Retrospective Study Open Access
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Sep 19, 2025; 15(9): 109175
Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.109175
Anxiety and depression in recurrent implantation failure after frozen-thawed embryo transfer and efficacy of endometrial receptivity testing
Ya-Bin Guo, Bin Tang, Ling Zhang, Xue Wu, Center of Reproductive Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde 415000, Hunan Province, China
Zhi-Hua Huang, Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde 415000, Hunan Province, China
ORCID number: Ya-Bin Guo (0009-0006-3259-6701); Bin Tang (0009-0009-8978-9119); Ling Zhang (0009-0003-9980-8906); Xue Wu (0009-0005-5662-1097); Zhi-Hua Huang (0009-0005-0339-5460).
Author contributions: Guo YB designed the study, analyzed the data, and performed the experiments; Guo YB, Tang B, Zhang L, and Wu X collected the data; Guo YB and Huang ZH prepared the manuscript; and all authors read and approved the final manuscript.
Institutional review board statement: This study was approved by the Medical Ethics Committee of the First People’s Hospital of Changde city.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zhi-Hua Huang, Associate Chief Physician, Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), No. 818 Renmin Road, Changde 415000, Hunan Province, China. hzhgyb@163.com
Received: May 14, 2025
Revised: June 22, 2025
Accepted: July 15, 2025
Published online: September 19, 2025
Processing time: 104 Days and 2 Hours

Abstract
BACKGROUND

Despite advances in the use of in vitro fertilization-embryo transfer (ET) in couples with infertility, recurrent implantation failure (RIF) after ET is still a major problem affecting women, with great psychological and economic burdens for the patient and his/her family.

AIM

To investigate the psychological burden (anxiety and depression) and evaluate the clinical benefits of endometrial receptivity testing (ERT) in patients experiencing RIF following frozen-thawed ET.

METHODS

A retrospective cohort study analyzed 371 patients experiencing RIF after assisted reproductive treatment at the First People’s Hospital of Changde City between January 2021 and June 2024. Demographic and clinical data were systematically collected through standardized questionnaires. Psychological assessment utilized validated instruments: The Self-Rating Depression Scale for depression evaluation and the Self-Rating Anxiety Scale for anxiety assessment. Participants were stratified by psychological status (anxiety/non-anxiety and depression/non-depression) to analyze influencing factors for anxiety and depression. The cohort was further categorized into the ERT and non-ERT groups based on ERT implementation to comparatively analyze their clinical outcomes. Additionally, they were divided into clinical and nonclinical pregnancy groups to identify factors affecting clinical pregnancy using univariate and multivariate logistic regression models. Compared with the non-ERT group, the 226 patients who underwent ERT-guided ET achieved a higher clinical pregnancy rate, thicker endometrium on transfer day, fewer embryos transferred, and a lower miscarriage rate.

RESULTS

The study identified a substantial psychological burden, with anxiety prevalence at 55.0% (mean Self-Rating Anxiety Scale score, 50.89 ± 9.34) and depression at 61.2% (mean Self-Rating Depression Scale score, 55.55 ± 9.48). Multivariate analysis identified annual household income > 100000 yuan as protective factors against both anxiety and depression, whereas advanced maternal age (> 35 years) and multiple implantation failures (≥ 3) served as risk factors. Additionally, anxiety-specific risk factors included prolonged infertility treatment (> 5 years) and the spouse’s status as an only child. As to depression-specific risks, chronic infertility (> 3 years) and higher educational attainment (college/bachelor’s degree or higher) were key determinants, whereas urban residence was a protective factor. Age > 35 years was a risk factor for clinical pregnancy in patients experiencing RIF, whereas blastocyst-stage ET, a higher number of embryos transferred, and thicker endometrium were protective factors.

CONCLUSION

Patients experiencing RIF are particularly susceptible to anxiety and depression, and advanced maternal age and multiple implantation failures represent salient risk factors. Clinicians should implement proactive and evidence-based interventions to mitigate these psychological burdens. For patients experiencing RIF, ERT-guided ET demonstrates significant potential to improve assisted reproductive outcomes.

