Abstract
BACKGROUND: Oil-based contrast medium in hysterosalpingography has been recommended as an approach to improve fertility in recent years. However, this approach has rarely been applied to patients with unknown recurrent implantation failure (RIF). This randomized clinical trial aimed to assess the effects of intrauterine oil-based contrast infusion on frozen embryo transfer (FET) prognosis and pregnancy outcomes among patients with unknown RIF. METHODS: This multicenter prospective randomized clinical trial was conducted between November 2019 and December 2022. A total of 224 patients with unknown RIF were randomized to the intrauterine oil-based medium infusion group or the control group at a 1:1 ratio. The oil-based contrast group was intrauterine infused with ethiodized poppy seed oil at a dose of 5 ml before FET, and the control group underwent only a standard FET. The primary outcome was the live birth rate (LBR). The secondary outcomes were implantation rate, clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), and early miscarriage rate. RESULTS: One hundred patients completed intrauterine oil-based medium infusion followed by FET within 120 days. The intention-to-treat analysis demonstrated balanced baseline characteristics between groups. The oil-based medium group exhibited significantly higher CPR (56% vs. 37.4%, rate ratio (RR) 1.498, 95% CI 1.109-2.023, P = 0.007) and implantation rates (median 50% [interquartile range, IQR 0-100%] vs. median 50% [IQR 0-50%], P = 0.010) compared to controls. However, no statistically significant differences were observed in LBR (39% vs. 27.1%, RR 1.439, 95% CI 0.969-2.138, P = 0.069) or OPR (40% vs. 27.1%, RR 1.476, 95% CI 0.997-2.168, P = 0.049), with the latter approaching borderline significance. Subgroup analyses revealed enhanced CPR specifically in RIF patients aged 35-39 years (P = 0.041) and with gonadotropin-releasing hormone agonist (GnRHa) pretreatment hormone replacement therapy (HRT) (GnRHa-HRT) endometrial preparation protocol (P = 0.008). However, no disparities were observed in the LBR and OPR. Within-group comparison of oil-based medium infusion protocols showed that GnRHa-HRT significantly improved reproductive outcomes versus HRT protocols, including LBR (52.2% vs. 26.1%, RR 1.894, 95% CI 1.035-3.466, P = 0.023), CPR (71.7% vs.39.1%, RR 1.983, 95% CI 1.198-3.283, P = 0.002), OPR(P = 0.047), and implantation rate(P = 0.021), which might be attributed to the thickening of the endometrium (P = 0.027). CONCLUSIONS: Infusion with an oil-based medium did not increase the LBR in terms of FET prognosis among patients with unknown RIF. However, compared with HRT, an oil-based contrast agent combined with a GnRHa-HRT FET increased the endometrial thickness and the LBR. These findings suggest synergistic effects of dual interventions, proposing a potential personalized strategy for refractory RIF cases. Further large-scale RCTs and deeper mechanism studies are warranted to validate clinical applicability. TRIAL REGISTRATION: This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and registered at the Chinese Clinical Trial Registry Center ( http://www.chictr.org.cn/index.html , no ChiCTR1900024273) on July 4th, 2019.