Focal Adenomyosis and Uterine Junctional Zone Abnormalities: Predictors of Live Birth Rates in Women with Infertility and Adenomyosis Undergoing Assisted Reproduction Technologies

doi:10.21203/rs.3.rs-8239654/v1

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Focal Adenomyosis and Uterine Junctional Zone Abnormalities: Predictors of Live Birth Rates in Women with Infertility and Adenomyosis Undergoing Assisted Reproduction Technologies

https://doi.org/10.21203/rs.3.rs-8239654/v1

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Purpose: Previous studies have shown that adenomyosis increases the incidence of failure and recurrent miscarriage in patients undergoing in vitro fertilization embryo transfer.This study aimed to evaluate the relationship between the MRI characteristics of women with infertility and adenomyosis and their assisted reproduction technologies outcomes.

Methods: This prospective observational cohort study included 1679 women diagnosed with adenomyosis via 3D ultrasound who underwent assisted reproduction technologies at reproductive center between October 2021 and December 2023. Pelvic magnetic resonance imaging was performed, and assessments were conducted according to standard diagnostic criteria. Baseline demographics, magnetic resonance imaging manifestations, as well as parameters and outcomes of the first embryo transfer cycle were collected. Clinical and imaging predictors of live birth in patients with adenomyosis were identified.

Results: In total, 1,400 women with infertility and adenomyosis underwent magnetic resonance imaging and completed assisted reproduction. The mean age of the participants was 31.84±3.56 years. Ongoing pregnancies were achieved in 815 women, representing an ongoing pregnancy rate of 58.21%, whereas 787 women had live births, indicating a live birth rate of 56.21%. Multivariable logistic regression of magnetic resonance imaging characteristics identified focal adenomyosis and junctional zone abnormalities as predictors of live birth rates.

Conclusion: This study represents a large-scale prospective observational cohort study to explore the relationship between magnetic resonance imaging features of adenomyosis and clinical outcomes of assisted reproduction technologies. Focal adenomyosis and junctional zone abnormalities emerged as factors influencing live birth rates.

focal adenomyosis

junctional zone abnormalities

live birth rate

magnetic resonance imaging

Adenomyosis is a condition characterized by the benign invasion of endometrial tissue into the myometrium, presenting as either diffuse or localized growth. The mean frequency of adenomyosis at hysterectomy is 20%–30% [1,2].The prevalence of adenomyosis in series where the diagnosis was based on imaging is approximately 20%−30% [3,4].Whereas among patients with infertility, the prevalence of adenomyosis ranges from 21%–33%, rising to nearly 50% in those showing clinical symptoms [5].

Assisted reproductive technologies (ART) are essential for managing infertility in patients with adenomyosis. A study has indicated that adenomyosis contributes to 38.2% of in vitro fertilization (IVF) failures and 34.7% of cases of recurrent pregnancy loss [6], underscoring its significant impact on ART outcomes. Additionally, the largest cohort study with a 10-year time span included 7608 pregnant patients with adenomyosis and 566,153 pregnant women without any history of endometriosis. This study found that adenomyosis was 52.1% more likely to present a complication (OR = 1.521). Specifically, compared to non-endometriosis patients, pregnant women with adenomyosis have a higher incidence of IUGR (OR = 1.257 (95% CI: 1.064–1.485) (p = 0.007)); preterm delivery (OR = 1.422 (95% CI: 1.264–1.600) (p = 0.0001)); cesarean delivery (OR = 1.099 (95% CI: 1.002–1.205) (p = 0.046)); hypertensive disorders (OR = 1.177 (95% CI: 1.076–1.288) (p = 0.0001)); (abruption placentae OR = 1.197 (95% CI: 1.008–1.422) (p = 0.040)), and (spontaneous abortion OR = 1.529 (95% CI: 1.360–1.718) (p = 0.0001)) [7].Moreover, in 2024, a case-control study by de Rozario et al. associated adenomyosis with adverse obstetric outcomes, including increased risks of cesarean delivery, intrauterine growth restriction, postpartum hemorrhage, preeclampsia, and prior spontaneous miscarriages [8].

Adenomyosis may exhibit diverse morphological patterns, ranging from mild localized expansion of the junctional zone (JZ) to extensive myometrial hyperplasia and fibrosis, potentially affecting uterine tension and the contour of the endometrial cavity [5]. These variations result in diverse and complex imaging manifestations. While some patients present with subtle and isolated features, others display multiple and severe abnormalities, with various features potentially coexisting or being fully expressed.

