Factors influencing clinical pregnancy failure in patients with RIF treated with the IVF-ET technique: a cohort analysis based on a propensity score approach

doi:10.21203/rs.3.rs-3248465/v1

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Factors influencing clinical pregnancy failure in patients with RIF treated with the IVF-ET technique: a cohort analysis based on a propensity score approach

https://doi.org/10.21203/rs.3.rs-3248465/v1

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Objective

To investigate the risk factors for clinical pregnancy in patients with recurrent embryo implantation failure (RIF) treated with in vitro fertilization-embryo transfer (IVF-ET) technique.

Methods

1074 patients treated with IVF-ET were matched for propensity score to reduce the effect of confounding factors. The final endometrial receptivity analysis (ERA) group and the conventional frozen embryo transfer (FET) group were each matched to 204 cases, with 201 in the failed pregnancy group and 207 in the successful pregnancy group. Their basic demographic characteristics and relevant clinical data were collected, and the Kaplan-Meier method was used to estimate the survival curves of the patients' pregnancy rates, and the factors influencing them were analysed using Cox regression models.

Results

The success and failure rates of clinical pregnancies in patients with RIF were 50.74% and 49.26%, respectively. Patients in the failed pregnancy group did not receive an ERA, had > 3 previous implantation failures, and were transferred with a single embryo, with no quality embryos transferred.

Conclusion

Not receiving an ERA, having > 3 previous implantation failures, using single embryo transfer and not transferring quality embryos are risk factors for clinical pregnancy in patients with RIF.

IVF

recurrent embryo implantation failure

clinical pregnancy failure

risk factors

With the rapid development of society, changes in people's lifestyles, deteriorating living environments, as well as increased social pressure and artificial termination of pregnancy, infertility has become the third most prevalent human disease after cancer and cardiovascular diseases [1]. In China, no fewer than 50 million women suffer from infertility, accounting for about 15% of women of childbearing age [2]. Infertility is defined as the absence of a clinical pregnancy in a couple who have been sexually active for at least twelve months without the use of contraception [3]. Infertility affects 5–8% of couples in developed countries and up to 30% in developing countries [4]. Assisted Reproductive Technology (ART) offers hope to families desiring a new life, and includes Artificial Insemination, In Vitro Fertilization - Embryo Transfer (IVF-ET) and a range of techniques derived from it. IVF-ET, also known as 'in vitro fertilization', is a technique in which the egg and sperm are removed from the body, fertilized outside the body, developed into an embryo and then transferred back into the mother's uterus to achieve conception. In vitro fertilization-embryo transfer is a relatively recent but rapidly developing research technique [5].

Embryo implantation is the process by which an embryo migrates and attaches itself to the surface of the endometrial cavity and then buries itself deeper and deeper into the endometrium, eventually 'settling'. In assisted reproduction, the failure to conceive after three or even more IVF attempts is known medically as Recurrent Embryo Implantation Failure (RIF). RIF remains the speed-limiting step in ART. Many researchers have used the observation of an intrauterine gestational sac on ultrasound as a criterion for implantation success or failure when describing RIF [6, 7]. Endometrial Receptivity Analysis (ERA) is a genetic diagnostic method based on transcriptional genomics, which analyses the expression of 248 genes associated with the window of implantation, allowing a more accurate assessment of the endometrial window of implantation status and finding the right "window of implantation" (WOI) for the woman undergoing treatment [8]. "It is an important tool in the treatment of recurrent embryo implantation failure [8]. To the best of our knowledge, there is a lack of relevant studies on pregnancy risk factors in the RIF population in China. Therefore, the aim of this study was to investigate the risk factors affecting pregnancy in the Chinese RIF population and to provide a basis for relevant institutions and personnel to develop effective strategies.

Study subject

Patients with RIF who received infertility treatment at Jinjiang District Maternal and Child Health Hospital in Chengdu City between November 1, 2019 and August 31, 2022 were selected for this study and their relevant data were collected. Verbal informed consent was obtained from all participants. Inclusion criteria: age between 18 and 45 years; BMI between 18.5 and 30 kg/m2; couples experiencing multiple embryo implantation failures (at least 3 cycles of embryo transfer, or transfer of at least 3 quality blastocysts with a Gardner score of 4BB or higher) [9]; at least 1 remaining blastocyst with a Gardner score of 4BB or higher. Exclusion criteria: patients with genetic disorders, anatomical abnormalities of the reproductive tract, infections; patients with more severe abnormal semen quality or weak spermatozoa in the male partner. Ultrasound-confirmed uterine malformations, abnormal karyotype, hormonal or metabolic disorders and known clinical autoimmune disorders. Patients with incomplete documentation of relevant clinical outcomes such as pregnancy and delivery.

