Influence of endometriosis on the outcomes of assisted reproductive technology in poor ovarian responders with previous implantation failures

Objective To evaluate whether endometriosis (EMS) adversely affects the embryological and clinical outcomes of assisted reproductive technology (ART) in poor ovarian responders (PORs) with repeated implantation failure undergoing spindle view-assisted intracytoplasmic sperm injection (SV-ICSI).

This retrospective study included women aged 35 -44 years who underwent ART with SV -ICSI at a single fertility center between January 2023 and December 2024. All participants fulfilled the Bologna criteria for POR and had experienced at least three previous failed embryo transfer cycles. Patients with laparoscopically confirmed EMS were assigned to the EMS group (n=36), whereas age-matched patients without a history or ultrasonographic evidence of EMS were selected as controls in a 1:3 ratio (n=108).

The baseline characteristics were comparable between the two groups. No significant differences were observed between the EMS and control groups in key embryological parameters including fertilization rate, cleavage rate, good -quality cleavage embryo rate, and blastocyst formation rate . Similarly, ART-related clinical outcomes did not differ significantly between the two groups, including implantation rate (13.0% vs. 11.7%), clinical pregnancy rate (19.4% vs. 18.5%), and clinical abortion rate (28.6% vs. 40.0%).

In this retrospective cohort of patients with POR with repeated implantation failure, no statistically significant association was found between EMS and embryological or ART-related clinical outcomes. However, given the limited sample size and reliance on surrogate reproductive endpoints, these findings should be considered preliminary and hypothesis generating and require confirmation in larger prospective studies incorporating live birth outcomes.

Endometriosis; Poor ovarian response; Repeated implantation failure; Assisted reproductive technology; Intracytoplasmic sperm injection

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 altere d 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 micromani pulation 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 stimu lation, 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]. POR patients generally exhibit fewer retrieved oocytes, limited embryo availability, and lower clinical pregnancy rates than normal responders, even when optimized stimul ation strategies are applied [12]. ART outcomes in POR patients may be influenced by multiple factors, including maternal age, ovarian reserve parameters, stimulation protocols, embryo quality, and gynecologic di seases 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 (AFC s), particularly in the presence of ovarian endo metriomas [16,17 ]. Surgical excision of endometriomas has also been consistently associated with postoperative decline s 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 c ytokines 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 conco mitant 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. Importantly, evidence focusing specifically on patients with POR with 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.