Although pathology is considered the “gold standard” for diagnosing adenomyosis, its application is limited by its invasive nature. Moreover, clinical diagnosis for patients with infertility desiring conception relies primarily on symptoms and imaging examinations such as transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI). MRI, a non-invasive and highly accurate diagnostic tool, is often employed as a second-line examination for diagnosing adenomyosis, with reported sensitivity and specificity of 88%–93% and 67%–91%, respectively [9]. However, the specific impact of individual imaging characteristics on diagnosis and prognosis remains unclear. Additionally, the coexistence of different imaging features may reflect varying degrees of disease severity and exhibit distinct effects on pregnancy outcomes. Consequently, previous studies have explored the relationships between various imaging parameters (e.g., uterine diameters [10], number of imaging abnormalities [11,12], internal versus external adenomyosis [13,14], and high--intensity myometrial spots [15]) and disease diagnosis or prognosis.

Therefore, in this study, we aimed to evaluate the relationship between the MRI characteristics of women with infertility and adenomyosis and their ART outcomes, as indicated by ongoing pregnancy and live birth rates.

Participants

This prospective observational cohort study was registered with the Chinese Clinical Trial Registry (ChiCTR2100047809; 2021-06-26) and approved by our ethics committee (ethics approval no.: LL-SC-2021-011; approval date: 25 June 2021). Patient recruitment began in October 2021 and concluded in December 2023.

The inclusion criteria were women requiring ART who met the following criteria: aged between 20–38 years, body mass index ranging from 18.5–28 kg/m², and a diagnosis of adenomyosis via TVUS according to the 2015 and 2018 morphological uterus sonographic assessment criteria [16,17]. All ultrasound diagnoses were performed by two qualified radiologists. The exclusion criteria were: (1) contraindications for IVF or intracytoplasmic sperm injection in either partner (e.g., poorly controlled type I or type II diabetes; unexplained liver disease or liver dysfunction; renal disease or kidney dysfunction; severe anemia; history of deep vein thrombosis, pulmonary embolism or cerebrovascular accidents; poorly controlled hypertension or diagnosed heart disease; history of cervical, endometrial, or breast cancer; and unexplained vaginal bleeding); (2) any conditions affecting pregnancy outcomes, including reproductive tract anomalies (e.g., septate uterus > 1 cm, bicornuate uterus, unicornuate uterus), untreated hydrosalpinx, uterine fibroids > 4 cm in diameter, endometrial thickness < 8 mm, and pituitary tumors or malignancies in any organ or tissue; (3) uncorrected hyperprolactinemia, thyroid dysfunction, or adrenal disease; and (4) undergoing preimplantation genetic testing cycles.

Study Methods

Eligible patients were informed about the study who subsequently provided their written consent before participation. Pelvic MRI was performed by two qualified radiologists. Diagnosis of diffuse adenomyosis via MRI was based on three parameters [3,18]: (1) maximum JZ thickness (JZmax), defined as the maximum thickness of the low-intensity band at the endometrial-myometrial interface; (2) maximum ratio between JZmax and myometrial thickness (ratio max), defined as the ratio of JZmax to the corresponding myometrial thickness at the same level; and (3) presence of hyperintense regions within the myometrium. Focal adenomyosis manifests on T2WI as oval, irregular, or quasi circular masses within the myometrium, with unclear boundaries and low signal intensity similar to the JZ. Scattered punctate or patchy high signal intensity can also be seen within the lesion, manifesting as cystic dilation or bleeding within the lesion [18]. Additionally, basic demographics and MRI features were recorded, including JZmax, presence of hyperintense regions within the myometrium, focal adenomyosis, and JZ abnormalities (e.g., indistinct or poorly defined JZ and finger-like projections).

Ovarian stimulation protocols included antagonist, long, and ultra-long regimens were also recorded. Follicle-stimulating hormone doses were adjusted based on ovarian function, ranging between 112.5–300 IU. Triggering was initiated when follicles with a diameter ≥ 18 mm accounted for more than 50% of all follicles with a diameter ≥ 12 mm. Embryos and blastocysts were scored according to the Gander grading system [19]. Specifically, high-quality embryos were defined as embryos ≥ 6-cell, Grade II, or blastocysts ≥ 4 BB. A maximum of two embryos were transferred per cycle. Frozen embryo transfer protocols included natural, hormone replacement, or gonadotropin-releasing hormone agonist (GnRHa) pretreatment cycles.

