Immune Profile Analysis and Biomarker Identification in Women With Repeated Implantation Failure or Unexplained Recurrent Spontaneous Miscarriage

Implantation is a determining step in human reproduction which requires the transition from a pro-inflammatory state to an anti-inflammatory state allowing the implantation of a competent embryo within a receptive endometrium, and then the maternal immunotolerance towards the alloantigenic fetus. Repeat implantation failures (RIFs), that refers to the fail to achieve a clinical pregnancy after the transfer of at least 3-4 good quality embryos or two blastocysts, and unexplained recurrent spontaneous miscarriage (RM) (≥2-3) could be related in some patients to immune imbalances characterized by an excessive and prolonged inflammatory response and/or a defect of anti-inflammatory regulation. In this context, several therapies have been evaluated in patients with RIFs or RMs in order to restore the immune balance, with heterogeneous results. No serum biomarker assay has been routinely approved to identify patients with immune imbalances that may explain repeated pregnancy failures and to predict the success of the subsequent IVF/ICSI cycle. The immunological analysis on peripheral blood will be based on the determination of the proportions of immune subpopulations (e.g. CD4+ et CD8+, TH1, TH2, TH17, Treg, ILC 1, ILC2, and ILC3) on the one hand and the circulating level of plasma cytokines on the other hand.

Inclusion Criteria:For patients :Women aged 18 to 39 yearswomen with a history of RIF or unexplained RMwomen with a negative diagnostic work-up (including pelvic ultrasound and hysteroscopy, parental karyotype, thyroid function test, and anti-thyroid and anti-phospholipid antibodies)women with a basal FSH level <10IU/l and AMH level >1.5ng/mlwomen with a regular menstrual cycle of 30+/-5 dayswomen receiving a new cycle of in vitro fertilization (IVF) +/- intracytoplasmic sperm injection (ICSI) for patients in the RIF group or a first cycle of IVF +/-ICSI for patients in the RM groupwomen received written and oral information and signed an informed consentFor control groups:Controls recruited in the Obstetrics and Gynecology Department with at least one live birth after a spontaneous pregnancy (with a time to conception of less than 12 months for each pregnancy) Voluntary oocyte donors recruited within the CECOS de Picardie (having presented at least one live birth with a delay necessary to conceive of less than 12 months)Controls recruited in the Reproductive Medicine and Biology Department having presented at least one live birth (spontaneous with a delay to conceive of less than 12 months for each pregnancy or after one or two MPA procedures) and benefiting from an IVF+/-ICSI procedure for secondary infertilityControls recruited in the department of Medicine and Reproductive Biology with a normal infertility assessment and benefiting from an IVF procedure with ICSI on male indication.Exclusion Criteria:Ongoing pelvic and/or systemic infectionChronic infectious endometritisActive neoplasiaAutoimmune and autoinflammatory diseaseCeliac diseaseThrombophilia (including positive anti-phospholipid antibodies)Endocrine pathology (including dysthyroidism and diabetes)EndometriosisPolycystic ovary syndrome and ovulatory disordersPremature ovarian failureIVF by oocyte donationTubal obstructions or lesions, uterine and cervical anomaliesPartners with extreme oligoastheno-spermia and/or sperm DNA fragmentation >30Sperm donationsPatients unable to give informed consent