluated by ultrasound through the observation of the number and the location of gestational sacs at 5-6 weeks and confirming the embryo heart pulsation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: July 11, 2019
• Est. primary completion date: September 25, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 20 Years to 45 Years

Eligibility

All patients were evaluated in accordance with the following inclusion and exclusion criteria;

Inclusion Criteria:

1. Having at least three implantation failures following IVF

2. Having primary infertility

3. Age under 45 years old

4. Having regular menstrual cycles

5. BMI under 30

Exclusion Criteria:

1. Having polycystic ovary syndrome

2. The presence of uterine pathology;

3. Poor ovarian reserve

4. Having chromosomal abnormalities

5. Presence of auto anti-bodies such as anti-TPO, anti-TG, ACA, APA, ANA, and anti-dsDNA

6. Presence of mutations involving the coagulation system such as deficiency of factor XII, Pro C, Pro S

7. Positive HIV, HCV or HBV tests

Related Conditions & MeSH terms

• Recurrent Implantation Failure

Intervention

Other:
• Peripheral Blood Monouclear Cell
Blood samples (20 mL) were taken from individual patients at the time of ovulation induction. Then PBMC were isolated and cultured (20-30 million cells) 48 hour at the presence of hCG (10IU/ml daily). Afterward,15-20 million PBMCs in 500 microlitres PBS were injected into the uterine cavity two days before embryo transfer (ET) using ET catheter.
• Phosphate Baffer Saline
Only 500 microlitres PBS will be injected into the uterine cavity, instead of PBMCs, two days before embryo transfer (ET) using ET catheter.

Locations

Country	Name	City	State
Iran, Islamic Republic of	Valiasr Hospital	Tabriz

Sponsors (1)

Lead Sponsor	Collaborator
SCARM Institute, Tabriz, Iran

Country where clinical trial is conducted

Iran, Islamic Republic of, 

References & Publications (15)

Al-Azemi M, Raghupathy R, Azizieh F. Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. Clin Exp Obstet Gynecol. 2017;44(1):98-103. — View Citation

Bulmer JN, Longfellow M, Ritson A. Leukocytes and resident blood cells in endometrium. Ann N Y Acad Sci. 1991;622:57-68. Review. — View Citation

Chaouat G, Lédée-Bataille N, Zourbas S, Ostojic S, Dubanchet S, Martal J, Frydman R. Cytokines, implantation and early abortion: re-examining the Th1/Th2 paradigm leads to question the single pathway, single therapy concept. Am J Reprod Immunol. 2003 Sep; — View Citation

Chou CH, Chen SU, Shun CT, Tsao PN, Yang YS, Yang JH. Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device. Sci Rep. 2015 Oct 15;5:15157. doi: 10.1038/srep15157. — View Citation

Granot I, Gnainsky Y, Dekel N. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction. 2012 Dec;144(6):661-8. doi: 10.1530/REP-12-0217. Epub 2012 Oct 1. Review. — View Citation

Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online. 2004 Dec;9(6):692-715. Review. — View Citation

Ideta A, Sakai S, Nakamura Y, Urakawa M, Hayama K, Tsuchiya K, Fujiwara H, Aoyagi Y. Administration of peripheral blood mononuclear cells into the uterine horn to improve pregnancy rate following bovine embryo transfer. Anim Reprod Sci. 2010 Jan;117(1-2): — View Citation

Kosaka K, Fujiwara H, Tatsumi K, Yoshioka S, Higuchi T, Sato Y, Nakayama T, Fujii S. Human peripheral blood mononuclear cells enhance cell-cell interaction between human endometrial epithelial cells and BeWo-cell spheroids. Hum Reprod. 2003 Jan;18(1):19-2 — View Citation

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348-57. — View Citation

Nakayama T, Fujiwara H, Maeda M, Inoue T, Yoshioka S, Mori T, Fujii S. Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: HCG enhances the effects of PBMC. Hum Reprod. 2002 Jan;17(1):207-12. — View Citation

Okitsu O, Kiyokawa M, Oda T, Miyake K, Sato Y, Fujiwara H. Intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failu — View Citation

Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril. 2012 May;97(5):1039-43. doi: 10.1016/j.fertnstert.2012.03.010. Epub 2012 Mar 30. Review. — View Citation

Tomassetti C, Meuleman C, Pexsters A, Mihalyi A, Kyama C, Simsa P, D'Hooghe TM. Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link? Reprod Biomed Online. 2006 Jul;13(1):58-64. Review. — View Citation

Yoshioka S, Fujiwara H, Nakayama T, Kosaka K, Mori T, Fujii S. Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF-embryo transfer. Hum Reprod. 2006 Dec;21(12):3 — View Citation

Yu N, Yang J, Guo Y, Fang J, Yin T, Luo J, Li X, Li W, Zhao Q, Zou Y, Xu W. Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves endometrial receptivity in mice with embryonic implantation dysfunction. Am J Reprod Immunol. 20 — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	pregnancy occurrence	Laboratory tests (beta-hCG test)	"12 days after embryo transfer"
Primary	examination of inflammatory cytokines (IL-1B, TNF-a and INF-Y) secretion levels in supernatant	ELISA technique	"48 hours after culturing"
Secondary	Clinical pregnancy rate in patients with recurrent implantation failure (RIF)	detection the number and location of gestational sacs by ultrasound	"in 5-6 weeks"
Secondary	The live birth rate by patients with recurrent implantation failure (RIF)	By gynecologists and obstetricians will monitor	"After about 9 months of positive ßHCG test"
Secondary	The miscarriage rate in patients with recurrent implantation failure (RIF)	By gynecologists and obstetricians will monitor	"When ever during the pregnancy period (up to 9 months)"