Comprehensive data were collected post-assisted reproduction for a single completed transfer cycle (fresh or frozen), including baseline endocrine profile, antral follicle count, ovarian stimulation protocol and duration, total dose of stimulation agent, hormone levels and follicle count on trigger day, oocyte yield, number of mature oocytes, fertilized oocytes, high-quality embryos, and high-quality blastocysts, blastocyst culture outcomes, fresh or frozen transfer details, embryo grading and endometrial thickness at transfer for both fresh and frozen transfers. Additionally, pregnancy outcomes were tracked to live births for pregnant participants, while non-pregnant patients exited the study after one cycle.

Ongoing pregnancy was defined as the detection of a viable intrauterine fetus on ultrasound 68–70 days post-transfer. Live birth was defined as the delivery of a live infant at ≥ 28 weeks of gestation.

Statistical Analysis

Data analysis and visualization were conducted using the R software (version 3.6.3). Continuous variables were analyzed using Wilcoxon rank sum tests; non continuous variables were assessed using Fisher's exact tests and Pearson's Chi squared tests. Use univariate and multivariate logistic regression to analyze the relationship between clinical and imaging indicators and live birth in patients with adenomyosis.

In this study, 1,679 women diagnosed with adenomyosis via 3D ultrasound and undergoing ART met the inclusion criteria, of whom 1,400 diagnosed with adenomyosis via MRI and were included in the analysis. The baseline characteristics of enrolled patients are presented in Table 1. The MRI features of adenomyosis are detailed in Table 2. ART parameters and pregnancy outcomes are summarized in Table 3. The mean age of the participants was 31.84±3.56 years. Ongoing pregnancies were recorded in 815 women (ongoing pregnancy rate: 58.21%), and 787 women had live births, indicating a live birth rate of 56.21%.

Univariate logistic regression analyses were performed to compare clinical and MRI parameters between women who achieved live births and those who did not. The results revealed significant differences in age, number of follicles, anti-Müllerian hormone levels, gravidity, repeated pregnancy loss, number of embryos transferred, two pronucleus zygote (2PN), high-quality blastocysts, and transferred high-quality embryos, endometrial thickness, focal adenomyosis, focal combined with diffuse adenomyosis, abnormal JZ, presence of moderate-to-severe intrauterine adhesions and a scarred uterus, and fresh embryo transfer. Conversely, no significant differences were observed in the uterine diameters (anteroposterior, transverse, longitudinal, and average), uterine wall thickness (anterior, posterior, and fundal), and JZ measurements (anterior wall, posterior wall, and maximum thicknesses). Detailed results are provided in Tables 4 and 5.

Subsequently, multivariate logistic regression analyses were performed to compare clinical and MRI parameters between women who achieved live births and those who did not. The results revealed that focal adenomyosis and JZ abnormalities were predictors of live births in patients with adenomyosis (Table 6). MRI images of focal adenomyosis, and abnormal JZ were showed in Supplementary Figure 1 and 2.

To the best of our knowledge, this study represents the first large-scale prospective observational cohort study to explore the relationship between MRI-detected features of adenomyosis and clinical outcomes of ART, indicated by live birth rates. We found that focal adenomyosis and JZ abnormalities predict live birth rates in adenomyosis.

Most existing studies suggest that women with adenomyosis experience higher miscarriage rates and lower ongoing pregnancy and birth rates[6,20]. In a meta-analysis conducted in 2017, Younes et al. reviewed a total of 18 studies, including nine clinical studies, four prospective cohort studies, and five retrospective cohort studies. Among these studies, six reported that the IVF miscarriage rate was higher in women with adenomyosis, while three studies reported no significant impacts. This discrepancy may stem from the lack of classification or staging of adenomyosis in these studies, as well as differences in the characteristics of the study cohort and the unknown severity of the condition, making it challenging to draw objective and accurate conclusions [6]. Nonetheless, in 2018, Stanekova et al. reported that, after excluding embryo factors, the miscarriage rate in women with adenomyosis was significantly higher than that in those without [20].

