The EMT is an effective means of predicting endometrial receptivity, and patients with a thin endometrium were associated not only with lower pregnancy outcomes [3] but also with higher perinatal and neonatal risks [16]. We defined a thin endometrium in this study as EMT ≤ 7.5 mm on hCG trigger day which is the threshold commonly used in the literature [2, 9, 16].
Some studies have pointed out that the pregnancy rate of patients with an EMT of 7–8 mm is lower than that of patients with an EMT > 8 mm in FET cycle [17]. According to Liu et al., the pregnancy rates decline as the EMT decreases below 7 mm in FET cycles [18]. The etiology of thin endometrium is complicated, mainly including endocrine disorder and endometrial injury caused by various reasons, as well as age factors and idiopathic thin endometrium. The main pathophysiological features of thin endometrium are: poor growth of glandular epithelium, high blood flow impedance of uterine radial artery, decreased expression of vascular endothelial growth factor and poor vascular development [19]. Thin endometrium affect pregnancy outcomes, may be associated with the local high oxygen concentrations near the endometrial basal layer. The endometrial oxygen tension is mainly affected by the uterine spiral arteries. When the basal layer is thin or absent, the implanting embryo is much close to the spiral artery and the high vascularity and oxygen concentrations near the basal endometrium, compared with the normal endometrial surface with low oxygen tension [20]. However, some scholars believe that there is no obvious correlation between EMT and pregnancy rates, or there is only a correlation when EMT is combined with other relevant parameters for statistical analysis [21]. Gingold et al. [22] suggested that endometrial pattern, rather than endometrial thickness, affects the pregnancy outcomes. EMT is not the only factor that affects endometrial receptivity, but it is one of the main factors. Thin endometrium may reduce the implantation rate of the embryo, thus adversely affecting the pregnancy outcomes. Our study found that women with EMT ≤ 7.5 mm on hCG trigger day, if the EMT increased to 7.5 mm during the subsequent FET cycle, the pregnancy outcomes of them were better than that of women whose EMT cannot reach 7.5 mm on FET cycle. This is a summary of our central data and a supplement to previous studies. Our data show that if the EMT of patients with thin endometrium can be increased to 7.5mm during FET cycle, the pregnancy outcomes can be improved.
To the best of our knowledge, the nomogram we developed here is the first to predict the probability of an EMT > 7.5 mm in the subsequent frozen cycle for women with a thin endometrium. In our analysis of 628 thin endometrial patients who adopted the “freeze all” strategy, we found that the absence of a hysteroscopic adhesiolysis history, and the presence of PCOS, the application of clomiphene in the ovarian stimulation process, and the application of a GnRH agonist short protocol, mild stimulation protocol, natural cycle protocol for ovarian stimulation, and natural cycle for endometrial preparation in the next frozen cycle increased the possibility of EMT > 7.5 mm in the subsequent frozen cycle. The AUC of the predictive model was 0.76, denoting good discrimination. The model was tested on an independent validation cohort of 454 patients, and also showed a good discriminative capacity (AUC 0.71). Additionally, the model calibrated well in both the modeling and validation cohorts.
Our nomogram is a user-friendly graphical model based on clinically significant characteristics. We predict that it will help determine whether it is necessary to cancel the fresh cycle and freeze the embryo for endometrial preparation to obtain an EMT of ≥7.5 mm in patients undergoing IVF/ICSI treatment when the EMT ≤ 7.5 mm on HCG trigger day. Our model could also provide individualized and targeted consultations for patients with a thin endometrium.
We screened a number of characteristics that might affect endometrial growth (Table 1), and identified those for MLR analysis by preliminary screening through univariate logistic regression analysis combined with a study of the literature and clinical experience. Stepwise backward variable selection was used to determine independent predictors, which identified five meaningful variables: hysteroscopic adhesiolysis history, PCOS, application of clomiphene in ovarian stimulation process, ovarian stimulation protocol, and endometrial preparation protocol.
