Endometriosis (EMS) is a chronic inflammatory gynecological disorder characterized by the presence of endometrial-like tissue outside the uterine cavity and affects approximately 10% of women of reproductive age [1-3]. EMS is a prevalent yet debilitating condition that is strongly associated with infertility, making it one of the most common gynecologic disorders related to infertility [1,2,4]. Several mechanisms have been proposed to explain EMS-associated infertility, including chronic peritoneal inflammation [5,6], oxidative stress and an altered follicular microenvironment [7], impaired follicular development and reduced oocyte quality [8], and altered endometrial receptivity [9].

Since the first successful birth following in vitro fertilization (IVF) in 1978, assisted reproductive technology (ART) has become a fundamental therapeutic option for women with infertility who fail to conceive spontaneously. Advances in ovarian stimulation protocols, embryo culture systems, and micromanipulation techniques, particularly intracytoplasmic sperm injection (ICSI), have expanded the indications for ART to include women with repeated implantation failure, diminished ovarian reserve, and advanced maternal age.

Poor ovarian responders (PORs) represent a clinically challenging subgroup among women undergoing ART. The Bologna criteria were proposed to standardize the definition of POR by incorporating advanced maternal age, abnormal ovarian reserve markers, and reduced responses to previous ovarian stimulation, and remain the most widely accepted and internationally validated definition of POR [10]. More recently, the POSEIDON classification was introduced to further individualize the prognosis and treatment strategies for patients with a low prognosis undergoing ART [11]. PORs generally exhibit fewer retrieved oocytes, limited embryo availability, and lower clinical pregnancy rates than normal responders, even when optimized stimulation strategies are applied [12].

ART outcomes in PORs may be influenced by multiple factors, including maternal age, ovarian reserve parameters, stimulation protocols, embryo quality, and gynecologic diseases such as EMS [13-15]. However, the effect of coexisting gynecologic conditions, particularly EMS, on ART outcomes in this population remains controversial.

Several studies have reported impaired ovarian reserve in women with EMS, reflected by decreased anti-Müllerian hormone (AMH) levels and antral follicle counts (AFCs), particularly in the presence of ovarian endometriomas [16,17]. Surgical excision of endometriomas has also been consistently associated with postoperative declines in ovarian reserve markers [14,18-20]. Furthermore, experimental and clinical studies have suggested possible reductions in fertilization rates and oocyte quality in patients with EMS, potentially mediated by inflammatory cytokines and oxidative stress [7-9].

Conversely, other studies and meta-analyses have demonstrated comparable fertilization rates, embryo quality, and pregnancy outcomes between patients with and without EMS undergoing ART, particularly when key pelvic factors are bypassed [15,21]. Large population-based analyses have further suggested that isolated EMS may not independently compromise live birth rates after IVF and that adverse outcomes are often confounded by concomitant infertility diagnoses [13]. These conflicting findings suggest that the detrimental effects of EMS on ART outcomes may be context-dependent and influenced by patient characteristics, such as ovarian reserve status and prior implantation history. Evidence specifically addressing patients with both poor ovarian response and repeated implantation failure remains limited.

Spindle view-assisted ICSI (SV-ICSI) was introduced as an advanced micromanipulation technique that enables visualization of the meiotic spindle (MS), potentially minimizing oocyte damage and optimizing sperm injection orientation. MS morphology is correlated with fertilization, blastocyst development, and euploidy rates [21]. Given the previous reports of spindle abnormalities and oxidative damage in oocytes from women with EMS [5,7,21,22], this approach may be particularly relevant in patients with POR, whose oocyte quality is often compromised.

Therefore, the present study was conducted to evaluate the effect of EMS on embryological parameters and ART-related clinical outcomes in patients with POR with repeated implantation failure who underwent SV-ICSI. By comparing age-matched patients with POR with and without EMS, we aimed to clarify whether EMS should be considered a prognostic factor for ART success in this highly selected patient population.