Key Words: Recurrent implantation failure; Frozen-thawed embryo transfer; Psychological distress; Uterine receptivity assessment; Reproductive outcomes

Core Tip: Repeated implantation failures, i.e., three consecutive embryo transfer failures, occur in ≥ 20% of patients undergoing assisted conception, which not only imposes a huge economic burden on the patients but also brings about greater physical and psychological trauma. This study investigated the incidence of anxiety and depression in patients experiencing repeated implantation failures and analyzed factors influencing these conditions to propose a feasible and effective intervention model aimed at alleviating psychological distress and ultimately improving clinical pregnancy and birth rates.



INTRODUCTION

In China, infertility is clinically defined as the failure to achieve pregnancy after 1 year of regular unprotected intercourse in couples living together[1]. The evolution of assisted reproductive technology (ART) has offered new hope for conception among couples with infertility[2]. Contemporary data indicate that clinical pregnancy rates for conventional in vitro fertilization-embryo transfer (ET) and intracytoplasmic sperm injection remain modest at approximately 40%[3,4]. Among ART approaches, frozen-thawed ET (FET) has emerged as a fundamental strategy, which involves the cryopreservation of viable embryos for subsequent thawing and transfer during optimal cycles[5]. FET demonstrates improved outcomes with clinical pregnancy rates > 50% per transfer cycle and implantation rates > 40%; however, a significant proportion of morphologically competent embryos still fail to successfully implant - a clinical challenge referred to as “implantation failure”[6]. Recurrent implantation failure (RIF) is a condition characterized by unsuccessful implantation following (1) ≥ 3 ETs; (2) Transfer of 4-6 high-grade cleavage-stage embryos; or (3) ≥ 3 high-quality blastocysts, which affects 10%-15% of FET cycles[7]. The etiology of RIF is multifactorial, involving embryonic competence, endometrial receptivity (ER), immunological factors, and other unidentified mechanisms[8-10].

Notably, patients experiencing RIF constitute approximately ≥ 20% of ART recipients, presenting substantial clinical and psychosocial challenges. In addition to the considerable financial burden, these individuals often experience profound psychological distress that may precipitate familial discord, marital strain, or even relationship dissolution, with particularly detrimental effects on women[11]. Empirical evidence confirms that psychological stressors can negatively influence in vitro fertilization outcomes through endocrine dysregulation and increased uterine contractility, thereby compromising embryo implantation[12]. Women experiencing RIF endure not only the physical demands of treatment but also multidimensional pressures spanning financial, familial, and social domains, rendering them vulnerable to various psychological comorbidities, such as low self-esteem, mood disturbances, anxiety disorders, and clinical depression[13]. These findings underscore the critical need for targeted psychological support in this patient population. A comprehensive understanding of the determinants of anxiety and depressive symptoms in patients experiencing RIF represents an essential foundation for the development of effective interventions.

Patients experiencing RIF require targeted interventions to increase treatment success. A study indicated that endometrial non-receptivity is a principal contributing factor to RIF[14]. The human endometrium exhibits embryo acceptance capability exclusively during the temporal window of implantation (WOI). Conventional clinical practice has relied on standardized estimations of WOI timing. However, significant interindividual variability in WOI characteristics implies that implantation failure may occur even in some patients receiving high-quality embryos[15]. Consequently, the development of robust methodologies for ER assessment represents a critical need for optimizing ET outcomes in RIF cases. A significant advancement in this field emerged in 2019 with Yikon Genomics’ development of ER testing (ERT)[16]. This innovative RNA sequencing-based technology comprehensively evaluates the expression profiles of more than ten thousand genes in endometrial tissue, utilizing artificial intelligence and machine-learning algorithms to precisely classify endometrial status into three distinct phases: Pre-receptive, receptive, and post-receptive. ERT enables the formulation of patient-specific ET protocols for subsequent menstrual cycles, thereby facilitating ET synchronization with individual WOI characteristics to maximize implantation potential[17]. The present study adopted a dual approach: (1) Examining the prevalence and determinants of anxiety and depression among patients experiencing RIF; and (2) Evaluating the clinical efficacy of ERT technology and identifying prognostic factors influencing pregnancy outcomes. These findings are anticipated to provide clinically actionable insights for increasing reproductive success in this challenging patient population.

