Although the field of assisted reproductive techniques (ART) has shown remarkable progress in the past few decades, the pregnancy rate after one cycle of in-vitro fertilization embryo transfer (IVF-ET) remains unacceptably low. Some couples experience implantation failure that is thought to be due to poor endometrial receptivity, embryonic defects, or multifactorial causes [1]. Several uterine pathologies, including a thin endometrium and altered expression of immunological factors and adhesion molecules are likely to be responsible for the reduced endometrial receptivity [2]. Mild uterine cavity abnormalities such as endometrial polyps (EP), micro-EP, and disturbances of the uterine environment such as chronic endometritis (CE) can be readily evaluated and treated by applying hysteroscopic techniques alone, or in combination with pathological diagnosis. Unlike traditional hysteroscopy, the office hysteroscopy procedure is convenient, acceptable, minimally invasive, and does not require cervical dilatation, anesthesia, or hospitalization [3]. Office hysteroscopy by transvaginal ultrasound (TVS) is now widely offered before embryo transfer (ET) [4] in many reproductive centers to women suspected of having uterine disorders, or to those with repeated implantation failure (RIF) [5].

Nevertheless, there is ongoing controversy regarding the timing and value of hysteroscopy for ART. Mao et al. [6] concluded that hysteroscopy increases the implantation and clinical pregnancy rates in women with RIF. However, there is currently insufficient data to confirm the value of hysteroscopy for patients with one implantation failure. In the present study, we performed office hysteroscopy in women who had experienced one or more implantation failures. This was carried out prior to the next frozen embryo transfer (FET), with the aim of assessing the value of office hysteroscopy for improving clinical pregnancy and live birth outcomes.

A total of 1876 patients who met the inclusion criteria were included in this study. The average age of participants was 31.15 $\pm$ 3.56 years (range 20–38 years), and the mean gravida and mean parity were 0.18 $\pm$ 1.06 and 0.15 $\pm$ 0.37, respectively. The average BMI was 21.96 $\pm$ 2.93 kg/m${}^2$. The average infertility duration was 3.51 $\pm$ 2.45 years (range 1–16 years), with 1066 cases of primary infertility and 810 cases of secondary infertility. The main reasons for infertility included pelvic factors (n = 1410), male factor (n = 217), ovulatory disorder (n = 154), and unknown (n = 95). Among the study cohort, 1395 underwent IVF and 481 underwent ICSI. Furthermore, 1318 had undergone one previous ET, and 558 had undergone two or more previous embryo transfer/frozen embryo transfer (ET/FET) cycles, all of which resulted in failed pregnancies.

Patients were divided into four groups according to their pathological diagnosis and hysteroscopic findings. These were the CE group (CE only without EP, n = 392), the CE plus EP group (both CE and EP, n = 586), the EP group (EP only with no CE, n = 385), and the disease-free group (neither CE or EP, n = 513).

Table 1 shows the demographic and baseline characteristics of patients stratified by the pathological diagnosis. No significant differences were observed between the four patient groups in terms of age, BMI, causes and types of infertility, duration of infertility, insemination method, trigger day E2 level, and the number of oocytes retrieved (all p $>$ 0.05). However, significant differences were found in terms of infertility types, COS protocol, and the number of previous failed ET cycles (p 0.05).

Following hysteroscopy and subsequent antibiotic treatment for the CE and the CE plus EP patients, in the next FET cycle no significant differences were found between the four groups in terms of endometrial preparation method, type and number of frozen embryos transferred, interval between hysteroscopy and FET, and there was significance differences in endometrial thickness on transfer day (Table 2).

As shown in Table 3, significant differences in the biochemical pregnancy (57.7% vs. 60.5% vs. 57.4% vs. 66.4%, p = 0.009), clinical pregnancy (50.5% vs. 50.4% vs. 49.5% vs. 58.2%, p = 0.014), and live birth (42.7% vs. 43.1% vs. 42.6% vs. 51.0%, p = 0.011) rates were observed between the four groups. Moreover, pregnancy outcomes for the CE plus EP group were superior to those of the other three groups.

