Recurrent 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.

Specialized immunological studies in the diagnostics of idiopathic infertility and recurrent miscarriages have limited applicability, as the role of the immune system in these conditions is not thoroughly understood. In ovulatory cycles, changes occur in the populations of uterine lymphocytes, which may influence the receptivity of the endometrium and the implantation of the embryo. Particularly notable are the changes in natural killer (NK) cells, which reach their peak during the luteal phase and regulate the invasion of the trophoblast. The dominant NK cells exhibit a CD56bright phenotype and differ in cytokine profiles from peripheral blood cells. Cyclical changes also affect macrophages and T lymphocytes; however, it is unclear whether their proportions differ in women with reduced fertility. There is a need to investigate how the composition of lymphocytes in blood influences the populations in the endometrium. The aim of this study is to analyze the correlation between peripheral and endometrial lymphocytes in women with idiopathic infertility and recurrent miscarriages, compared to fertile women.

A low plasma level of mannose binding lectin (p-MBL) is associated with unexplained recurrent pregnancy loss (RPL), but it is not investigated if it is associated with unexplained reproductive failure in general, including recurrent implantation failure (RIF) after assisted reproductive technology (ART) (including IVF, ICSI and FET), recurrent pregnancy loss (RPL) after spontaneous conception, and RPL after ART.

This study aims to investigate the role of uNK cells and the association with prednisolone.

The aim of the study is to estimate the incidence of CE, evaluate the endometrial microorganism of CE, and investigate the therapeutic benefits of antibiotics for women with unexplained recurrent miscarriage and CE.

Recurrent miscarriages (RM) affects 3% of all fertile couples, but remains unexplained in most cases, limiting therapeutic options. Possibly the maternal immune system plays a role in recurrent miscarriage. Prednisolone suppresses the immune system and might enable development of normal pregnancy. In this randomized controlled clinical trial the investigators will study the effect of prednisolone on the live birth rate in patients with RM. Secondary, the tolerability and safety for mother and child and the cost-effectiveness is investigated. In the study one group of pregnant women with RM and gestational age \<7 weeks will receive prednisolone, the other group will receive a placebo. Total use of the medicine during this study is 8 weeks, further care during the study is routinely antenatal care. Subjects will be asked to fill in 4 short questionnaires and will have contact with a research nurse at different time points to gain information on the course of the pregnancy and possible side effects. Results of the study will be implemented in (inter) national guidelines, to effect everyday practice.