MATERIALS AND METHODS
Study population

Clinical data from 371 patients diagnosed with RIF who underwent ART treatment at The First People’s Hospital of Changde City between January 2021 and June 2024 were retrospectively analyzed. The inclusion criteria were as follows: (1) Diagnosis of RIF with the willingness to undergo FET; (2) Failure to achieve a clinical pregnancy following at least two consecutive transfers of high-quality embryos, defined as a minimum cumulative total of four day-3 embryos and two blastocysts; (3) Age < 40 years at the time of oocyte retrieval; and (4) Availability of complete medical records. The exclusion criteria were as follows: (1) Concurrent severe reproductive system or endocrine disorders; (2) Untreated hydrosalpinx (without proximal tubal ligation); (3) Previous endometrial pathology; (4) Significant psychological trauma within the preceding 12 months; (5) Chromosomal abnormalities in either partner; (6) Current malignancy; (7) Endometrial thickness < 7 mm before FET; (8) Congenital uterine anomalies; (9) Treatment discontinuation during the study period; and (10) Incomplete clinical documentation. Participants completed a structured questionnaire survey, with 410 questionnaires distributed and 371 valid responses obtained, resulting in a response rate of 90.49%.

Methods

Data collection: Demographic and clinical data were extracted from patients’ electronic medical records. Demographic characteristics included age, body mass index, marital status, educational attainment, annual household income, only-child status, and residential area. Clinical parameters comprised the duration of infertility, cause of infertility, and the embryo type transferred.

Psychological evaluation: Psychological status was assessed using standardized questionnaires: The Self-Rating Depression Scale (SDS) for depressive symptoms and the Self-Rating Anxiety Scale (SAS) for anxiety symptoms. Depression assessment (SDS): The 20-item SDS utilizes a 4-point Likert scale (1-4) for each item. The sum of all item scores was converted to a standardized score by multiplying by 1.25, with the result rounded to the nearest integer. Based on Chinese normative data, SDS scores were interpreted as follows: 53-62, mild depression; 63-72, moderate depression; 72, severe depression (cutoff value, 53 points). Anxiety assessment (SAS): Similarly, the 20-item SAS employs a 4-point rating scale (1-4). The total raw score was transformed into a standardized score using the same conversion method (× 1.25 and rounding). According to Chinese norms, SAS scores were categorized as mild anxiety (50-59), moderate anxiety (60-69), and severe anxiety (> 69; cutoff: 50).

ERT protocol

Patients were stratified into two cohorts: Those who underwent ERT-guided personalized ET (ERT group) and those who followed the standard protocol (non-ERT group). The treatment regimen was initiated on day 3 of the menstrual cycle with oral estradiol valerate (4-6 mg/day) for 14 days, followed by intramuscular progesterone (specification, 1 mL: 20 mg) at 60 mg/day for 5 days for endometrial preparation. In the ERT group, endometrial biopsies were obtained on day 6 of progesterone administration. The duration of progesterone administration for transformation was adjusted based on the ERT results before FET. The non-ERT group proceeded directly to FET on day 6 of progesterone supplementation. Pregnancy outcomes were assessed through serial monitoring: Serum human chorionic gonadotropin quantification 12 days after FET, followed by transvaginal ultrasound confirmation of clinical pregnancy, which was defined as visualization of an intrauterine gestational sac, 30 days after FET for human chorionic gonadotropin-positive cases. Study participants were subsequently classified into either the clinical pregnancy or nonclinical pregnancy groups. Primary outcome measures included miscarriage rate, number of embryos transferred, ET on the day of transfer, and clinical pregnancy rate.

Data processing

The psychological status questionnaire survey was conducted by trained interns from our hospital. Before data collection, all investigators underwent standardized training to ensure a clear understanding of the study’s objectives and significance, key research components, appropriate questionnaire administration, and mandatory requirements for obtaining informed consent. Patient communication techniques were employed during the survey. To ensure data accuracy, all questionnaires were independently double-entered into Excel by two researchers, followed by systematic cross-verification to maintain data integrity and reliability.