1. Patients This retrospective study included women aged 35 -44 years who underwent ART with SV -ICSI at a single fertility center between January 2023 and December 2024. The study was approved by the Institutional Review Board of the fertility hospital, which waived the requirement for informed consent owing to the retrospective nature of the study. Poor ovarian response (POR) was defined according to the Bologna criteria [10] as the presence of at least two of the following three features: 1) advanced maternal age (≥40 years) or any other risk factor for POR; 2) a previous episode of POR, defined as a cancelled cycle or retrieval of ≤3 oocytes following conventional ovarian sti mulation; and 3) an abnormal ovarian reserve test, defined as an AFC <7 follicles or an AMH level <1.1 ng/mL . In addition, two episodes of POR after maximal ovarian stimulation were considered sufficient to define POR in the absence of advanced maternal age or abnormal ovarian reserve test results [9]. Among women with POR, those with a history of at least three failed embryo transfer cycles were included in the study [2 3,24]. All study participants underwent SV -ICSI and fresh embryo transfer cycles. Those who underwent complete embryo cryopreservation after oocyte retrieval were excluded from this study. The study population was classified into an EMS group and a non -EMS group. The EMS group included patients with laparoscopically confirmed EMS. The non-EMS group included patients with no prior diagnosis of EMS or ultrasonographic findings suggestive of EMS. Controls were selected from the eligible non-EMS population using age matching at a 1:3 ratio. For each patient in the EMS group, three controls were randomly selected from the age -matched non-EMS pool using a random number generator. A total of 144 women were included in the final analysis: 36 in the EMS group and 108 in the non-EMS group. 2. Procedures [24] Oocyte retrieval was performed either during a natural cycle or after controlled ovarian stimulation. Controlled ovarian stimulation was conducted using recombinant follicle -stimulating hormone, including Follitrope® (LG Life Science, Seoul, Korea), Gonal -F® (Serono, Istanbul, Turkey), or human menopausal gonadotropin (IVF-M HP®; LG Life Science). Ovarian stimulation protocols consisted of either a long gonadotropin -releasing hormone (GnRH) agonist regimen or a GnRH antagonist regimen. Final oocyte maturation was induced using recombinant human chorionic gonadotropin (Ovidrel®; Merck KGaA, Darmstadt, Germany) or a GnRH agonist (Decapeptyl ®; Ferring, Malmo, Sweden) once the leading follicles reached an appropriate diameter. To maximize the fertilization rate, all retrieved oocytes were fertilized using SV-ICSI, exclusively [24]. SV-ICSI was performed uniformly in all participants to optimize fertilization outcomes and minimize procedural variability. Based on evidence demonstrating a higher proportion of good- quality embryos with SV -ICSI than with conventional ICSI [24,25], our in stitution has adopted this technique as the standard fertilization method for all POR patients since 2023. For SV-ICSI, metaphase II oocytes with a visible first polar body (PB) were transferred into warm ICSI medium (MRC#ICSI ; MARIA Research Center, Seoul, Korea) during micromanipulation. Sperm injection was performed under an inverted microscope (IX73; Olympus, Tokyo, Japan) equipped with polarized light microscopy and a heated stage maintained at 36.5 -37.5°C. The MS and PB were identified and aligned before sperm injection. To optimize spindle visualization, oocytes were gently rotated using holding and injection pipettes until the clearest spindle image was obtained. When the spindle was visualized, sperm were injected with the spindle positioned in the 0 o’clock direction. When the spindle could not be visualized, an injection needle was introduced at the 3 o’clock position while the PB was positioned at 0 o’clock . Fig. 1 illustrates MS localization in living human metaphase II oocytes using the inverted method according to the angle of deviation relative to the PB position. After microinjection, oocytes were cultured individually in equilibrated culture medium (MRC#ID16 ; MARIA Research Center) at 37°C in an incubator containing 5% CO₂ [24]. 3. Measures of ART-related embryological and clinical outcomes [24] Embryological and clinical outcomes were compared between the EMS and non -EMS groups. The evaluated outcomes included fertilization, cleavage, good -quality cleavage embryo, blastocyst formation, good-quality blastocyst, implantation, clinical pregnancy, and clinical abortion rates [24]. The fertilization rate was defined as the proportion of injected oocytes that formed two pronuclei. The cleavage rate was defined as the number of day 3 embryos divided by the total number of fertilized oocytes. A good-quality cleavage embryo was defined as an embryo with more than five regular blastomeres and <10% fragmentation on day 3. The good-quality cleavage embryo rate was calculated as the number of good -quality cleavage embryos divided by the total number of fertilized oocytes. Blastocyst formation rate was defined as the number of embryos that developed to the blastocyst stage divided by the total number of fertilized oocytes. Implantation rate was defined as the number of gestational sacs confirmed by transvaginal ultrasonography divided by the number of embryos transferred. Clinical pregnancy was defined as the presence of at least one gestational sac on transvaginal ultrasono graphy, and the clinical pregnancy rate was calculated as the number of transfer cycles resulting in clinical pregnancy divided by the total number of transfer cycles. The clinical abortion rate was defined as the number of pregnancy losses, including ecto pic pregnancies, before 20 weeks of gestation divided by the total number of clinical pregnancies [24]. 4. Statistical analysis Continuous variables are presented as mean±standard deviation, and categorical variables are presented as number (percentage). Comparisons between the EMS and control groups were performed using an unpaired t-test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. Multivariable logistic regression analysis was performed to evaluate the independent association between EMS and clinical outcomes related to ART and embryo quality. EMS was entered as the primary independent variable, and age, body mass index (BMI), AMH level, number of retrieved oocytes, and number of transferred embryos were included as adjustment variables because these variables are well-established determinants of ART outcomes and are considered potential confounders based on their established clinical relevance. All statistical analyses were performed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). A two-sided P-value <0.05 was considered statistically significant.

