Ultrasound evaluation of changes in endometrial receptivity from the day of ovulation to the day of transfer in patients with a history of intrauterine adhesions: a prospective cohort study

Introduction

Intrauterine adhesions (IUAs) are characterized by endometrial fibrosis, with partial to complete occlusion of the uterine cavity (1-4). The reported prevalence of IUA varies from 2.9% to greater than 50%, depending on the studied population, diagnostic methods, and classification system used (5,6). The principal clinical manifestations include amenorrhea, changes in menstrual flow, and abnormal pregnancy (7).

Hysteroscopic adhesiolysis is the standard treatment for removing IUA and restoring uterine structure (8). However, multiple studies have reported high rates of infertility and pregnancy complications in patients with IUA even after surgical repair (9-11). The exact mechanisms are not well established and are presumably associated with poor endometrial receptivity (ER) (12).

Transvaginal sonography (TVS) is a common diagnostic method for evaluating ER. In our previous study (13), we conducted an ultrasound evaluation of ER changes from the ovulation day to the transfer day in patients with a normal uterine cavity during natural cycles and observed several changes, such as morphology changes from type C to type B, increased endometrial thickness, and decreased volume. Liu et al. (14) reported that the changes in endometrial volume could aid in predicting the in vitro fertilization (IVF) outcome, whereas the changes in endometrial thickness and endometrial blood flow were not predictive. On the basis of these findings, we sought to determine whether patients with a history of IUA show similar ER changes.

To address these questions, we aimed to identify the changes in ER indices from the ovulation day to the transfer day in patients with a history of IUA during natural cycles. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2034/rc).

Methods

Study design and participants

We conducted a prospective cohort study of infertile women with a history of IUAs undergoing frozen-thawed embryo transfer (FET) at the Reproductive & Genetic Hospital of CITIC-Xiangya (Changsha, China) from March 2019 and September 2023, and 161 women who met the inclusion criteria were enrolled in the analysis. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of the Reproductive & Genetic Hospital of CITIC-Xiangya (No. LL-SC-2019-023). Informed consent was obtained from all individual participants.

The inclusion criteria were as follows: (I) FET performed after adhesiolysis; (II) a natural FET cycle; (III) age 20–35 years; (IV) a body mass index of 18–24 kg/m²; and (V) at least 1 high-quality embryo. The exclusion criteria were as follows: (I) endometriosis, adenomyosis, or adenomyoma; (II) endometritis; (III) congenital uterine malformations; (IV) untreated hydrosalpinx; and (V) uterine cavity fluid due to diverticulum of caesarean section (diameter ≥2 mm).

Adhesiolysis

All included patients underwent complete adhesiolysis in the Reproductive & Genetic Hospital of CITIC-Xiangya before the IVF procedure. Hysteroscopic adhesiolysis of the IUA was performed by an experienced surgeon while the patient was under general anesthesia. IUA was graded according to the American Fertility Society classification (15). The adhesions were incised using bipolar energy (Olympus, Tokyo, Japan) and/or hysteroscopic scissors (Karl Storz, Tuttlingen, Germany) until the uterine cavity was reached. After surgery, a heart-shaped intrauterine balloon (Cook Medical, Bloomington, IN, USA) or a Foley catheter was inserted into the uterine cavity in patients with moderate–severe adhesions. Crosslinked hyaluronan gel (MateRegen, BioRegen Biomedical, Changzhou, China) was used in routine fashion. All patients received standardized postoperative antibiotic therapy (0.25 g of cefuroxime axetil and 0.5 g of tinidazole orally, twice a day) for 7 days. None of the patients received hormone replacement therapy (HRT) for endometrial healing following the operation. For patients with mild IUAs, transfer was considered in the month of surgery or the following month. Patients with moderate-to-severe adhesions could generally enter the transfer cycle after two menstruations.

IVF procedure

On the basis of the cause of infertility, fertilization was achieved by means of IVF or intracytoplasmic sperm injection. Freezing and thawing were performed according to the manufacturer’s instructions (Vitrolife AB, Gothenburg, Sweden). A maximum of two frozen embryos were transferred. Thawed cleavage-stage embryos were transferred on the third day after fertilization (blastocysts were transferred on the fifth day after fertilization). The embryo morphology scores were assigned according to the ASEBIR (Spanish Society for the Study of Reproductive Biology) consensus (16).

Ultrasound measurement

All included patients underwent TVS scans on the day of ovulation and embryo transfer. All ultrasound indicators for ER evaluation were examined by the same sonographer with the same ultrasound instrument (Voluson E8, GE HealthCare, Chicago, IL, USA).