Statistical analysis

Data were analyzed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, United States). Continuous variables were presented as mean ± SD and compared using independent samples t-tests. Categorical variables were expressed as frequencies and percentages, and between-group differences were assessed by χ2 tests. Multivariate logistic regression models were constructed to identify significant factors associated with anxiety, depression, and pregnancy failure. For all analyses, significance was set at P < 0.05.

RESULTS
Anxiety and depression assessment in patients experiencing RIF

Among the 371 patients experiencing RIF, the mean anxiety score was 50.89 ± 9.34, and the average depression score was 55.55 ± 9.48. Using standard cutoff values (anxiety, 50 points; depression, 53 points), 55.0% of the patients screened positive for anxiety symptoms and 61.2% for depressive symptoms. According to the anxiety and depression scores, of 371 patients, 204 experienced anxiety, whereas 167 did not; 227 patients experienced depression, whereas 144 did not (Table 1).

Table 1 Comparative analysis of Self-Rating Anxiety Scale and Self-Rating Depression Scale scores among study participants.
Total (n = 371)
Group
Score
SAS score50.89 ± 9.34Anxiety (n = 204)57.91 ± 4.67
Non-anxiety (n = 167)42.31 ± 5.73
SDS score55.55 ± 9.48Depression (n = 227)62.00 ± 4.92
Non-depression (n = 144)45.38 ± 4.92
Factors associated with anxiety and depression in patients experiencing RIF by univariate analysis

Univariate analysis of the 204 anxiety-positive cases vs 167 anxiety-negative cases revealed significant intergroup differences (P < 0.05) regarding age, marital status, annual household income, infertility duration, infertility cause, spouse’s only-child status, duration of fertility treatment, and number of failed implantation attempts. Similarly, significant differences (P < 0.05) were observed for age, educational attainment, annual household income, residential area, infertility duration, infertility cause, and number of failed implantation attempts between 227 patients with and 144 without depression (Table 2).

Table 2 Univariate analysis of factors associated with anxiety and depression in patients with recurrent implantation failure.
Characteristics
Anxiety group (n = 204)
Non-anxiety group (n = 167)
χ2/t
P value
Depression group (n = 227)
Non-depression group (n = 144)
χ2/t
P value
Age (years)--9.6550.002--13.0010.000
≤ 358395--9286--
> 3512172--13558--
BMI (kg/m2)22.08 ± 2.0921.82 ± 2.281.1490.25121.91 ± 2.0422.04 ± 2.380.5810.562
Marital status--5.1710.023--0.2530.615
First marriage103104--12978--
Remarriage10163--9866--
Educational attainment--0.4020.526--2.1600.023
Senior high school/technical secondary school or below9180--9477--
College/bachelor's degree or above11387--13367--
Annual household income (in ten thousand yuan)--9.9310.007--21.832< 0.0001
< 54919--5315--
5-108887--11560--
> 106761--5969--
Occupation--1.1170.773--5.2190.157
Work unit5138--4841--
Self-employed4642--6226--
Farmer5449--6241--
Unemployed5338--5536--
Residential area--1.9220.166--7.0380.008
Urban115106--12398--
Rural8961--10446--
Type of infertility--0.7030.402--0.1670.683
Primary8476--9664--
Secondary12091--13180--
Infertility duration (years)--13.0120.002--9.4260.009
< 35158--5060--
3-58159--8654--
> 57250--9130--
Cause of infertility--9.8710.020--9.8960.019
Male-factor5157--7038--
Female-factor8645--7655--
Combined male-female-factor3133--3133--
Unexplained 3632--5018--
Female party’s only-child status--1.1000.294--0.0560.813
Yes8377--9961--
No12190--12883--
Spouse’s only-child status--5.6020.018--2.0360.154
Yes12471--12669--
No8096--10175--
Infertility treatment duration (years)--17.0330.001--7.2020.066
< 16857--7847--
1-34060--6238--
3-53724--4417--
> 55926--4342--
Number of failed implantation attempts--12.3010.001--18.081< 0.0001
291105--10096--
≥ 311362--12748--
Multivariate analysis of anxiety-related factors in patients experiencing RIF