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 (OR, 0.795; 95% CI, 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 embryologic al 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 [1 4]. 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 difference s 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 i ncluded in the multivariable logistic regression model, the adjusted estimate s 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, rASRM 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 POR, 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, th is study should be regarded as hypothesis generating and should serve as a basis for future large-scale prospective investigations. Conflict of interest The authors declare no conflict of interest. Ethical approval The study was conducted in accordance with the guidelines of the Declaration of Helsinki. Thi s retrospective study was approved by the Institutional Review Board (IRB) of Maria Fertility H ospital (IRB No. HR -2026-56-01). Patient consent The requirement for informed consent was waived due to the retrospective nature of the stud y and the guaranteed anonymity of the participants. Funding information This research received no external funding.

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Spindles in living human metaphase II oocytes imaged using the inverted method according to the angles of deviation relative to the position of the polar body. (A) 0 o’ clock, (B) 3 o’ clock, (C) spindle invisible. PB, polar body. Fig. 2. Meiotic spindle distribution according to the angles of deviation relative to the position of the polar body between poor ovarian responders with and without endometriosis. (A) 0 o’ clock, (B) 1 o’ clock, (C) 2 o’ clock, (D) 3 o’ clock, (E) 4 o’ clock, (F) 5 o’ clock, (G) 6 o’ clock, (H) spindle invisible. EMS, endometriosis. Table 1. Comparison of baseline clinical and cycle characteristics between poor ovarian responders with and without endometriosis Endometriosis group (n=36) Control group (n=108) P-value Age (yr) 41.67±2.14 41.67±2.12 1.000a Parity 0.11±0.32 0.20±0.47 0.187a Body mass index (kg/m2) 22.31±4.46 23.54±5.50 0.187a Basal AMH levels (ng/mL) 0.77±0.62 0.87±0.87 0.535a Number of previous implantation failures 4.33±2.51 4.31±2.31 0.968a Total gonadotropin dosage 3,175.71±1,103.91 3,555.02±1,142.05 0.088a Endometrial thickness on the trigger day (mm) 9.11±1.41 9.57±1.99 0.133a Retrieved oocytes 5.58±4.10 7.12±5.01 0.099a Transferred embryos 1.50±0.65 1.67±0.66 0.377a Superovulation methods 0.108b Natural 4/36 (11.1) 4/108 (3.7) Controlled ovarian hyperstimulation 32/36 (88.9) 104/108 (96.3) Premature LH surge preventiond 0.740b GnRH agonist 4/32 (12.5) 10/104 (9.6) GnRH antagonist 28/32 (87.5) 94/104 (90.4) Percentage of blastocyst transfer 9/36 (25.0) 27/108 (25.0) 1.000c Values are presented as mean±standard deviation or number (%). AMH, anti-Müllerian hormone; GnRH, gonadotropin-releasing hormone. aP-value by unpaired t-test. bP-value by Fisher’s exact test. cP-value by chi-square test. dIncluded only patients who underwent controlled ovarian stimulation. Patients undergoing natural cycle assisted reproductive technology were excluded. Table 2. Comparison of embryological and clinical outcomes between poor ovarian responders with and without endometriosis Endometriosis group (n=36) Control group (n=108) P-value Fertilization rate 109/143 (76.2) 414/525 (78.9) 0.498a Cleavage rate 105/109 (96.3) 400/414 (96.6) 0.776b Good-quality cleavage embryo rate 60/109 (55.0) 230/414 (55.6) 0.924a Blastocyst rate 26/109 (23.9) 90/414 (21.7) 0.638a Implantation rate 7/54 (13.0) 21/180 (11.7) 0.797a Clinical pregnancy rate 7/36 (19.4) 20/108 (18.5) 0.902a Clinical abortion rate 2/7 (28.6) 8/20 (40.0) 0.678b Values are presented as number (%). aP-value by chi-square test. bP-value by Fisher’s exact test.