Introduction
Endometriosis is a common gynecological disorder that affects 10% of females in their reproductive age [
1]. A characteristic pathological manifestation of endometriosis is the occurrence of endometrial tissue beyond the confines of the uterine cavity. Pelvic pain and infertility are the primary clinical manifestations of endometriosis. Around 40% of endometriosis patients experience infertility, while 70–85% of endometriosis patients suffer from pelvic pain. Furthermore, 25–48% of infertility patients and 71–87% of women with chronic pelvic pain have endometriosis [
2]. endometriosis considerably impact the quality of life for affected individuals, leading to a notable reduction in their overall well-being. Additionally, it places a substantial economic burden on society.
Endometriosis is an important contributing factor to infertility [
3]. A study involving 203 histologically confirmed cases of peritoneal endometriosis and 1,292 infertile patients without endometriosis (control group) found that the proportion of primary infertility was significantly elevated in the endometriosis group. However, the proportions of normal menstrual cycles and levels of AMH were similar between the two groups, suggesting that infertility in patients with mild endometriosis is unrelated to ovarian reserve function. This finding confirms that within the subgroup of infertile patients with regular menstrual cycles, patent fallopian tubes on at least one side, and normal routine semen analysis results, there exists a population without direct evidence of moderate to severe endometriosis. It is estimated that up to 50% of this subgroup may have mild endometriosis [
4].
In clinical practice, accurately predicting the pregnancy outcomes of endometriosis patients undergoing IVF is crucial. Considering treatment impact, individual parameters, and laboratory tests, the development of an effective, convenient, and intuitive clinical predictive model enables healthcare professionals to estimate the probability of successful pregnancy based on specific patient conditions. This facilitates optimal treatment plan selection and personalized care while giving patients realistic expectations regarding their circumstances and the nomogram analysis results.
The current study successfully developed a predictive nomogram model by integrating independent influencing factors of pregnancy outcomes. The model quantifies, visualizes, and graphically represents the logistic regression results, enabling inference of variable values by graph and displaying continuous prediction probabilities [
5]. It aims to obtain the probability of clinical pregnancy in individuals with endometriosis, providing improved guidance and facilitating clinical practice. For the above reasons, the present research retrospectively assessed the clinical and laboratory data of endometriosis patients throughout the entire IVF-ET process. Using the available data, a predictive nomogram model for clinical pregnancy in individuals with endometriosis was developed. The model was internally and clinically validated to ensure its accuracy and reliability. The main aim of this model is to guide prognosis and assist in the development of individualized treatment plans for endometriosis patients.
Discussion
Endometriosis is a multifaceted clinical syndrome characterized by the involvement of multiple factors in its development. The specific etiology and underlying mechanisms of endometriosis remain unclear. Current evidence suggests that factors such as prenatal exposure to estradiol, short menstrual cycles, and smoking are high-risk factors for endometriosis. Additionally, low birth weight, early menarche, and smoking are also associated with an increased risk of Endometriosis development [
8]. Many infertile patients are diagnosed with endometriosis when seeking infertility treatment. Moreover, infertility is an independent influencing factor for the diagnosis of mild endometriosis [
9]. It is widely recognized that patients with endometriosis often experience poorer pregnancy outcomes [
10,
11]. Predicting and enhancing ovarian responsiveness in these patients during ovulation induction has become an urgent concern for reproductive specialists. The aim is to attain improved pregnancy outcomes and address this crucial aspect of patient care.
This research conducted a multivariate logistic regression analysis to determine the independent influencing factors for the clinical pregnancy rate in fresh IVF/ICSI cycles of endometriosis patients. The factors that demonstrated a significant impact included female age, ASRM stage, postoperative to IVF duration, stimulation protocol, AFC, AMH, number of oocytes retrieved, number of high-quality cleavage embryos and number of embryos transferred. Per these independent factors, a nomogram model was constructed. This model quantifies and visualizes the outcomes of the logistic regression analysis and allows for the estimation of the values of independent variables, thereby predicting the probability of clinical pregnancy in individuals. The nomogram model is different from other clinical models in the past as it is more intuitive and practical. It enables clinicians to calculate the expected clinical pregnancy rate for the current treatment cycle based on the individual characteristics of the patient. This facilitates the adoption of personalized treatment plans to improve the clinical pregnancy rate. This approach can also reduce the psychological burden and economic pressure on patients [
12].
The study revealed a considerable negative correlation between female age and pregnancy outcomes, indicating that older age is associated with poorer outcomes. Previous research has indicated that advanced female age can adversely affect oocyte quality and quantity, leading to an increased incidence of abnormal chromosome structure and number. Additionally, it can negatively impact endometrial receptivity. These factors collectively contribute to decreased clinical pregnancy and live birth rates in endometriosis patients [
13]. A large-scale clinical study involving 51,959 fresh transfer cycles demonstrated that female age is the most significant factor contributing to decreased live birth rates and increased miscarriage rates [
14]. In women aged over 35 years, there is a notable decline in ovarian response to gonadotropins, resulting in reduced oocyte quality and quantity. Furthermore, for women aged 40 and above, there is a significantly higher proportion of clinical low response, with rates reaching up to 50% [
15]. Therefore, encouraging endometriosis patients to undergo assisted reproductive techniques at an earlier stage is crucial to enhance clinical pregnancy and live birth rates.
