Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis

Abstract

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58–3.00; p < 0.00001; OR 2.03; 95% CI 1.22–3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40–4.16; p = 0.002; OR 3.73; 95% CI 1.13–12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58–3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55–3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice.

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…PIBF inhibition significantly increased miscarriages despite successful implantation. The increase in miscarriage was associated with an increase in NK activity [104][105][106]. In the equine model, an exciting interaction between galectin and PIBF has been observed protecting pregnancy [107].…”

“…Progesterone is an essential hormone that may be given orally or applied topically for pregnancy maintenance [101][102][103]. NK cells do not have receptors for this hormone; however, T cells do [102][103][104]. The factor induced by progesterone, PIBF, generates a tolerogenic TH2 response in the endometrium and consequently may affect NK cell migration and response [105].…”

“…A recent review by Busnelli et al [104] revisited several procedures regarding recurrent pregnancy loss. The intrauterine infusion of autologous peripheral blood mononuclear cells (PBMC) seems to reduce endometriosis [105].…”

“…Thus, the infused cells provide a tolerogenic milieu for embryo implantation. Also, a mild positive effect of subcutaneous G-CSF injection inducing clinical pregnancy post embryo implantation was observed [104]. One possible mechanism of tolerance induced by G-CSF is the inhibition of NK cytotoxicity activity [104].…”

“…Also, a mild positive effect of subcutaneous G-CSF injection inducing clinical pregnancy post embryo implantation was observed [104]. One possible mechanism of tolerance induced by G-CSF is the inhibition of NK cytotoxicity activity [104]. It is nevertheless unclear why the beneficial effect of G-CSF is subcutaneous and not intrauterine.…”