All variables demonstrating significant associations with anxiety levels in the univariate analysis of 371 patients were subsequently entered into a multivariate logistic regression model. The regression analysis treated anxiety status as the binary outcome variable (0: Non-anxiety, 1: Anxiety), and significant univariate factors served as covariates. The multivariate analysis revealed that annual household income exhibited a protective effect, with both the 50000-100000 yuan [hazard ratio (HR) = 0.336, P = 0.002] and > 100000 yuan (HR = 0.369, P = 0.008) categories showing significantly lower anxiety risk than the < 50000 yuan reference group. Moreover, prolonged infertility treatment (> 5 years) emerged as a significant risk factor (HR = 3.089, P = 0.004) relative to the < 1-year reference group. Additional independent risk factors included advanced maternal age (> 35 years; HR = 2.124, P = 0.002), spouse’s only-child status (HR = 2.078, P = 0.002), and multiple implantation failures (≥ 3 attempts; HR = 2.192, P = 0.002). These findings are presented in detail in Table 3.

Table 3 Multivariate logistic regression analysis of anxiety-related risk factors in patients with recurrent implantation failure.
Variable
β
SE
Wald
P value
HR
95%CI
Constant-0.3400.5390.3980.5280.712-
Age (0: ≤ 35, 1: > 35)0.7530.2409.8760.0022.1241.328-3.397
Marital status (0: First marriage, 1: Remarriage)0.3660.2362.3950.1221.4420.907-2.291
Annual household income (0: < 5 thousand yuan)--9.6080.008--
1: 5-10 thousand yuan-1.0910.3589.2630.0020.3360.166-0.678
2: > 10 thousand yuan-0.9970.3737.1450.0080.3690.177-0.766
Infertility duration (0: < 3 years)--2.9810.225--
1: 3-5 years0.1500.3310.2060.6501.1620.607-2.225
2: > 5 years-0.4390.3491.5830.2080.6450.325-1.278
Cause of infertility (0: Unexplained)--5.3980.145--
1: Male-factor-0.0360.3430.0110.9160.9650.492-1.891
2: Female-factor0.4400.3371.7120.1911.5530.803-3.300
3: Combined male-female-factor-0.3050.4000.5820.4460.7370.336-1.614
Spouse’s only-child status (0: No, 1: Yes)0.7320.2369.6140.0022.0781.309-3.300
Infertility treatment duration (0: < 1 year)--19.2820.000--
1: 1-3 years-0.6230.3293.5940.0580.5360.282-1.021
2: 3-5 years0.2060.3630.3210.5711.2290.603-2.504
3: > 5 years1.1280.3938.2260.0043.0891.429-6.676
Number of failed implantation attempts (0: 2, 1: ≥ 3)0.7850.2529.7260.0022.1921.339-3.591
Multivariate analysis of depression-associated risk factors in patients experiencing RIF

A multivariate logistic regression analysis was performed incorporating factors that demonstrated significant differences (P < 0.05) in the initial univariate analysis of the anxiety profiles of 371 patients. Depression status served as the dichotomous outcome variable (0: Depression, 1: Non-depression), with significant univariate factors entered as covariates. The results revealed that higher annual household income (> 100000 yuan) conferred protection against depression compared with the < 50000 yuan reference (HR = 0.278, P = 0.001). When unexplained infertility was set as the reference, both female-factor infertility and combined male–female-factor infertility were associated with a lower risk of depressive symptoms (female factor, HR = 0.438, P = 0.023; combined factor, HR = 0.261, P = 0.001). Compared with an infertility duration of < 3 years, > 3 years was identified as a risk factor for depression (3-5 years, HR = 1.901, P = 0.034; > 5 years, HR = 3.129, P < 0.001). Furthermore, age > 35 years (HR = 2.008, P = 0.004), higher educational attainment (college/bachelor’s degree or higher; HR = 1.705, P = 0.030), and ≥ 3 implantation failure attempts (HR = 2.211, P = 0.002) were all significant risk factors for depression. In contrast, urban residence (HR = 0.450, P = 0.002) emerged as a protective factor. Complete multivariate regression results are presented in Table 4.