The endometrial thickness was measured in the longitudinal plane. The Gonen criterion (17) was adopted to classify endometrial morphology as follows: type A, a homogeneous hyperechogenic endometrium lacking a visible central echogenic line; type B, an echo of the endometrium similar to that of the surrounding uterine muscle layer, with the central echogenic line either missing or not obvious; and type C, a “triple-line” endometrium, composed of a protruding outer and central hyperechogenic lines and inner hypoechogenic areas (Figure 1).

Figure 1 Two-dimensional ultrasound image showing endometrial morphology. (A) Type A. (B) Type B. (C) Type C.

The movement of the endometrium was observed over a 3-minute period and divided into five types based on the study by Ijland et al. (18) as follows: (I) positive wave, the wave from the cervix to the fundus; (II) negative wave, the wave from the fundus to the cervix; (III) static wave, the endometrium in a static state; (IV) bidirectional wave, endometrium of both the fundus and the cervix contracting simultaneously; and (V) random wave, an irregular motion with uncertain direction or multiple starting points.

Classification of endometrial blood distribution was based on the Applebaum criteria (19) as follows: (I) vessels that penetrate the hypoechoic area but do not enter the hyperechoic outer endometrial margin; (II) vessels that penetrate the hyperechogenic outer edge of the endometrium but do not enter the hypoechogenic internal area; and (III) vessels that enters the hypoechogenic internal area of the endometrium (Figure 2).

Figure 2 Power Doppler image showing the blood flow pattern of the endometrium. (A) Pattern I. (B) Pattern II. (C) Pattern III.

The ultrasound device was switched to three-dimensional (3D) mode with power Doppler. The outline of the endometrium was depicted via virtual organ computer-aided analysis (VOCAL) software. The endometrial volume, vascularization index (VI), vascularization flow index (VFI), and flow index (FI) were also analyzed (20,21) (Figure 3).

Figure 3 Three-dimensional image showing the vascularization parameters of the endometrium and endometrial volume. The yellow circle depicts the area of the endometrium, with 4.73 as its volume.

Outcome measures

All patients were followed up for outcomes after transfer; no patients were lost to follow-up in this study, and no values for key variables of interest due to prospective data collection were missing. The serum human chorionic gonadotropin (HCG) levels were measured at 14 days after cleavage embryo transfer (12 days after blastocyst transfer), and TVS scans were performed 4 weeks after transfer to observe the location and survival of pregnancy.

The primary outcome was clinical pregnancy, which was considered an intrauterine pregnancy confirmed via ultrasound. According to whether clinical pregnancy had been achieved, all included patients were divided into a pregnancy group and nonpregnancy group. The differences in the ER ultrasound indices between the pregnant and nonpregnant groups were analyzed. Additionally, pairwise comparisons were conducted to evaluate the changes in ER from ovulation day to transfer day in the entire study population, pregnant group, and nonpregnant group. According to the degree of IUA, the included patients were further allocated to the mild IUA subgroup or moderate-to-severe IUA subgroup, and the aforementioned analyses were performed for each subgroup.

Statistical analysis

The demographic distribution of patients was analyzed using the Kolmogorov-Smirnov test. Continuous variables are represented as the mean ± standard deviation (SD), while categorical variables are expressed in as frequency (percentage). The Mann-Whitney test or Student t-test was used to evaluate continuous variables, while the Chi-squared test or the Fisher’s exact test was used to evaluate differences in categorical variables. The differences in continuous ultrasound indicators were evaluated with the Wilcoxon signed-rank test or paired t-test, and the categorical ultrasound indicators were evaluated with the McNemar Chi-squared test. All the statistical analyses were performed with R software version 4.3.2 (The R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics and ultrasound parameters

The flowchart for patient inclusion is shown in Figure 4. The overall clinical pregnancy rate was 67.70% (109/161). There were no significant differences in patient characteristics between the pregnancy and nonpregnancy groups (P>0.05). With respect to the ultrasound ER parameters on ovulation day, compared with the nonpregnant group, the pregnant group had a significantly higher endometrial volume (P=0.029), subendometrial volume (P=0.021), subendometrial VI (P=0.028), and subendometrial VFI (P=0.022). On the transfer day, the proportion of type B endometrial morphology (P<0.001) and the frequency of endometrial peristalsis (P=0.009) were significantly greater in the pregnant group (Table 1).

Figure 4 Flowchart of patient inclusion.