A cross-sectional study showed that AFC is significantly reduced in endometriosis patients compared to women without endometriosis [
16]. AFC is one of the early predictive indicators used in ovarian stimulation cycles [
17]. The POSEIDON criteria define AFC < 5 in both ovaries as diagnostic indicators of “expected poor ovarian response” and “unexpected poor ovarian response”. These criteria significantly affect the clinical pregnancy rate in individuals with poor ovarian response [
18]. The current study also reflects the important role of AFC in predicting the clinical pregnancy rate in individuals with endometriosis. AMH, secreted by granulosa cells in growing pre-antral and small antral follicles, is currently considered the gold standard for assessing ovarian reserve, as it is not influenced by the menstrual cycle [
19]. However, a retrospective cross-sectional study comparing ovarian responses in endometriosis patients and women with other causes of infertility undergoing IVF/ICSI stimulation showed that the ovarian response in endometriosis patients was considerably reduced than in the control group. This difference persisted even after adjusting for age, gonadotropin dosage, and AMH levels [
20].
However, some research found that the AMH can only predict the number of oocytes but not their quality [
21,
22]. In a study involving infertile patients undergoing IVF/ICSI, endometriosis significantly reduced AFC, AMH levels, retrieved oocytes, follicular maturation rate, and pregnancy rate compared to the control group. However, it did not affect the live birth rate. Moreover, preoperative removal of endometriosis before IVF/ICSI improved follicular maturation rate and pregnancy rate but did not increase the live birth rate [
23]. In addition to AFC and AMH, basal FSH is another indicator of ovarian responsiveness in women. But in our study, basal FSH was not included in the model. Similar studies have previously concluded that FSH is to be inferior to AMH and AFC [
24,
25]. Basal FSH levels are widely variable across menstrual cycles.
Severe endometriosis (classified as stage III-IV according to rAFS) was linked to a reduced cumulative clinical pregnancy rate per retrieval cycle [
26]. This study also revealed a reduced clinical pregnancy rate in fresh transfer cycles for patients with rAFS stage III-IV, which may be attributed to the adverse effects of altered follicular fluid microenvironment on oocyte quality and developmental potential.Additionally, the severity of endometriosis may adversely affect the incidence of gestational diabetes, placenta previa, and small for gestational age in assisted reproductive technology (ART) pregnancies [
27‐
29]. However, these conclusions are currently subject to debate as Geber et al. [
30] found no correlation between IVF outcomes and the severity of endometriosis. Further detailed analysis and extensive research are needed in future studies.
There is still controversy regarding whether pre-implantation GnRH-a administration improves pregnancy outcomes in endometriosis patients. Studies have found that pre-treatment with GnRH-a before frozen embryo transfer in individuals with adenomyosis does not enhance clinical pregnancy and live birth rates [
31]. Meta-analyses by Cao et al. [
32] suggest that the GnRH-a long protocol in IVF-ET of endometriosis patients demonstrated improved clinical pregnancy rates in RCT studies. However, no notable variations were observed in non-RCT studies with different down regulation protocols. In the present research, the long agonist protocol was found to be an independent protective factor for clinical pregnancy in endometriosis patients, which may be related to the improvement of endometrial receptivity in endometriosis patients by the GnRH-a long protocol [
33].
Furthermore, this study demonstrated a correlation between the time interval from laparoscopic surgery to IVF and pregnancy outcomes. The improved pelvic environment and enhanced endometrial receptivity in some endometriosis patients resulting from laparoscopic surgery may contribute to increased clinical pregnancy rates. However, as the time interval increases, the risk of endometriosis recurrence also increases. Additionally, young endometriosis patients who have obtained high-quality embryos can still achieve favorable clinical pregnancy rates. By increasing the number of embryos transferred, the clinical pregnancy rate can be further improved, which provides confidence for young endometriosis patients to pursue assisted reproductive techniques to conceive. Therefore, incorporating these independent influencing factors into the nomogram model is expected to obtain a more accurate predictive ability to guide clinical applications.
This study successfully developed a predictive nomogram model for the fresh cycle pregnancy outcome in patients with endometriosis, considering diagnostic criteria, individual parameters, and relevant laboratory tests. The model demonstrated an AUC of 0.807 (95% CI = 0.782–0.832) in the model group and an AUC of 0.800 (95% CI = 0.761–0.84) in the validation group, indicating a high discriminative ability and good predictive accuracy and specificity. It provides a more comprehensive reference for the development of clinical guidelines and medical decision-making. However, retrospective studies may introduce certain selection biases and result in potential deviations. Autoimmune diseases and other systemic comorbidities are factors affecting pregnancy rates, the model primarily predicts clinical pregnancy probabilities in endometriosis patients devoid of these comorbidities, albeit based on frequently utilized clinical parameters. Furthermore, this model necessitates external validation before clinical implementation.
In conclusion, the predictive nomogram model constructed in this study can be employed to predict and analyze pregnancy outcomes in endometriosis patients. Compared to traditional logistic regression models, the nomogram model is more simple, intuitive, and practical and can provide higher value in clinical applications.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.