Thus, researchers have long been focused on identifying factors and indicators that influence pregnancy outcomes. Accordingly, some studies suggest that JZ thickening in women with adenomyosis negatively impacts pregnancy outcomes. Three distinct layers can be distinguished in the T2-weighted images of women of reproductive age: the endometrium with a high intensity, the outer myometrium with an intermediate intensity, and a low-intensity band in between, referred to as the JZ. The JZ, a unique myometrial band-like structure, was first described by Hricak et al. in 1983 on MRI [21]. A comparison of histological measurements of excised uterine tissue with MRI data revealed that the hyperintense layer on MRI corresponded to the endometrial thickness. Conversely, the low-intensity band only contained the innermost myometrium, characterized by increased cellular density, corresponding to the thickness of the JZ. Subsequently, a more recent study further confirmed the match between the MRI-identified JZ and the histological inner myometrium [22]. Additionally, a retrospective study using the Morphological Uterus Sonographic Assessment (MUSA) criteria to diagnose the outcome of donor assisted pregnancy in patients with adenomyosis showed that uterine volume and diffuse uterine muscle thickening are not related to assisted reproductive outcomes. Instead, the increase in focal lesion diameter is significantly correlated with a decrease in live birth rate, with a decrease coefficient of 0.91; for every 1 cm increase in lesion diameter, the birth rate decreases by 11 times [23]. In contrast to the above results, a prospective observational study on the impact of adenomyosis on in vitro fertilization outcomes in women undergoing donor oocyte transfer in 2024 analyzed the effects of focal adenomyosis, diffuse adenomyosis, or adenomyoma on assisted reproductive outcomes. The results showed that patients with JZ abnormalities had a relative risk of miscarriage that increased by more than three times (relative risk [RR], 3.28; 95% confidence interval [CI], 1.38-7.78). Moreover, the risk of miscarriage doubled in patients with diffuse JZ thickening and severe adenomyosis, while no significant difference was observed in patients with focal adenomyosis [24].

Furthermore, in 2010, Piver et al. explored the relationship between MRI-detected JZ thickness and IVF outcomes, and found a negative correlation between JZ thickness and IVF implantation rates. On this basis, they suggested that MRI-detected JZ thickness could serve as the optimal negative predictor for implantation failure [25]. Thereafter, in recent years, multiple studies have indicated that JZ thickening is associated with implantation failure and mitigated pregnancy rates. After controlling for factors such as advanced age, uterine anomalies, and thin endometrial thickness, studies showed that when the number of transferred embryos, number of high-quality embryos, and pre-transfer endometrial thickness were consistent, the clinical pregnancy rate was significantly lower in the group with a JZmax ≥ 12 mm compared to those with a JZmax < 12 mm [26, 27]. Conversely, the results of this study did not identify JZ thickness as an independent factor influencing the ongoing pregnancy rate or birth rate in women with adenomyosis undergoing assisted reproduction.

Our multiple regression analysis found that focal adenomyosis is one of the reasons affecting the live birth rate of ART in infertile patients. However, unlike previous literature, our study did not find a relationship between the thickness of the JZ and adverse live birth outcomes. Instead, the results of this study revealed that JZ abnormalities on MRI, such as indistinct or difficult-to-observe areas and finger-like indentations, were independent factors influencing live birth outcomes in women with adenomyosis undergoing assisted reproduction.

Most studies and clinicians rely on three main MRI criteria for diagnosing adenomyosis, namely, JZ thickness, JZ-to-myometrium ratio, and the presence of hyperintense regions in the myometrium. However, in 2017, Lisa Agostinho et al. [18] reported several MRI manifestations of adenomyosis beyond these three primary criteria. Additionally, JZ interruption and irregular morphology on 3D ultrasound are listed as ultrasound diagnostic criteria for adenomyosis. Moreover, in 2023, Harmsen et al. [28] described a comparison of MRI and ultrasound features in women with adenomyosis, noting that high-signal intensity spots in the JZ or myometrium on T2-weighted images indicated ectopic endometrial tissue, cystic dilation of endometrial glands, or hemorrhagic lesions. Meanwhile, on transvaginal ultrasound, this appeared as sub-endometrial high-echo lines and buds, JZ interruptions, or hypoechoic cystic areas in the central or external myometrium. Therefore, other JZ abnormalities should be considered for inclusion in the MRI diagnostic criteria in addition to JZ thickening. Thus, the findings of this study expand the scope of MRI diagnostic standards for adenomyosis and provide valuable supporting evidence.

In 2021, an observational cohort study on the MRI manifestations of women with adenomyosis revealed that 109 participants (44.0%) presented exclusively with external adenomyosis. Specifically, the lesion was located in the outer myometrium, separated from the endometrium by an intact JZ and myometrium. Conversely, 78 participants (31.5%) had internal adenomyosis, marked by JZ abnormalities, while maintaining a normal outer myometrium [13]. Owing to the unique anatomical structure of the endometrium, which lacks a submucosal layer for tissue protection, the basal layer and glands are in direct contact with the myometrium. Therefore, repeated endometrial injuries may compromise the integrity of the JZ. Moreover, stromal trophoblasts invade the decidua during embryo implantation. This process triggers initial JZ remodeling, extracellular matrix alterations, uterine smooth muscle relaxation, and spiral artery remodeling, thereby facilitating deep trophoblast invasion [29]. Thus, deficiencies or incomplete remodeling of the inner myometrium are among the contributors to implantation failure. Therefore, in addition to the inflammatory environment caused by adenomyosis, structural changes in the JZ may impair decidualization, leading to inadequate spiral artery remodeling. This disruption in uterine physiology may compromise embryo implantation and successful pregnancy [30].