Changes in ultrasound indicators

The type C endometrial morphology was most common on ovulation day, but on the transfer day, type B morphology was the most common for the entire population, pregnant population, and nonpregnant population. From the day of ovulation to the day of transfer in the overall population, there was a significant increase in endometrial thickness (P<0.001) and significant decreases in other ultrasound indicators (P<0.05).

Except for the frequency of endometrial peristalsis (P<0.001), there were no significant differences in the ultrasound indicators in the nonpregnant group. Except for that of the subendometrial volume (P=0.017), the change in the pregnancy group was similar to that in the general population (Table 2).

We further subtracted the absolute values of each ultrasound indicator on the day of ovulation from the absolute values on the transfer day. Patients were classified into no change, increased, or decreased groups according to a change of 0, >0, or <0, respectively. The probability of pregnancy was greater in patients in the decreased group with subendometrial VI, FI, or VFI as compared to patients in the increased group (Table 3).

Subgroup analysis according to the degree of IUA

Patient characteristics and ultrasound parameters

The clinical pregnancy rate of patients with moderate-to-severe IUA (six with severe IUA) was 68.60% (59/86), and that of patients with mild IUA was 66.67% (50/75). There were no significant differences in any of the characteristic between the pregnancy and nonpregnancy groups among patients with either moderate-to-severe or mild IUA (P>0.05; Table 4).

On the day of ovulation, subendometrial FI (P=0.047) was significantly greater in the pregnant group than in the nonpregnant group in patients with moderate-to-severe IUA; however, the endometrial volume (P=0.005), subendometrial volume (P=0.003), and frequency of endometrial peristalsis (P=0.011) were significantly greater in the pregnant group of patients with mild IUA. On the transfer day, the proportions of type B endometrial morphology (P<0.001), endometrial thickness (P=0.009), endometrial volume (P=0.015), and subendometrial volume (P=0.044) and the frequency of endometrial peristalsis (P=0.023) were significantly greater in the pregnant group than in the nonpregnant group among patients with mild IUA.

Changes in ultrasound indicators

Type C endometrial morphology was more prevalent on the day of ovulation, but on the day of transfer, type B morphology was more prevalent in the entire population, pregnant group, and nonpregnant group among patients with moderate-to-severe or mild IUA.

There were significant increases in endometrial thickness (P=0.002), endometrial VI (P=0.019), and endometrial VFI (P=0.010) and significant decreases in other ultrasound indicators from the ovulation day to the transfer day in the group of patients with moderate-to-severe IUA (P<0.05).

Furthermore, there was a significant increase in endometrial thickness (P=0.011) and significant decreases in other ultrasound indicators in the group of patients with mild IUA (P<0.05).

In the nonpregnancy group, the frequency of endometrial peristalsis was significantly lower (P<0.005), and there was no significant difference in other ultrasound indicators between the patients with moderate-to-severe IUA and those with mild IUA (P>0.05).

Except for a significant decrease in endometrial VI (P=0.013) and subendometrial FI (P=0.014), the changes in other ultrasound indicators in the pregnancy group were similar to those in the overall group among patients with moderate-to-severe IUA. In addition, except for significantly reduced endometrial FI (P=0.040), the changes in other ultrasound indicators in the pregnant group were similar to those in the overall group among patients with mild IUA (Table 5).

The probability of pregnancy was greater in the increased group than in the decreased group; however, the subendometrial FI and VFI were lower in the decreased group in patients with moderate-to-severe IUA. Meanwhile, the probability of pregnancy was greater only in the decreased group of patients with subendometrial FI but not in the increased group of patients with mild IUA (Table 6).

Discussion

In this study, we performed ultrasound assessments of ER changes from the day of ovulation to the day of transfer in patients with a history of IUA during natural cycles of FET. The results revealed that the changes in the ER ultrasound indices in patients with a history of IUA were similar to those in patients with a normal uterine cavity: the morphology of the endometrium mostly changed from type C to type B, the thickness of the endometrium increased, and the volume and frequency of peristalsis decreased. The blood supply of both the endometrium and subendometrium decreased significantly in the pregnant group but not in the nonpregnant group. In the moderate-to-severe IUA population, there were no significant differences in the ER indicators between pregnant and nonpregnant patients, whereas among patients with mild IUA, the endometrial thickness, volume, and blood supply were greater, while endometrial peristalsis was more common in the pregnant group than in the nonpregnant group.