Fig. 2 shows the distribution of MS positions relative to the PB position based on the angle of deviation in the EMS and control groups. The distribution of MS orientation did not differ significantly between the two groups (P=0.485), indicating comparable spindle orientation patterns during SV-ICSI and suggesting that procedural differences in spindle visualization were unlikely to account for differences in embryological or clinical outcomes.

Table 1 presents a comparison of the baseline clinical characteristics between the EMS group and control group. No significant differences were observed between the two groups in terms of age, parity, BMI, basal AMH levels, number of previous implantation failures, total gonadotropin dosage, endometrial thickness on trigger day, number of retrieved oocytes, or number of transferred embryos (all P>0.05). In addition, the distribution of superovulation methods, premature LH surge prevention protocols, and proportion of blastocyst transfer cycles were comparable between the EMS and control groups.

Table 2 summarizes the embryological and clinical outcomes according to the presence of EMS. The fertilization rate was comparable between the EMS and control groups (76.2% vs. 78.9%; P=0.498). Similarly, no significant differences were observed in the cleavage rate (96.3% vs. 96.6%; P=0.776), good-quality cleavage embryo rate (55.0% vs. 55.6%; P=0.924), or blastocyst formation rate (23.9% vs. 21.7%; P=0.638). Clinical outcomes were also similar between the two groups. The implantation rate did not significantly differ between the EMS and control groups (13.0% vs. 11.7%; P=0.797), and comparable clinical pregnancy rates were observed (19.4% vs. 18.5%; P=0.902). Furthermore, the clinical abortion rate was not significantly different between the groups (28.6% vs. 40.0%; P=0.678).

After adjusting for age, BMI, AMH level, number of retrieved oocytes, and number of transferred embryos, EMS was not independently associated with clinical pregnancy outcomes (odds ratio, 0.795; 95% confidence interval, 0.284-2.224; P=0.662).

The present study was conducted to clarify whether EMS independently affects ART outcomes in a particularly vulnerable population-PORs with a history of repeated implantation failure. This subgroup represents a clinical scenario in which both embryo competence and implantation potential are already compromised, making the additional impact of EMS a critical concern in treatment decision-making and patient counseling. In this retrospective cohort of women who underwent SV-ICSI, EMS was not associated with adverse embryological or clinical outcomes. Key parameters, including fertilization rate, cleavage rate, good-quality embryo rate, blastocyst formation rate, implantation rate, and clinical pregnancy outcomes, were comparable between patients with and without EMS.

In the present study, POR was defined according to the Bologna criteria, which are the most widely accepted diagnostic criteria for POR. Although the POSEIDON classification provides a more refined prognostic stratification for patients with low prognosis undergoing ART, the present study adopted the Bologna criteria because they remain the most widely accepted and internationally validated diagnostic criteria for POR. Because this was a retrospective study, the complete clinical information required for accurate POSEIDON stratification was not consistently available for all patients.

Although EMS is a well-established cause of infertility [5-8, 26,27], whether these pathophysiological alterations translate into poorer ART outcomes remains controversial. Importantly, many pathophysiological processes implicated in EMS-associated infertility [8] primarily affect natural conception and are partially bypassed during ICSI-based ART.

Several previous studies have reported findings consistent with ours, suggesting that EMS itself does not independently compromise ART outcomes. Large population-based analyses and recent reviews have shown that fertilization, embryo development, implantation, and pregnancy outcomes are generally comparable between women with and without EMS once ovarian reserve and the effects of previous ovarian surgery are considered [13,15,19].

In contrast, several studies have reported poorer ART outcomes in women with advanced-stage EMS or ovarian involvement [14]. Meta-analyses have suggested lower implantation and clinical pregnancy rates in patients with stage III/IV disease, while reductions in ovarian reserve associated with advanced disease and previous ovarian surgery have also been consistently documented [16-18]. These findings suggest that the adverse ART outcomes reported in some studies may largely reflect reduced ovarian reserve or the effects of prior ovarian surgery, rather than the independent effect of EMS itself. The discrepancy between these studies and our findings may therefore be explained by differences in disease severity, surgical history, patient selection, and study design. Furthermore, because all the participants in the present study were PORs with repeated implantation failure who underwent SV-ICSI, the dominant determinants of treatment outcomes were likely diminished oocyte quantity and intrinsic embryo competence, potentially attenuating the relative contribution of EMS.