Repeated or severe intrauterine operation will cause damage to endometrium. For example, when performing curettage, surgical instruments will directly contact endometrium. Improper operation hurts basal layer and muscular layer of the endometrium, which may result in intrauterine adhesions (IUAs). Due to the limited repairment of the endometrium, scar wound is formed, which will eventually lead to local or complete occlusion of the uterine cavity, and develop into thin endometrium [23]. With the development of hysteroscopic technology, hysteroscopic adhesiolysis has become the standard method for the treatment of IUAs. Patients with intrauterine adhesions are only allowed to undergo IVF/ICSI after hysteroscopic adhesiolysis and re-examination of hysteroscopy indicate that the uterine cavity morphology has returned to normal. In patients with IUAs, the morphology of the uterus may be restored by hysteroscopic adhesiolysis, but the function of the endometrium may not be completely restored. Our study found that patients with thin endometria who have a history of IUAs were less likely to have an EMT > 7.5 mm in the frozen cycle. If the patient’s endometrium is “hypotrophic” because of the IUA history, they can try direct fresh embryo transfer. Interestingly, we found that thin endometrial women with PCOS were significantly more likely to have an EMT > 7.5 mm in the following frozen cycle versus thin endometrial women without PCOS. The “freeze all” strategy was originally proposed for patients with PCOS [24]. Frozen embryo transfer can recover the ovary from ovarian stimulation and the exposed endometrial lining may also be shed, providing a new starting point for both. For thin endometrial women with PCOS, frozen embryo transfer may obtain a thicker endometrium and reduce the risk of OHSS.
During IVF/ICSI, clomiphene can promote the growth of ovarian follicles, resulting in auxiliary stimulation. However, clomiphene is a selective estrogen receptor modulator that exhibits both estrogenic agonist and estrogenic antagonist activities at the endometrial level, thereby affecting endometrial thickness and receptivity [25, 26]. Based on our findings, we recommend frozen embryo transfer for patients with thin endometria receiving clomiphene for ovarian stimulation to allow the endometrial lining to grow and possibly thicken. Another factor influencing the probability of EMT > 7.5 mm in the frozen cycle is the ovarian stimulation protocol. In our study, the applications of a GnRH agonist short protocol, mild stimulation protocol, and natural cycle protocol were associated with an increased probability of EMT > 7.5 mm in the frozen cycle compared with a GnRH agonist long protocol. This may be related to the clomiphene applied in the mild stimulation protocol.
The type of endometrial preparation protocol most suitable for patients with a thin endometrium is controversial. We found that a natural cycle was more likely to be associated with an EMT > 7.5 mm for thin endometrial women during frozen embryo transplantation compared with those using programmed and minimal ovarian stimulation cycles. Some studies [27–29] reported that pregnancy outcomes and the endometrial thickness of patients with a natural cycle were significantly higher than in those with a programmed cycle, and that the decrease in clinical pregnancy rate in those with a programmed cycle may be related to endometrial receptivity damage and early closure of the “implantation window”. However, it is noteworthy that the populations of these studies include patients with a thin endometrium but are not restricted to them. Another study [30] identified no difference in pregnancy outcome between patients with a natural and programmed cycle. Additionally, Zheng et al. [31] found that embryo implantation and clinical pregnancy rates of thin endometrial patients with a programmed cycle were significantly higher than in those with a natural cycle, suggesting that the programmed cycle is more suitable. However, there was no difference in endometrial thickness between the two groups.
Our predictive model can evaluate the probability of EMT > 7.5 mm in frozen embryo transfer for each patient with a thin endometrium. Our study found that when the EMT of patients with a thin endometrium increased to 7.5mm during the frozen embryo transfer cycle, the pregnancy outcomes were better. Therefore, our nomogram could help clinicians refer patients with a thin endometrium either to receive fresh embryo transfer directly or to adopt a “freeze all” strategy for frozen embryo transfer. Of course, the application of a “freeze all” strategy needs to consider many factors, and our findings only provide advice at the endometrial level. However, our model cannot be used to predict pregnancy outcomes, and further research is needed. Our study is also limited by its retrospective nature that cannot exclude all potential biases, and the fact that the conclusions should be further tested in a randomized controlled study. Additionally, our study only included data from one reproductive center, and there were no independent verification cohorts from other hospitals.