Table 4 Multivariable logistic regression analysis of depression-associated risk factors in patients with recurrent implantation failure.
Variable
β
SE
Wald
P value
HR
95%CI
Constant-0.7870.5132.3490.1252.196-
Age (0: ≤ 35, 1: > 35)0.6970.2448.1780.0042.0081.245-3.239
Educational attainment (0: Senior high school/technical secondary school or below, 1: College/bachelor’s degree or above)0.5330.2454.7320.0301.7051.054-2.757
Annual household income (0: < 5 thousand yuan)--13.9300.001--
1: 5-10 thousand yuan-0.5450.3792.0690.1500.5800.276-1.219
2: > 10 thousand yuan-1.2810.38411.1480.0010.2780.131-0.589
Residential area (0: Rural, 1: Urban)-0.7990.2609.4360.0020.4500.270-0.749
Infertility duration (0: < 3 years)--12.7230.002--
1: 3-5 years0.6420.3044.4750.0341.9011.048-3.446
2: > 5 years1.1410.32112.6430.0003.1291.669-5.868
Cause of infertility (0: Unexplained infertility)--11.1260.011--
1: Male-factor-0.5310.3762.0000.1570.5880.281-1.228
2: Female-factor-0.8240.3625.2010.0230.4380.216-0.891
3: Combined male-female-factor-1.3440.42110.2110.0010.2610.114-0.595
Number of failed implantation attempts (0: 2, 1: ≥ 3)0.7940.2569.6100.0022.2111.339-3.652
Comparative analysis of pregnancy outcomes between the ERT and non-ERT groups

Compared with the non-ERT group, the ERT group demonstrated significantly better reproductive outcomes, including higher clinical pregnancy rates, greater ET on the day of transfer, fewer embryos transferred, and lower miscarriage rates (all P < 0.05, Table 5).

Table 5 Pregnancy outcome comparison: Endometrial receptivity testing vs non-endometrial receptivity testing groups, n (%).
Variable
Clinical pregnancy rate
Endometrial thickness on the day of transfer (mm)
Number of embryos transferred
Miscarriage rate
ERT group (n = 226)115 (50.9)9.67 ± 0.731.26 ± 0.2114
Non-ERT group (n = 145)45 (31.0)9.38 ± 0.701.39 ± 0.2018
χ2/t14.1913.7602.8964.335
P value0.00020.00020.0040.037
Univariate analysis of clinical pregnancy predictors

Based on pregnancy outcomes, patients were stratified into the nonclinical (n = 211) and clinical (n = 160) pregnancy groups. Univariate analysis revealed significant associations between clinical pregnancy and maternal age, embryo type transferred, number of embryos transferred, total treatment cycles, ET, and anxiety/depression status (P < 0.05). No significant correlations were found with body mass index, infertility type, or infertility duration (P > 0.05). The complete analysis is presented in Table 6.

Table 6 Univariate analysis of clinical pregnancy determinants.
Variable
Clinical pregnancy group (n = 160)
Non-clinical pregnancy group (n = 211)
χ2/t
P value
Age (years)40.251< 0.0001
≤ 3510771
> 3553140
BMI (kg/m2)22.05 ± 2.3021.87 ± 2.070.9250.355
Type of infertility3.7890.052
Primary60100
Secondary100110
Infertility duration (years)1.0420.594
< 34367
3-56377
> 55467
Embryo type transferred26.251< 0.0001
Blastocyst-stage embryo9569
Cleavage-stage embryo65142
Number of embryos transferred (n)1.33 ± 0.471.16 ± 0.373.8980.0001
Total treatment cycles1.53 ± 0.501.85 ± 0.416.839< 0.0001
Endometrial thickness (mm)10.08 ± 0.619.17 ± 0.5514.980< 0.0001
Anxiety6.4160.011
Yes100104
No60107
Depression4.7230.030
Yes108119
No5292
Multivariate analysis of factors influencing clinical pregnancy in patients experiencing RIF