The patients included in this study were all patients with recurrent embryo implantation failure (RIF). 239 patients in the ERA group and 513 patients in the FET group were included in the study who met the criteria before propensity score matching. A caliper matching method was used, with a caliper value of 0.02 and a matching ratio of 1:1. Ultimately, the ERA and FET groups were successfully matched to 204 pairs. Among them, there were 207 cases in the successful pregnancy group and 201 cases in the failed pregnancy group.

Endometrial sampling and processing

Patients in the ERA group received personalised embryo transfer (PET), while those in the FET group received only conventional frozen embryo transfer. patients in the ERA group underwent ERA testing under hormone replacement therapy (HRT) cycles or natural cycles [10]. In the HRT cycle, 300 mg of progesterone softgels Utrogestan (CYNDEA PHARMA SL; Olvega, Spain) were taken every 12 hours at the beginning for 120 ± 3 h. A sterile pipette (Jiaobao Healthcare Technologies Ltd, China) was used to collect 50 to 70 mg of endometrial biopsy samples from the base of the uterus on Dydrogesterone tablets (dydrogesterone) (Abbott Biologics Ltd.; Amstelveen, The Netherlands) were administered twice daily (P + 5) 20 mg on day 5 after the start of menstruation. Endometrial specimens were sampled 7 days after the luteinizing hormone surge (LH + 7) or 7 days before the administration of human chorionic gonadotropin (hCG + 7) during the natural cycle. All endometrial specimens were transferred to frozen tubes (Biosigma S.p.A.; Kona, Italy) containing 1.5 mL of RNA late solution (Qiagen GmbH; Hilden, Germany) and shaken vigorously to stabilize the genetic material in the tissue. Endometrial specimens were kept at 4°C for at least 4 hours or stored at -20°C and then shipped at room temperature for final ERA testing. patients in the FET group did not receive ERA but underwent transfer of embryos 120 to 126 hours after luteal transformation.

Variable selection

Risk factors for pregnancy failure in older infertile patients receiving ART were set as follows.

Dependent variable: IVF-ET clinical pregnancy success, IVF-ET clinical failure.

Independent variable: Variable setting: 0 for ERA, 1 for FET; 0 for age < 35 years, 1 for age ≥ 35 years; 0 for BMI < 24kg/m2, 1 for ≥24kg/m2; 0 for sinus follicle count (AFC) ≥ 4, 1 for < 4; 0 for anti-Müllerian testicular hormone (AMH) ≥ 2, 1 for < 2; 0 for follicle stimulating hormone (FSH) ≥ 1.7, 1 for 1 for less than 1.7; 0 for ≤ 3 previous implantation failures, 1 for > 3 previous implantation failures; 0 for normal endometrial thickness, 1 for abnormal; 0 for single embryo transfer, 1 for transfer of two embryos; 0 for no quality embryos transfer, 1 for quality embryos transfer.

Clinical pregnancy criteria: first pelvic ultrasound performed 30 to 35 days after embryo transfer, with at least one gestational sac and primitive cardiac pulsation detected in the uterine cavity and no gestational sac outside the uterus.

Miscarriage criteria: Miscarriage after ART can be defined as spontaneous termination of pregnancy throughout the gestational cycle, including embryo abortion and stillbirth. Biochemical pregnancy failure is defined as positive serum hCG 2 weeks after embryo transfer and no gestational sac detected on ultrasound 1 month later. Biochemical pregnancies, spontaneous abortions and ectopic pregnancies are all considered pregnancy failures.

