Infertility has been a growing global medical issue, and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) has become a reliable option for those who are having unresolved infertility in achieving successful conception. Assisted reproductive technology (ART) has been evolving over the past 30 years, but despite the continuous development, the overall clinical pregnancy rate following IVF/ICSI treatment remains at approximately 30-40% (Munné et al., 2019) and one of the key-limiting factors is implantation failure (Su and Fazleabas, 2015). Recurrent implantation failure (RIF) affects approximately 10% of the global ART patients (Busnelli et al., 2020), bringing serious psychological distress and huge financial burden. Until now, a great number of clinical approaches have been employed to increase pregnancy rate of RIF patients by mitigating risk factors such as poor gamete/embryo quality, chromosomal abnormalities, undetected uterine pathologies, endocrine dysfunctions, autoimmune disorders, abnormal coagulation, inadequate culture conditions, and improper embryo transfer methods (Das and Holzer, 2012). In order to improve pregnancy outcome of RIF patients, we may make use of preimplantation genetic screening, hysteroscopy, immunotherapy, endocrine and metabolic conditioning, anticoagulation therapy, anti-infection, Chinese medicine and acupuncture treatment and so on. Despite considerable efforts, the improvement in achieving a successful and healthy pregnancy has been marginal.

On the other hand, there has been significant research conducted in the last few decades regarding endometrial physiologic function from embryo implantation to fetal delivery (Casper, 2011). Thereinto, endometrial receptivity has been considered as a pivotal factor influencing embryo implantation for RIF patients (Lédée et al., 2016). Techniques such as microarray and RNAseq in transcriptomic analysis, as well as digital pathology in immunohistochemistry (IHC) analysis, are potential to translate research progress in endometrial receptivity assessment into diagnostic practice (Griffin and Treanor, 2017, Miravet-Valenciano et al., 2015).

Endometrial receptivity array (ERA) is a personalized window of implantation (WOI) test through transcriptomic analysis. It was developed to address undiagnosed endometrial defects that could hinder successful pregnancies (Sauerbrun-Cutler et al., 2021). Based on the theory that successful implantation requires synchrony between the embryo and the receptive endometrium (Simón et al., 2000), the ERA utilizes a set of 238 genes expressed differently during the menstrual cycle to determine the precise endometrial dating and enable personalized embryo transfer (Díaz-Gimeno et al., 2011). This approach has been proven superior over standard histological methods in terms of accuracy, reproducibility, and improved clinical outcomes for patients who suffered RIF and those who were at first IVF/ICSI appointment (Díaz-Gimeno et al., 2013, Simón et al., 2000). More recently, literature has emerged that offers contradictory findings about the efficacy of ERA in clinical practice (Bassil et al., 2018, Churchill et al., 2017, Ruiz-Alonso et al., 2013). In addition to displaced windows of implantation, pathological WOI can also contribute to implantation failure (Sebastian-Leon et al., 2018), which might account for the controversial result.

Endometrial immune profiling is another diagnostic tool used to analyze the endometrial local immune reaction occurring in the mid-secretory phase of menstrual cycle which is a critical time for the implantation window. This immune profiling enables the implementation of personalized immune therapies to enhance the chance of a successful pregnancy, including endometrial scratching, exposure to high concentration of estrogens in the proliferative phase, immunotherapy, hormonal adaptation of the luteal phase and luteal hCG supplementation (Lédée et al., 2020). Previous researches have proposed that successful embryo implantation and development required continuous and appropriate immune homeostasis in the maternal-fetal interface, where endometrial immune cells play multiple regulator roles, for instance, accelerating trophoblast invasion, spiral artery remodeling and placenta formation (Faas and de Vos, 2017, Huppertz et al., 2012, Meyer et al., 2017, Smith et al., 2009). Consequently, any disturbances in endometrial immune cells may disrupt normal maternal-fetal dialogue and may lead to adverse pregnancy outcomes.

To date, ERA and endometrial immune profiling are two novel mainstream methods on endometrial receptivity assessment. However, there is a lack of studies that have simultaneously investigated the effectiveness of these two approaches, which is essential for clinicians in addressing the challenging fertility issue in women with multiple implantation failure. Our previous study suggested that the incidence of displaced WOI and endometrial immune dysregulation in multiple implantation failure patients was high, and their pregnancy outcomes seems could be improved by ERA and immune profiling separately or in combination (Jia et al., 2022). However, there were a few limitations, involving a small sample size, deficiencies in methods of balancing baseline characteristics, and lack of comparison among the three test groups. Therefore, the paper presented here provides a deeper examination of whether they could achieve a successful pregnancy after personalized embryo transfer (pET) and/or individualized immune therapy by expanding the sample size and using the propensity score-matching method. Additionally, the association between endometrial immune profiling and ERA phases was assessed and the results of these two endometrial receptivity assessments were compared between multiple implantation failure patients with embryo implantation and non-implantation.