ER plays a decisive role in the success of pregnancy (22). Endometrial thickness, morphology and volume are the most commonly used indicators in clinical practice (23). In this study, in patients with a history of IUA, the thickness of the endometrium increased while the volume decreased from the ovulation day to the transfer day, which is consistent with what we observed in patients with a normal uterine cavity (13). Thus volume reduction may be due to endometrial compaction, which is considered to be associated with an increased clinical pregnancy rate (24,25). These changes were more pronounced in patients with mild IUA, possibly because damage to the endometrium was more severe in patients with moderate-to-severe IUA, leading to the endometrial changes being less pronounced in these patients. The morphology of the endometrium, whether in patients with adhesions or a normal uterine cavity, changes from mainly type C to mainly type B, which reflects the transition process of the endometrium to the secretory phase in response to hormones as preparation for embryo implantation.

We found that the frequency of endometrial peristalsis decreased from the day of ovulation to the day of transfer regardless of pregnancy; that is, the endometrium gradually became calm during embryo implantation. However, on the day of transfer, the frequency of endometrial peristalsis in the group was higher than that in the pregnancy group. This suggests that although the frequency of endometrial peristalsis needs to be reduced in the endometrium, it seems that some peristalsis is still needed to achieve pregnancy, and this phenomenon is consistent with that observed in patients with a normal uterine cavity (13).

Endometrial and subendometrial blood flow can be objectively and reliably measured with 3D power Doppler ultrasound. Interestingly, the blood supply of the patients in the pregnant group was significantly lower than that of the patients in the nonpregnant group, especially in terms of changes in subendometrial FI. Previous research has suggested that subendometrial FI is the strongest predictive factor among 3D Doppler flow indices (26). Fraser et al. (27) reported that there was a significant increase in the middle-to-late follicular phase, followed by a substantial decrease. Raine-Fenning et al. (28) also found that endometrial and subendometrial blood flow on 3D ultrasound increased during the proliferative phase, peaking approximately 3 days prior to ovulation before decreasing from the nadir 5 days post-ovulation; moreover, they discovered that the degree of change in endometrial perfusion is a more important determinant of the ER. This finding is consistent with what we observed in this study and in patients with a normal uterine cavity (13).

Although hysteroscopy is considered a safe surgery, it is not without certain complications, such as uterine perforation, bleeding, severe pain, and infection. For infertile women, preoperative medication treatment may be advisable. However, there is no conclusive data to determine which preoperative treatment is the best. Etrusco et al. reported that the use of norgestrel acetate/estradiol and oral dienogest/ethinylestradiol treatment can rapidly, satisfactorily, and inexpensively prepare the endometrium before office hysteroscopy and outpatient hysteroscopy, respectively, thereby improving surgical outcomes and patient compliance (29,30). These experiences are worth learning and may serve as a reference.

Our work has several significant advantages. First, we prospectively analyzed a cohort to examine the changes in multiple ER ultrasound indicators from the day of ovulation to the day of transfer in patients with a history of IUA. Second, we further analyzed the changes in endometrial ER in patients with mild or moderate-to-severe disease. However, this study also involved several limitations. First, only the natural cycles of infertile populations were studied, and the reliability of these results needs to be further validated through larger samples and a wider population. Second, the clinical pregnancy rate was the focus of our study, so we did not track the live birth rate, and this should be examined in future. Moreover, among patients with moderate-to-severe IUA, the proportion of severe adhesions was relatively small, which may have a certain impact on the observation results. Additionally, patients with mild and moderate-to-severe adhesions had different time intervals between adhesiolysis and transfer. Whether this different time interval has an impact on receptivity was not examined in our study.

Conclusions

During the natural cycles of patients with a history of IUA, the morphology of the endometrium mostly changes from type C to type B, with an increase in endometrial thickness and a decrease in the volume and frequency of peristalsis. The blood supply of both the endometrium and subendometrium decreases significantly in pregnant women but not in nonpregnant women. The results of this study provide a better understanding of the changes in ER in patients with a history of IUAs, which may inform the pretransfer discussion with these patients.

Acknowledgments

The authors would like to thank the staff at the Reproductive Center and Imaging Department of the Reproductive & Genetic Hospital of CITIC-Xiangya for the data collection in the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2034/rc

Funding: This work was supported by grants from the National Key Research and Development Program of China (No. 2022YFC2702500), the Research Grant of CITIC-Xiangya (No. YNXM-201908), and the Hunan Provincial Grant for Innovative Province Construction (No. 2019SK4012).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2034/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of the Reproductive & Genetic Hospital of CITIC-Xiangya (No. LL-SC-2019-023). Informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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