Statistical analysis

All statistical analyses were performed using the statistical software R language version 4.2.3. The Kolmogorov-Smirnov test was used to test the distribution of continuous variables. All measurements were expressed as mean ± standard deviation (SD) or quartiles, median, and all categorical data were described as numbers and percentages. Comparisons of measures were made using the t-test or wilcoxon ran-sum test, and categorical data were tested using the chi-square test. Survival analysis was performed using the Kaplan-Meier method, using the number of transplant cycles as the unit of analysis. In the survival analysis, the cumulative clinical pregnancy rate and cumulative live birth rate were compared using the logrank test. Multivariate analysis was performed using Cox proportional risk models. P-values < 0.05 were considered statistically significant.

After propensity scores were matched at a ratio of 1:1, the ERA and control groups were matched to 204 cases each, and a balanced comparison between the two groups showed no statistically significant differences in all covariates (p>0.05), indicating that the baseline was balanced and well matched after the matching treatment was applied to both groups. See Table 1.

Table 1.Baseline profiles of patients in the ERA and FET groups after propensity score matching
Features	ERA（n=204）	FET（n=204）	x²/t/Z	P-value
Female age（y）	33.53±3.68	33.27±4.21	0.651	0.515
BMI（kg/m²）	21.32±2.71	21.25±2.73	0.262	0.793
AFC	17	16	0.644	0.802
	(11.00,22.00)	(11.25,21.75)
AMH（ng/ml）	3.51	3.78	1.040	0.230
	(2.41,5.61)	(2.77,5.42)
FSH（IU）	7.22	7.48	0.891	0.405
	(6.00,8.35)	(6.21,8.79)
No. of previous implantation failure	2	3	1.217	0.224
	(2.00,3.00)	(2.00,3.00)
Endometrial thickness（mm）	9.5	9	1.337	0.056
	(8.50,10.50)	(8.00,10.50)
No. of embryos transferred, n（%）			0.041	0.840
1	82(40.2)	84(41.2)
2	122(59.8)	120(58.8)
Number of high quality embryos, n（%）			0.288	0.866
0	74（36.3）	69（33.8）
1	81(39.7)	83(40.7)
2	49(24)	52(25.5)

Abbreviations: AMH, Anti-Müllerian hormone; BMI, body mass index; ERA, endometrial receptivity array; FET, frozen-thawed embryo transfer; FSH, folliclestimulating hormone.

Figure 1 shows the propensity score distribution jitter plot, which represents the distribution of propensity score values between the matched and unmatched patients in the ERA and FET groups (unmatched treatment units represent the unmatched ERA group, matched treatment units represent the matched ERA group The distribution of propensity score values between matched and unmatched patients (unmatched treatment units represent the unmatched ERA group, matched treatment units represent the matched ERA group, unmatched control units represent the unmatched FET group) gives an idea of the effect of matching. The position of the dots indicates the size of the patient's propensity score. The results in Figure 1 show that the distribution of propensity score values for the matched ERA and FET groups are relatively close to each other and the matching effect is good.

Of the 408 RIF patients investigated, 207 were diagnosed as clinically pregnant with a clinical pregnancy rate of 50.74%. The results of the survival analysis showed that the clinical pregnancy rate in the ERA group increased as the number of transfer cycles increased, with the clinical pregnancy rate in the ERA group being significantlyhigher than that in the FET group at all cycles, except from the third to the fourth cycle when the cumulative clinical pregnancy rate in both groups converged, and the difference was statistically significant (P < 0.05), as shown in Figure 2.

The Kaplan-Meier method was used to analyse the factors that may affect clinical pregnancy in patients with RIF. The results of the study showed that group, AMH, number of failed transfers, number of embryos transferred, and the availability of quality embryos for transfer had an impact on the patients' clinical pregnancy, with statistically significant differences (P < 0.05), as detailed in Table 2.

Table 3 Analysis of factors that may influence clinical pregnancy in patients with RIF by COX regression models: patients in the FET group had a smaller chance of obtaining a clinical pregnancy compared to those in the ERA group (HR=0.788, 95% CI 0.593-0.978, P<0.05). Patients with >3 previous transfer failures were less likely to achieve a clinical pregnancy compared to patients with ≤3 previous transfer failures (HR=0.058, 95% CI 0.026-0.128, P<0.05). Patients with two embryos transferred were more likely to achieve a clinical pregnancy than those with a single embryo transfer (HR=1.357, 95% CI 1.079-1.889, P<0.05). Patients with quality embryo transfer were more likely to achieve a clinical pregnancy than those without quality embryo transfer (HR=1.917, 95% CI 1.225-1.863, P<0.05).

