Comprehensive individualised interventions may improve clinical outcomes for patients with Recurrent Implantation Failure: Study
With the considerable decline in global fertility, reproductive physicians face greater pressure. The field of assisted reproductive technology is developing rapidly, with live birth rates of single-cycle embryo transfer reaching 40%–60%. However, some patients experience recurrent implantation failure (RIF). Despite the controversy regarding the definition of RIF, reproductive physicians strive to provide sufficient attention and active management whenever RIF occurs, regardless of whether the factors being considered pertain to the mother or embryo.
The evaluation methods and intervention measures recommended by the latest RIF Expert Consensus guidelines (2023) are limited mainly owing to their relatively low levels of evidence. Moreover, current management strategies are not supported by high-quality studies, whose relative scarcity is largely attributed to two factors. The first is the difficulty of conducting randomised controlled trials (RCTs), in which one group of patients with RIF may be assigned to the control group because of ethical issues inherent in research on RIF. The second is the difficulty of controlling for all factors potentially involved in implantation failure, which manifests as a multifactorial group of mixed mechanisms that can differ among patients with RIF. Therefore, it is difficult to recommend a single treatment strategy without classifying the precise mechanisms of RIF implantation failure.
In response to a 2021 article that proposed the exploration of the RIF mechanism using cohort research, authors’ team previously explored the possible mechanisms of RIF through retrospective and prospective cohort studies. However, few studies have subsequently evaluated the effectiveness of comprehensive individualised management for patients with RIF after classifying the RIF mechanism. To fill this research gap, authors aimed to investigate the clinical value of comprehensive individualised interventions after classifying the implantation failure mechanisms in patients with RIF.
In this single-centre retrospective cohort study, they collected endometrial samples from patients with RIF on the seventh day of ovulation during their natural cycle from June 2016 to December 2022. The inclusion criteria were patients with three or more non-preimplantation genetic testing (PGT) embryo transfer failures, two or more PGT embryo transfer failures and embryos available for freezing. The exclusion criteria were moderate to severe intrauterine adhesions, untreated hydrosalpinx, uterine fibroids (i.e., submucosal fibroids, intramural fibroids >4 cm or fibroids compressing the endometrium) and/or uterine malformations (i.e., double, bicornuate or unicornuate uterus or uterine mediastinum) and chromosomal or genetic abnormalities in couples.
Patients who met the inclusion criteria underwent an ovulation monitoring cycle before undergoing frozen embryo transfer. All patients underwent endometrial biopsy on the 7th day after ovulation, followed by endometrial histological dating, endometrial CD138 counting, endometrial immune-cell proportion measurement and endometrial microbiota testing. A difference of >2days between the endometrial histological dating and biopsy time was defined as a displaced window of implantation (WOI). An endometrial CD138 count of ≥1 was defined as positive WOI CD138. An abnormal endometrial immune-cell proportion was defined as any type of abnormal proportion of immune cells according to the reference standard. The endometrial microbiome analysis/analysis of the main pathogens in chronic endometritis (EMMA/ALICE) was used as the microbial testing platform.
After a comprehensive analysis of the evaluation results, individualised frozen embryo transfer cycles were planned and managed. Patients with RIF and displaced WOI were individually managed by delaying the transfer date by 1 or 2days. Patients with WOI CD138 positivity underwent frozen embryo transfer after antibiotic treatment. On the basis of the definition of an abnormal proportion of endometrial immune cells in the previous literature, the corresponding clinical interventions were as follows. Patients with elevated numbers of uterine natural killer (uNK) cells were treated with dexamethasone intrauterine infusion, whereas those with decreased numbers of uNK cells were treated with human chorionic gonadotropin intrauterine infusion. Patients with endometrial CD163/ CD68 positivity were treated with platelet-rich plasma intrauterine infusion, and patients with decreased Foxp3 expression were treated with immunoglobulin injection. Antibiotic treatment was administered on the basis of the detection of abnormal bacteria according to the EMMA/ALICE results. Lactobacillus vaginal supplementation was administered if the proportion was abnormal or the microbial quantity was excessively low, and empirical treatment was provided if all endometrial test results were negative. Empirical treatments (e.g., adjusting the endometrial preparation protocol and using aspirin and heparin) were used in patients with unexplained RIF.
The primary outcome was ongoing pregnancy, defined as the presence of at least one gestational sac in the uterine cavity on ultrasound at 12weeks of gestation. The cumulative ongoing pregnancy rate (cOPR) was defined as the probability of an ongoing pregnancy, including all frozen embryo transfer cycles during the study period.
The median number of failed transfer cycles was 3 (range, 2–12), and the cOPR was 58.0%. The rates of window of implantation (WOI) displacement, CD138 positivity, imbalanced endometrial immune-cell proportion, endometrial microbiota testing, multiple factors and unexplained RIF were 34.0%, 9.3%, 7.5%, 4.1%, 32.4% and 12.7%, respectively.
The cOPRs of the individualised frozen embryo transfers in patients having RIF with WOI displacement, WOI CD138 positivity, imbalanced endometrial immune-cell proportion, endometrial microbiota testing, multiple factors and unexplained RIF were 64.1%, 57.6%, 55.1%, 38%, 64.2% and 34.5%, respectively. After adjusting for basic characteristics through logistic regression analysis, the cOPRs of the WOI displacement group, WOI CD138 positive group and immune-cell proportion imbalanced group remained higher than that of the unexplained RIF group. However, the cOPR was comparable between the endometrial microbiota testing and unexplained RIF groups.
Herein, the overall cOPR of patients with RIF reached 60% by classification and individualised management based on the identification of the mechanism of implantation failure. However, the cOPR of patients undergoing empirical embryo transfer in whom there was no clear mechanism of implantation failure was only 34.5%. These findings may indicate the necessity of classifying the mechanism of implantation failure before providing comprehensive individualised interventions to improve the clinical outcomes in the management of RIF.
Comprehensive individualised interventions appear to be associated with improved clinical outcomes, but further research is necessary to confirm their efficacy. This study lays the groundwork for future prospective and controlled studies to validate these findings and explore mechanisms underlying RIF.
Source: Yuan Li, Qi Zhao, Xiangxiu Fan; BJOG: An International Journal of Obstetrics & Gynaecology, 2025; 0:1–9 https://doi.org/10.1111/1471-0528.18093