Several limitations of this study should be considered.

First, three limitations may have collectively reduced our ability to detect true differences between the EMS and non-EMS groups. The relatively small number of patients with EMS and the limited number of clinical pregnancy events may have reduced the statistical power to detect clinically meaningful differences between the groups. In addition, because the number of outcome events was limited relative to the number of covariates included in the multivariable logistic regression model, the adjusted estimates should be interpreted with caution owing to the limited stability and precision of the model. The relatively wide confidence intervals observed in the regression analysis further reflect the limited precision of the estimated effect sizes. The possibility of disease misclassification should also be considered. Women in the control group were classified based on the absence of a previous diagnosis and the absence of ultrasonographic findings suggestive of EMS; however, diagnostic laparoscopy was not routinely performed in these patients. Therefore, some women may have had undiagnosed minimal or superficial peritoneal EMS that was not detectable by ultrasonography and remained unrecognized. Such nondifferential misclassification would have likely biased the comparison toward the null and may have attenuated true differences between the groups. Another related limitation is the reliance on surrogate reproductive endpoints. As most patients were referred to outside obstetric centers after approximately 15 weeks of gestation for antenatal care and delivery, prospective assessment of live birth outcomes was not feasible in the present study. Accordingly, implantation and clinical pregnancy were used as surrogate reproductive outcomes, although live birth remains the most clinically meaningful outcome measure in ART research. This limitation is particularly important because EMS may influence reproductive outcomes beyond implantation and early clinical pregnancy, including late pregnancy loss and obstetric complications [28,29]; therefore, surrogate endpoints such as implantation and clinical pregnancy rates may not fully capture the potential reproductive effects of EMS. Taken together, these limitations may operate in the same direction: limited statistical power may reduce the ability to detect an existing difference, misclassification of women with undiagnosed EMS into the control group may dilute the contrast between the groups, and reliance on early surrogate endpoints may fail to capture differences emerging later in pregnancy. Therefore, their combined effects may bias the findings toward the null. Consequently, it remains difficult to determine whether the observed lack of statistically significant associations reflected a genuine absence of an effect of EMS or whether the true effect was masked by the combined influence of these limitations.

Second, because this study was conducted at a single fertility center, many patients had previously undergone EMS surgery at outside institutions, making detailed operative records, including accurate EMS staging and prior surgical details such as ovarian cystectomy, unavailable. Consequently, important clinical information, including the presence of deep infiltrating EMS, revised American Society for Reproductive Medicine stage, ovarian endometrioma characteristics, and details of previous ovarian surgery such as cystectomy, was unavailable because of the retrospective nature of this study. Therefore, subgroup analysis based on disease severity and evaluation of the independent effects of previous ovarian surgery on ovarian reserve and ART outcomes could not be fully evaluated.

Third, selection bias may have been present because only patients who underwent fresh embryo transfer were included in the analysis, whereas cycles involving elective embryo cryopreservation were excluded. Given the increasing use of frozen embryo transfer in contemporary ART practice, this selection may limit the generalizability of our findings. Future prospective studies that include both fresh and frozen embryo transfer cycles with live birth as the primary endpoint are warranted.

Fourth, the retrospective design limited our ability to fully evaluate other potential contributors to poor ovarian response, including autoimmune and systemic inflammatory conditions. Hence, heterogeneity in ovarian stimulation protocols should also be considered when interpreting the results. Although subgroup analyses according to stimulation protocols may have provided additional insights, such analyses were not feasible because of the limited sample size and insufficient statistical power.

In summary, our study did not identify a statistically significant association between concomitant EMS and embryological or ART-related clinical outcomes in PORs with repeated implantation failure. Given the retrospective design, limited sample size, and single-center setting, these findings should be interpreted with caution and should not be considered definitive evidence of the absence of an effect. Rather, this study should be regarded as hypothesis generating and should serve as a basis for future large-scale prospective investigations.