The results of the study showed that patients in the FET group were 0.788 times more likely to have a successful pregnancy than those in the ERA group, which is consistent with previous studies [11,12]. The physiological importance of the endometrium during pregnancy has received much attention in the field of reproductive medicine over the last few decades [13]. ERA can identify a suitable window of implantation (WOI) for patients with repeated embryo implantation failures. It has been found that approximately 50% of all pregnancy failures occur in the preclinical phase due to biochemical pregnancy or embryo implantation failure [14]. It is well known that successful pregnancy is closely related to the quality of the embryo, the endometrial receptivity and the synergy between the two. If the patient has failed to achieve a successful pregnancy despite multiple transfers of good quality embryos or even haploidentical blastocysts, the treatment process needs to take into account the endometrial receptivity factor. ERA is one of the most successful clinical applications for the diagnosis of endometrial receptivity, and it is one of the most successful clinical applications for the diagnosis of endometrial receptivity based on transcriptome analysis [16]. ERA is effective in increasing pregnancy rates in patients treated with IVF-ET.

In this study, the clinical pregnancy rate in the group with ≤3 previous embryo implantation failures was 50.58%, which was higher than that in the group with >3 previous embryo implantation failures by 30% (p<0.05), and COX regression analysis showed that patients with >3 previous embryo implantation failures were 0.058 times more likely to achieve pregnancy than those with ≤3 previous embryo implantation failures. This suggests that the pregnancy rate is related to the number of previous implantation failures, and that as the number of failed embryo transfers increases in infertility patients, the likelihood of achieving a successful pregnancy decreases, similar to previous studies [17]. This may be due to the fact that the higher the number of previous failed embryo transfers, the higher the medical costs and the greater the psychological strain on the patient. In addition, as the number of failures increases, the more likely it is that the patient will become infected and damaged in the uterus during the course of treatment, or it may be that the patient's own embryonic and endometrial environment does not meet the conditions for a successful pregnancy [18]. It is therefore important that patients who have had multiple failed transplants are given a planned, scientific health promotion to reduce their psychological stress. Targeted treatment of the causes of multiple failures should also be undertaken to improve clinical pregnancy rates by repairing the endometrium, improving the treatment of the embryos transferred, and finding the correct endometrial implantation window.

Table 2. Kaplan-Meier analysis of factors influencing clinical pregnancy in patients with RIF
Characteristics	Number of people(n=408)	Number of patients pregnancy(n=207)	Median	X²	P-value
Group
ERA	204	116	4	4.210	0.040
FET	204	91	4
Female age
<35	264	135	4	0.263	0.608
³35	144	72	5
BMI
Normal	341	171	4	0.127	0.721
Overweight/Obesity	67	36	4
AFC
Normal	148	73	5	0.646	0.422
Anomalies	260	134	4
AMH
Normal	284	135	5	3.908	0.048
Anomalies	124	72	4
FSH
Normal	306	158	4	1.061	0.303
Anomalies	102	49	5
No. of previous implantation failure
≤3	346	175	4	70.517	<0.001
>3	62	32	6
Endometrial thickness
Normal	232	120	4	0.085	0.770
Anomalies	176	87	5
No. of embryos transferred
1	166	65	5	6.201	0.013
2	242	142	4
Embryo Quality
Cycles with high-quality embryos	265	151	4	7.491	0.006
Cycles without high-quality embryos	143	56	5

The results of the current study showed that patients who had two embryos transferred during the course of treatment were 1.357 times more likely to have a successful pregnancy than those who had a single embryo transfer. Some studies have found that pregnancy rates generally tend to increase as the number of embryos transferred per session increases, up to three embryos and in some cases up to four embryos, and that transferring more embryos does increase the success rate of IVF-ET, but also increases the risk of multiple pregnancies. Multiple pregnancies can pose a threat to a woman's pregnancy and her life [19]. If a woman is not fit enough for a multiple pregnancy, the embryo may stop growing due to malnutrition or the baby may be born with a congenital defect such as mental retardation or low birth weight if effective measures are not taken [20]. The transfer of one or two or more embryos should be analysed from a medical point of view, based on clinical examination, laboratory tests, etc. and then combined with one's own physical condition, under the guidance of a professional doctor, in order to better allow the embryos to develop and improve the clinical pregnancy rate of the patient [21].

