Implantation failures in women with infertility associated endometriosis

Abstract

Endometriosis is currently considered as one of the most common diseases associated with infertility. A controversial issue is whether endometriosis per se exerts a detrimental effect on IVF outcomes. Failure of implantation due to endometriosis-associated infertility is a contradictory and widely discussed burden nowadays. The purpose of the study is to assess the quality of embryos and implantation rate in women with infertility associated with endometriosis. The study included infertile reproductive aged women, between 26 and 40 years who underwent IVF and ICSI procedures. The patients were divided into two groups: group I (n = 70) involved 70 patients with recurrent unilateral endometriomas, II control group (n = 50) with tubal factor infertility. The quality of the retrieved embryos was assessed according to the generally accepted classification of Gardner, indicating the rate of implantation in each group. Embryo transfer was performed in case of high quality embryos. Assessing the ovarian reserve indicators, in the group I patients with recurrent unilateral endometriomas the serum level of AMH was significantly lower (2.1 ± 1.75 vs. 3.2 ± 1.4, p < .005), as well as the number of retrieved oocytes (8.1 ± 3.9 and 10.1 ± 6.8, p < .005). The analysis of the results demonstrated that the duration of stimulation in the group patients with recurrent unilateral endometriomas was significantly higher in comparison with the group II (12.2 ± 1.8 and 10.2 ± 1.6 days, p < .001). Nevertheless, the number of good quality embryos retrieved was comparable in both groups (2.2 ± 1.5 and 2.8 ± 1.8). In the group I patients with recurrent unilateral endometriomas, there was a statistically significant decrease of implantation rate (17.1% vs. 24% p < .005). The results of the study revealed no statistical difference in embryo quality in the study cohort. However, it is important to note that a statistically significant difference in implantation rate in the group of endometriosis-associated infertility compared was obtained 1.5 times lower than in the control group (15.8% vs. 24.0% p < .005). The achieved results demonstrated an adverse IVF outcome in infertile women with recurrent endometrioma compared to the control group.

Keywords:

• Endometriosis-associated infertility
• embryogenesis
• implantation rate

Introduction

Several early studies declare that fertilization, implantation, and pregnancy rates in endometriosis patients were significantly compromised in comparison with controls [1,2]. The most recent retrospective study reported that implantation rate is the most reliable indicator of IVF outcome in patients with tubal factor infertility [3]. According to the 2010 SART registry, age-matched patients with endometriosis had comparable results with the overall population of women undergoing IVF. Due to contradictory data, further research is required.

It is believed that, endometriosis is frequently associated with infertility and it is believed that the impairment of endometrial receptivity may be one of the mechanisms involved in this condition [4].

Considering the variety of pathophysiological options, embryo implantation is suggested as a consecutive development that involves a series of physical and physiological interactions among the blastocyst trophectoderm and various endometrial cell-types, including the luminal and glandular epithelial and stromal cells [5].

It is important to note that, from a literature point of view, reduced implantation rates may have a triple etiology: reduced oocyte and embryo quality, endometrial receptivity defect, and/or altered interaction between the embryo and the endometrium [6]. But it is also very important to remember that corpus luteum function, progesterone production, implantation window, and endometrial competence and, consequently, about luteal phase deficiency (LPD) and support. LPD is described as a condition of insufficient progesterone exposure to maintain a normal secretory endometrium and allow for normal embryo implantation and growth.

The purpose of the study is to assess the quality of embryos and implantation rate in women with infertility associated with endometriosis.

Materials and methods

Retro prospective study was performed in the Department of Obstetrics and Gynecology with Course of Perinatology of Medical Institute of the RUDN University (Рeoples Friendship University of Russia) and in the center of reproduction and genetics ‘NOVA CLINIC’ between 2018 and 2019. The study group included infertile reproductive aged women, between 26 and 40 years who underwent IVF and ICSI procedures. The patients were divided into two groups: group I involved 70 (n = 70) patients with recurrent unilateral endometriomas, group II (n = 50) – 50 patients with tubal factor infertility. The dose of gonadotropins was determined on an individual basis according to age, day 2 serum AMH and echographic characteristics of the ovaries. Diameters of recurrent endometriomas were ≤4 cm. At ultrasound, the diameter of endometriomas was calculated as the mean of three perpendicular measurements. Actually, ovarian endometriomas were defined as round-shaped cystic masses with more than 1 cm in diameter, with thick walls, regular margins, and homogeneous low echogenic fluid content with scattered internal echoes, and without papillary proliferations. The diagnosis of the endometriotic cysts was performed and confirmed twice by ultrasound investigation. All patients participating in the study were given IVF/ICSI protocols with separate counting of antral follicles in the ovaries, with separate collection of oocytes into labeled Petri dishes before the IVF program, according to ultrasound, the number of visualized antral follicles in the ovary containing endometrioma was taken into account, as well as in the contralateral ovary. During transvaginal ultrasound-guided follicle puncture, the number of oocytes retrieved from the affected ovary and not containing endometrioma was also taken into account. The main morphological characteristics of the ‘competent’ oocyte were considered: the correctness of the form with a uniformly graduated cytoplasm, with an intact first polar body. Women carrying atypical lesions, i.e. cysts whose sonographic appearance was compatible but not distinctive for endometriosis were excluded. The quality of the retrieved embryos was assessed according to the generally accepted classification of Gardner, indicating the rate of implantation in each group. Embryo transfer was performed in case of high quality embryos.