Moreover, previous research has highlighted a negative correlation between uterine volume and infertility outcomes. A 2023 retrospective cohort study on patients with adenomyosis diagnosed via TVUS undergoing IVF treatment [10] reported that an increased uterine volume was associated with higher miscarriage rates and lower live birth rates. The study identified a uterine volume at eight weeks of gestation (90–130 cm³ for 6–8 weeks of gestation) as a turning point for higher miscarriage rates, as well as a uterine volume at 10 weeks of gestation (130–180 cm³ for 8–10 weeks of gestation, or > 180 cm³ for more than 10 weeks of gestation) as a turning point for lower live birth rates. Additionally, their analysis indicated that patients with a uterus larger than at eight weeks of gestation exhibited significantly higher miscarriage rates, along with lower live birth and cumulative live birth rates across all embryo transfer cycles (fresh and frozen). In contrast, the results of this study did not identify uterine volume as a significant factor influencing pregnancy or live birth outcomes in patients with adenomyosis undergoing assisted reproduction. However, this does not entirely rule out the potential impact of uterine dimensions or JZ thickening on reproductive outcomes. This is because it is possible that patients with larger uterine dimensions in this study may have received more clinical attention, thereby having received appropriate GnRHa pretreatment based on prior studies and clinical experience. Conversely, those with isolated JZ abnormalities identified on MRI, who were perceived as having “mild” conditions, might have been overlooked for GnRHa therapy. Consequently, these findings underscore the need for further randomized controlled trials to explore whether GnRHa pretreatment is beneficial for patients with isolated JZ abnormalities and to determine the optimal pretreatment duration for improving reproductive outcomes.

The strengths of this study include its large-scale and prospective study design. Additionally, our results revealed that focal adenomyosis and abnormal JZs affect the live birth rate of women with adenomyosis. Whereas unlike the results of other studies, no relationship was found between uterine size, JZ thickness, high echogenicity images of the myometrium, and pregnancy outcomes. Notably, previous studies have consistently reported reduced live birth rates in women with adenomyosis. Furthermore, Brosens et al. highlighted that implantation and placental abnormalities were key mechanisms underlying severe pregnancy complications, including late miscarriage, preterm birth, fetal growth restriction, and preeclampsia. These issues are attributed to deep placental damage caused by defective spiral artery remodeling in the JZ [31]. Further randomized controlled trials are warranted to develop targeted interventions for improving pregnancy outcomes in patients with focal adenomyosis and junctional zone abnormalities.

This study had some limitations. First, the participants were selected after a TVS scan and MRI showing signs of adenomyosis, although ultrasound and MRI have good specificity and sensitivity in the diagnosis of adenomyosis. On the other hand, our multiple regression analysis showed no statistical difference in age, the reason for this may be that the included patients were aged 20–38 years, which is relatively young among patients with infertility. Third, we excluded patients with endometrial thickness of <8mm, because we were mainly concerned about the thin endometrium caused by moderate-to-severe intrauterine adhesions, as well as other uterine factors that significantly affect implantation. However, this might have excluded a subset of patients where the adenomyosis affects endometrial proliferation. Further research should include propensity matching to analyze differences in pregnancy outcomes between patients with adenomyosis and those without adenomyosis.

Author contributions

Zhang Shunji, Peng Yangqin, and Gong Fei conceived and coordinated the study,

designed, performed and analyzed the experiments, and wrote the paper. Tang Yi, Cai Sufen, Li Xiaofeng, Guo Hui, Niu Qin, Li Xihong, Yi Zhengxiang, Wang Jian, Lin Ge conducted the data collection, data analysis, and revised the paper. All authors reviewed the results and approved the final version of the manuscript.

Funding statement

This work was supported by the Hunan Provincial Grant for Innovative Province Construction [grant number 2019SK4012] and the research grant of CITIC-Xiangya [grant number YWXM-202205].

Conflict of interest

The authors declare that they have no competing interests regarding authorship or publication of this study.

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Tables 1 to 6 are available in the Supplementary Files section.

No competing interests reported.

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Focal Adenomyosis and Uterine Junctional Zone Abnormalities: Predictors of Live Birth Rates in Women with Infertility and Adenomyosis Undergoing Assisted Reproduction Technologies

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