Table 3. Cox regression analysis of factors influencing clinical pregnancy in patients with RIF
Characteristics	β	SE	*wald*	P-value	Exp(β)	95%CI
Group
ERA	-	-	-	-	1.000	-
FET	-0.238	0.146	4.670	0.049	0.788	0.593-0.978
Female age	0.021	0.020	1.062	0.303	1.021	0.982-1.062
BMI	0.015	0.026	0.316	0.574	1.015	0.964-1.069
AFC	-0.002	0.012	0.037	0.847	0.998	0.975-1.021
AMH	0.029	0.030	0.950	0.330	1.030	0.971-1.092
FSH	-0.007	0.039	0.032	0.859	0.993	0.920-1.072
No. of previous implantation failure ≤3	-	-	-	-	1.000	-
>3	-2.846	0.409	48.376	<0.001	0.058	0.026-0.128
Endometrial thickness	0.036	0.042	0.736	0.391	1.037	0.954-1.127
No. of embryos transferred
1	-	-	-	-	1.000	-
2	0.305	0.172	3.961	0.039	1.357	1.079-1.889
Embryo Quality
Cycles without high-quality embryos	-	-	-	-	1.000	-
Cycles with high-quality embryos	0.179	0.100	3.817	0.043	1.917	1.225-1.863

The current study also found that patients who had quality embryos transferred during treatment were 1.917 times more likely to have a successful pregnancy than those who did not have quality embryos transferred during treatment. It has been found that the most appropriate method to minimise the incidence and risks associated with multiple pregnancies is single embryo transfer [22]. Globally, there is an increasing trend for patients to use single embryo transfer, but recent large-scale data also suggest that transfer of more than one embryo remains common in clinical practice [23]. There is growing evidence that information exchange occurs between the embryo and the endometrium during implantation [24]. The endometrium, characterised by embryo quality sensors, may pick up signals of embryo development to distinguish whether the embryo is developing normally and translate these signals into endometrial acceptance or rejection responses. Low quality embryos may send abnormal, harmful signals to the endometrium, resulting in a rejection response by the endometrium. These observations suggest that poor quality embryos may have a negative effect on endometrial acceptance [25]. It has also been found that the addition of low-quality embryos to RIF patients alongside the transfer of high-quality embryos facilitates live births and multiple births [26]. Therefore, appropriate and targeted treatment protocols should be adopted in clinical practice to improve the pregnancy rate of patients.

In this study, we only included patients who transferred the blastocysts. Performing embryo transferring at blastocyst stage is physiologically appropriate, given that the time is more closely to the natural implantation. Low evidence has been found in blastocyst transfer compared with fresh cleavage-stage embryos [27]. However, more work needs to be done in the future to understand the mechanisms, and larger populations and more scientific protocols are needed to assess the factors influencing pregnancy.

This study has a number of limitations. (1) The study was a retrospective cohort analysis, which introduces more bias than a prospective clinical cohort trial. (2) The sample size of the study was relatively small. However, we matched propensity scores between the two data sets so that there were no significant differences in baseline characteristics between the two groups, improving the scientific validity and reliability of the study results.

In this study of patients with RIF treated with IVF-ET, we found that patients without ERA, >3 previous implantation failures, single embryo transfer, and no transfer of quality embryos were all risk factors for clinical pregnancy in patients with RIF.

Conflict of interest

None.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics statement

The study protocol was reviewed and approved by [the Ethics Review Committee of Chengdu Xi'nan Gynecology Hospital], approval number [2023-016]. Signed informed consent was obtained from all participants.

Author contributions

YJ and ST led the research on this topic and provided all-round guidance on the design, writing and revision of the article.QZ analysed the data and produced the tables and images.ZA drafted the manuscript. All authors contributed to this article and agreed to submit this version.

Funding

This study was funded by the Science and Technology Innovation Team of Yunnan Universities for Research on Surveillance and Prevention and Control Strategies of Cross-border Important Infectious Diseases (No. K1322114).

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No competing interests reported.

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Factors influencing clinical pregnancy failure in patients with RIF treated with the IVF-ET technique: a cohort analysis based on a propensity score approach

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Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Materials and methods

Study subject

Endometrial sampling and processing

Variable selection

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

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