The clinical pregnancy outcomes (0: Pregnancy, 1: Non-pregnancy) of patients experiencing RIF served as the dependent variable. Significant variables identified in Table 6 were included as independent variables, with the following specifications: Total cycle number, number of embryos transferred, and ET were analyzed as continuous variables using their original values. Multivariate logistic regression analysis revealed that advanced maternal age (> 35 years) significantly increased the risk of failed clinical pregnancy. Conversely, blastocyst-stage ET, high number of transferred embryos, and greater ET demonstrated protective effects (P < 0.05). Notably, anxiety levels, depression scores, and total treatment cycles were not significantly associated with pregnancy outcomes. Complete results are presented in Table 7.

Table 7 Multivariate analysis of clinical pregnancy failure in recurrent implantation failure patients.
Variable
β
SE
Wald
P value
HR
95%CI
Constant14.8652.21045.2440.0002855143.310-
Anxiety (0: No, 1: Yes)0.3410.2791.5010.2201.4070.815-2.430
Depression (0: No, 1: Yes)0.3220.2861.2680.2601.3790.788-2.414
Age (0: ≤ 35, 1: > 35)1.4800.28926.3090.0004.3942.496-7.735
Embryo type transferred (0: Cleavage-stage embryo, 1: Blastocyst-stage embryo)-1.1070.28015.6380.0000.3300.191-0.572
Number of transferred embryos (continuous variable)-0.7860.3146.2790.0120.4560.246-0.843
Total treatment cycles (continuous variable)0.4970.2823.1160.0781.6440.947-2.856
Endometrial thickness (continuous variable)-1.5650.22050.4610.0000.2090.136-0.322
DISCUSSION

RIF represents a significant clinical challenge in ART, with multifactorial etiology involving embryonic, immunological, and uterine factors[8-10]. This condition is frequently accompanied by psychological comorbidities, particularly anxiety and depression. Current evidence presents that patients experiencing RIF undergoing medical interventions exhibited noticeable depressive symptoms and substantial deterioration in quality of life[18]. The psychological effect of RIF on patients undergoing ART is profound, often resulting in diminished treatment confidence and the development of anxiety–depressive disorders caused by cumulative psychological stress. Consequently, mental health assessment and intervention should constitute an integral component of RIF management.

In our cohort of 371 patients experiencing RIF, prevalence rates of anxiety (55.0%) and depression (61.2%) were high, underscoring the substantial psychological burden in this population. Multivariate regression analysis identified several significant psychosocial determinants: An annual household income > 100000 yuan served as a protective factor against both anxiety and depression, whereas advanced maternal age (> 35 years) and multiple implantation failures (≥ 3) emerged as independent risk factors. These findings align with existing literature documenting high levels of psychological distress, including doubt, irritability, and anxiety, among patients undergoing ART - with RIF cases demonstrating particularly severe manifestations[19,20]. International evidence has consistently shown that patients who had implantation failures experience significantly greater psychological distress during subsequent ETs compared with treatment-naïve individuals[21]. The substantial financial burden associated with repeated ART cycles further compounds this distress, with RIF placing considerable economic strain on families. Notably, higher household income serves as a protective factor by alleviating financial concerns associated with treatment costs. Additionally, > 5 years of infertility treatment and having an only-child spouse were specifically associated with increased anxiety risk. This observation may be explained by two key mechanisms: First, the cumulative effect of multiple treatment cycles significantly influences patients’ psychological resilience, as invasive procedures such as oocyte retrieval and ET can cause considerable physical discomfort with repeated attempts. This physical burden, combined with the emotional toll of repeated failures, contributes to worsening anxiety over time[22]; second, the sociocultural context plays a crucial role in patient distress. Deep-rooted traditional values in Chinese society regard childbearing as a fundamental female responsibility, creating substantial psychosocial pressure for infertile women. When the spouse is an only child, the pressure intensifies because of heightened expectations to “continue the family lineage”. Furthermore, repeated treatment failures often strain marital and family relationships, compounding emotional distress[23]. Furthermore, the findings of this study reveal distinct patterns for depression risk factors: Infertility duration > 3 years and higher educational level (college/bachelor’s degree or higher) were associated with increased risk, whereas urban residence demonstrated a protective effect. Chronic infertility appears to foster depressive symptoms through persistent concerns about reproductive potential. The relationship between educational attainment and depression presents a complex picture. Although some studies report an inverse correlation[24], the present data suggest that higher education may paradoxically increase depression risk in the Chinese context. This phenomenon may reflect the dual pressures faced by educated women - while benefiting from greater educational opportunities in China’s developing economy, they simultaneously face intense competition in an increasingly saturated job market, creating significant psychological stressors[22]. Geographical (rural vs urban) disparities in mental health outcomes are also evident, consistent with international findings[25-27]. Compared with urban residents, rural populations demonstrate higher depression rates, likely attributable to characteristic challenges including relative poverty and limited access to resources[28,29]. These environmental factors may contribute to the development of depressive disorders in disadvantaged regions.