Results

When analyzing the age of the examined women, it was noted that the age range in the main group was from 26 to 40 years old, the average age was 33.21 ± 3.3, and in the control group 32.54 ± 2.8 (Table 1).

Table 1. IVF–intracytoplasmic sperm injection cycle outcomes in patients with recurrent endometriomas and in control subjects.

Characteristics	Group I (n = 70)	Group II (n = 50)	p
Infertility duration	4.4 ± 1.8	4.1 ± 2.1	>.05
Age, years	33.21 ± 3.3	32.54 ± 2.8	>.05
AMH	2.1 ± 1.75	3.2 ± 1.4	<.05
Duration of ovulation induction	12.2 ± 1.8	10.2 ± 1.2	<.05
No. of IVF cycles	209	198	>.05
No. of oocytes	8.1 ± 3.9	10.1 ± 6.8	<.05
No. of embryos^a	2.8 ± 1.8	3.3 ± 2.2	>.05
No. of high-quality embryos (A+B)^b	2.2 ± 1.5	2.8 ± 1.8	>.05
Implantation rate per cycle (%)	17.1%	24%	<.05

^a Per cycle.

^b Characteristics according to the generally accepted classification of Gardner.

The results of the study demonstrated a statistically significant increase in the number of immature oocytes of metaphase MI and immature oocytes at the GV germinal vesicle stage in patients with infertility associated with endometriosis, compared with the control group (p < .005). There is deterioration in the quality of the retrieved oocytes in patients with the presence of endometriomas more than 3 cm in diameter.

Evaluating the ovarian reserve indicators, the serum AMH level was significantly lower in the 1st group (2.1 ± 1.75 compared to 3.2 ± 1.4 p < .005), as the number of oocytes retrieved (8.1 ± 3.9 and 10.1 ± 6.8, p < .005) (Table 1). The achieved results established that the duration of stimulation in recurrence group was significantly higher compared to the control group (12.2 ± 1.8 and 10.2 ± 1.6 days, p < .001). Of interest, the number of good quality embryos was concordant in two groups (2.2 ± 1.5 and 2.8 ± 1.8), hence, the rate of implantation in the 1st group was lower (17.1% vs. 24% p < .005). The similar findings were achieved by other scientists. In the course of independent studies, they concluded that patients with endometriosis-associated infertility undergoing IVF reflect with a significantly reduced level of all markers of the reproductive function, resulting in a lower pregnancy rate than in the control group [7–11] (Table 2).

Table 2. Characteristic of patients with endometriomas.

Size of endometriomas	Group I (n = 70)
≥10 mm	10 (14.3%)
10–20 mm	33 (47.1%)
20–30 mm	9 (12.9%)
30–40 mm	18 (25.7%)

According to individualized analysis among women with an endometriomas more than 3 cm, the frequency of implantation was 1.5 times lower than in the control group (15.8% vs. 24%, p < .005). Actually, in patients with the size of cyst less than 3 cm, the rate of pregnancy was comparable to the control group. Those findings support that the size of endometriomas affects the number of oocytes retrieved and the rate of implantation. Taking into account, the reliably low incidence of implantation due to endometriosis despite the comparable number of good quality embryos retrieved, it may require a more thorough assessment of the endometrial receptivity [11,12]. Therefore, the ambiguity of theories concerning the occurrence of endometriosis-associated infertility, prompts the researchers to further investigation of potential mechanisms of endometriosis (Figure 1).

Figure 1. Blastocyst micrographs ×200. Varieties of blastocysts. High-quality embryos (3AA, 4AA, 5AA, 6AA). Blastocyst of poor quality (2CC). (1) Trophectoderm. (2) Intracellular mass. (3) Blastocyst with the beginning of hatching. (4) Blastocyst culminating in the hatching. (5) Fragmentation above 50%.

Conclusions

The results of the study revealed no statistical difference in embryo quality in the study cohort. However, it is important to note that a statistically significant difference in implantation rate in the group of endometriosis-associated infertility compared was obtained 1.5 times lower than in the control group (15.8% vs. 24.0%, p < .005). The achieved results demonstrated an adverse IVF outcome in infertile women with recurrent endometrioma compared to the control group.

Disclosure statement

The authors declare that there is no potential conflict of interest.

Additional information

Funding

The publication has been prepared with the support of the ‘RUDN University Program 5-100’.