hCG-activated PBMC-therapy in RIF Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Recurrent Implantation Failure

Intervention / Treatment
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* Other: Peripheral Blood Monouclear Cell
* Other: Phosphate Baffer Saline


Participation Criteria
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Eligibility Criteria
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All patients were evaluated in accordance with the following inclusion and exclusion criteria; Inclusion Criteria: Having at least three implantation failures following IVF Having primary infertility Age under 45 years old Having regular menstrual cycles BMI under 30 Exclusion Criteria: Having polycystic ovary syndrome The presence of uterine pathology; Poor ovarian reserve Having chromosomal abnormalities Presence of auto anti-bodies such as anti-TPO, anti-TG, ACA, APA, ANA, and anti-dsDNA Presence of mutations involving the coagulation system such as deficiency of factor XII, Pro C, Pro S Positive HIV, HCV or HBV tests

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Peripheral blood mononuclear cells (PBMCs) were administered into the uterine cavity of RIF patients in this group. | Other: Peripheral Blood Monouclear Cell<br>* 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.<br>* Other names: PBMC;|
| Placebo Comparator: Control group<br>Phosphate buffer saline (PBS) as placebo was injected into the uterine cavity of RIF patients in this group. | Other: Phosphate Baffer Saline<br>* Only 500 microlitres PBS will be injected into the uterine cavity, instead of PBMCs, two days before embryo transfer (ET) using ET catheter.<br>* Other names: PBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pregnancy occurrence | Laboratory tests (beta-hCG test) | 12 days after embryo transfer | 
| examination of inflammatory cytokines (IL-1B, TNF-a and INF-Y) secretion levels in supernatant | ELISA technique | 48 hours after culturing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate in patients with recurrent implantation failure (RIF) | detection the number and location of gestational sacs by ultrasound | in 5-6 weeks | 
| The live birth rate by patients with recurrent implantation failure (RIF) | By gynecologists and obstetricians will monitor | After about 9 months of positive βHCG test | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent Implantation Failure, Peripheral blood mononuclear cell, Human chorionic gonadotropin