Finally, clinical pregnancy outcomes were evaluated in patients undergoing ERT, and contributing factors in RIF cases were analyzed. The results demonstrate that ERT significantly increases clinical pregnancy rates among patients experiencing RIF. This result is consistent with those of other studies. For instance, Tan et al[30] demonstrated that a significant proportion of patients with a history of implantation failure of a euploid embryo have a displaced WOI as detected by the ERT. FET success critically depends on optimal ER during embryo implantation. The human endometrium exhibits a narrow receptivity window, typically occurring 7 days post-luteinizing hormone surge, 5 days post-progesterone administration, or between days 20 and 24 of the menstrual cycle. Although traditional models presumed a fixed WOI, emerging evidence indicates substantial interpatient variability, with some demonstrating advanced, delayed, or abbreviated WOI periods - all of which adversely affect implantation success[31]. ERT addresses this variability by precisely identifying the optimal WOI through endometrial transcriptomic profiling, demonstrating guiding significance. This study revealed several significant associations: Advanced maternal age (> 35 years) emerged as an independent risk factor for reduced clinical pregnancy rates in patients experiencing RIF. Conversely, blastocyst-stage transfers, increased number of transferred embryos, and greater ET demonstrated protective effects. Maternal age remains a predominant determinant in the outcomes of fertility treatment, with advancing age correlating with diminished ovarian reserve, poor response to stimulation, high aneuploidy rates, and compromised embryo quality. These age-related factors, compounded by the cumulative physical and psychological burden of multiple failed cycles, substantially reduce treatment success[32]. The superior performance of blastocyst-stage ETs stems from extended in vitro culture that allows the natural selection of more viable embryos. This additional 2-3 days of cultivation enhances embryo-endometrium synchronization, better replicating natural conception dynamics and consequently improving implantation potential, compared with cleavage-stage embryos. Furthermore, transferring a modestly higher number of embryos can further improve implantation success, thereby increasing the overall pregnancy rates.

CONCLUSION

Collectively, patients experiencing RIF following ART frequently experience pronounced anxiety and depression, reflecting diminished psychological well-being. Key contributing factors include lower annual household income, chronic infertility, multiple failed implantation attempts, and a spouse’s only-child status. Given these findings, clinicians should prioritize mental health support for patients experiencing RIF, offering targeted psychological interventions to mitigate distress and bolster treatment confidence. Additionally, ERT demonstrates significant promise in optimizing FET outcomes for patients experiencing RIF. By guiding personalized transfer strategies, ERT may increase the clinical pregnancy rates, providing a valuable tool in the management of this challenging patient population.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Psychiatry

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B, Grade C

Novelty: Grade B, Grade C

Creativity or Innovation: Grade B, Grade B

Scientific Significance: Grade C, Grade C

P-Reviewer: Gravani S; Hosseini SJ S-Editor: Bai Y L-Editor: A P-Editor: Zhang XD

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