A logistic regression model was applied to identify the demographic and endometrial pathology factors associated with achieving a live birth in the FET cycles after hysteroscopy. These factors included age, BMI, AMH, causes and types of infertility, duration of infertility, insemination method, COS protocol, number of previous failed ET cycles, interval between hysteroscopy and FET, endometrial preparation method, endometrial thickness on the transfer day, number and type of embryos transferred, and endometrial pathological diagnosis. Multivariate logistic regression analysis revealed that live births were significantly related to the women’s age (odds ratio (OR): 0.962; 95% confidence interval (95% CI): 0.934–0.991, p = 0.01), COS protocol (OR: 0.708; 95% CI: 0.593–0.846, p 0.001), number of previous failed ET cycles (OR: 0.780; 95% CI: 0.621–0.980, p = 0.033), endometrial disorder of CE plus EP (OR: 1.551; 95% CI: 1.191–2.019, p = 0.001), interval time between hysteroscopy and FET (OR: 1.325; 95% CI: 1.265–1.388, p 0.001), endometrial thickness on the day of embryo transfer (OR: 1.096; 95% CI: 1.028–1.168, p = 0.005), and number and type of embryos transferred (OR: 2.051; 95% CI: 1.560–2.698, p 0.001 and OR: 1.787; 95% CI: 1.316–2.426, p 0.001), as shown in Table 4.

Uterine cavity abnormalities are considered to be a potentially adverse factor for pregnancy rates following the application of ART [3, 13]. Hysteroscopy allows the uterine cavity to be directly visualized, and intrauterine lesions to be treated immediately. Many centers consider hysteroscopy to be an important instrument in the diagnostic evaluation of uterine-dependent infertility and RIF [14, 15]. Unlike traditional hysteroscopy, office hysteroscopy procedures are minimally invasive and avoid the need for cervical dilatation, anesthesia, or hospitalization [3]. All women enrolled in this study tolerated office hysteroscopy and had no complications.

Currently, hysteroscopy is mainly used to evaluate infertile patients with uterine cavity abnormalities or RIF. Observational studies suggest that patients with uterine anomalies that are removed by hysteroscopy have better reproductive outcomes [16, 17]. Hysteroscopy may offer benefits for patients experiencing RIF, as indicated by the Good Practice Recommendation [5]. Following hysteroscopy, the live birth rate was significantly higher in RIF patients compared to control patients (relative risk (RR): 1.29; 95% confidence interval (95% CI): 1.03–1.62) [18]. Although the present study showed that hysteroscopy is helpful for RIF patients, there is a lack of high-quality studies to support its routine use as a screening and treatment tool in patients with a history of implantation failure. Hysteroscopy before the next frozen blastocyst transfer is recommended for patients with one implantation failure [19]. Moreover, once combined with CE screening (if required), the clinical pregnancy and live birth rates of CE patients were similar to those of the non-CE group. In the current study, patients with one or more implantation failures were enrolled before the next FET. Following adjustment for confounding variables, multivariate logistic regression analysis revealed the live birth rate in patients with one implantation failure was significantly higher than in patients with two or more implantation failures (odds ratio (OR): 0.708, 95% CI: 0.621–0.980, p = 0.033).

Hysteroscopy is a useful tool for the diagnosis and treatment of various intrauterine pathologies, while also allowing the collection of material for pathomorphological evaluation to diagnose CE. CE is a chronic inflammatory condition of the endometrium. In recent years, the attention of reproductive clinicians has increasingly focused on the impact of CE on fertility. Most authors consider CE to be a negative prognostic indicator for patients who have experienced a previous embryo transfer failure. Moreover, the treatment of CE can markedly improve pregnancy rates in IVF treatment [20, 21, 22]. However, it has also been reported that inappropriate antibiotic therapy can delay the recovery from CE and reduce pregnancy rates [23]. The present study found that pregnancy outcomes were associated with pathological outcomes after standardized treatment of CE. The biochemical pregnancy, clinical pregnancy, and live birth rates were significantly higher in the CE plus EP group compared to the disease-free group. Furthermore, similar pregnancy outcomes were observed between the CE group and the disease-free group.

In conclusion, office hysteroscopy combined with pathological diagnosis of the endometrium is a valuable technique for women with a history of implantation failure. This approach is not limited to RIF patients, and results in an increased pregnancy rate and a shorter time to achieve a live birth in ART.

The data sets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request.

TL collected and analyzed data, and wrote the manuscript. LL collected data. LX participated in data analysis and writing of the manuscript. WH contributed to the study design and to revision of the manuscript. The final manuscript was read and approved by all authors, and all authors agreed to submission of the manuscript to CEOG. All authors contributed to editorial changes in the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This research was carried out in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee, West China Second University Hospital, Sichuan University (Approval number, 2019-048). All patients have signed the consent form before assisted reproductive technology (ART).

The authors wish to thank the staff of the Department of Reproductive Medicine of West China Second University Hospital of Sichuan University.

This research received no external funding.

The authors declare no conflict of interest.