Intramural leoimyoma without endometrial cavity distortion may negatively affect the ICSI - ET outcome

Uterine fibroids affect 20–50% of women of reproductive age [1]. They contribute to a variety of clinical problems, including infertility, recurrent pregnancy loss, menorrhagia, and pelvic pressure and fullness, as well as complications of pregnancy. It was estimated that leiomyomata are the sole cause of infertility in only 2–3% of cases when all other factors have been ruled out [2].

Athough the exact mechanism of infertility in women with myoma is unknown, the theories of pathogenic mechanisms include mechanical blockage of tubal ostia impairing sperm or embryo transport through the fallopian tubes, abnormal vascularization, abnormal endometrial development, chronic intracavitary inflammation, an abnormal endocrine milieu, and increased uterine contractility [3].

There is a controversy on the impact of uterine leiomyomata on the outcome of assisted reproductive technologies (ARTs). According to recent review, evidence supports the concept that submucosal fibroids and intramural fibroids that distort the endometrial cavity impair in vitro fertilization (IVF) outcomes. It remains unclear, however, whether intramural and subserosal fibroids, in the setting of a normal endometrial cavity, have similar effects [4].

In some studies it was shown that pregnancy and implantation rates were significantly lower in women with intramural fibroids undergoing IVF/ICSI compared with age-matched controls [5‐9]. On the contrary, it other studies, it was reported that IVF/ICSI outcome was not affected by the presence of intramural or subserosal fibroids [10‐16].

The purpose of this study was to assess the impact of intramural fibroids with the diameter of <7 cm that do not distort the endometrial cavity on the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) cycle outcome in terms of pregnancy (PR) and abortion rates (AR).

A comparison of the no fibroid and fibroid groups with regards to patients’ clinical and laboratory characteristics are given in Table 1. Since the patients were matched for age and numbers oocyte retrieved there were no significant differences between the 2 groups (32.66 ± 5.3 years vs. 32.95 ± 3.98 years, NS, independent sample t-test; and 9.55 ± 4.34 oocytes vs. 9.11 ± 5.13 oocytes, NS, independent sample t-test).

Because only the women with tubal or male factor infertility were included, male factor contributed to the etiology of infertility for most cases in both fibroid and control groups (85.5% vs. 82.7%, respectively, NS, ײ test). Tubal factor was responsible for 14.5% of infertility in the fibroid group and 17.3% in the control group (NS, ײ test).

A comparison of ICSI-ET outcome by the presence of fibrod with the mean diameter 49.61 ± 12.32 cm is given in Table 2. The clinical pregnancy rate (PR) was significantly higher in the control than in the fibroid group (39.9% vs. 25.8%, respectively, p = 0.04, ײ test). In fibroid group the implantation rate was significantly lower than control group (20.97 ± 37.93 vs.32.89 ± 43.18%, p = 0.04). The odds ratio for clinical pregnancy was 0.525 (95% confidence interval 0.284 – 0.969, p = 0.039). However, the first trimester spontaneous abortion rates (AR) for clinical pregnancies was 9.2% (2/16) for fibroid and 12.5% (11/120) for controls (p < 0.05, ײ test). Furthermore the live birth rates were not statistically significantly different in both groups (30.9% (93/301) for no fibroid group, 17.7% (11/62) for fibroid group, p > 0.05, ײ test).

The aim of the current study was to determine whether the presence of intramural fibroids with the diameter of <7 cm has an influence on the PR and AR after ICSI-ET treatment. In this age matched case control study, it was found that the clinical PR per transfer was significantly lower in the group of patients with intramural fibroids, even when there was no deformation of the uterine cavity. However the AR was not significantly affected by the presence of intramural fibroids.

Although many studies have investigated the impact of intramural and subserosal fibroids on IVF outcomes, the effect of intramural fibroids not distorting intrauterine cavity is controversial issue. One recent prospective study results [17] are in agreement with our study. This study compared 112 women with intramural fibroids less than 5 cm in size with 322 women without fibroids. The pregnancy, ongoing pregnancy and live birth rates in the study group were 23.6, 18.8 and 14.8% compared with 32.9, 28.5 and 24% in the control group, respectively (P < 0.05) [17]. Recent meta-analysis also suggested that the presence of non-cavity-distorting intramural fibroids were associated with lower clinical pregnany and live birth rates in women undergoing IVF treatment [18].

A recent prospective study results [15] were also well correlated with our study, although the difference has not been reached statistically significant value. This study compared 61 patients with intramural fibroids less than 5 cm with 61 matched controls. All participants had normal endometrial cavities on hysterosalpingogram, the average fibroid size was 1.5 cm. Compared with the controls, the fibroid group had lower implantation rates (13.6% versus 20.2%), lower pregnancy rates (34.4% versus 47.5%), and higher miscarriage rates (33.3% versus 20.7%), which highlighted the potential negative impact of small intramural fibroids on IVF outcomes [15].

A recent systematic literature review concerning the effect of fibroids on fertility in patients undergoing ART evaluated six articles and concluded that there was a significant negative impact on implantation rate in the intramural myoma groups vs. the control groups (16.4 vs. 27.7% OR 0.62 (0.48-0.8)). The pregnancy and delivery rates per transfer cycle were also significantly lower in myoma groups. It was concluded that a surgical approach in patients with a history of previous failed attempts with intramural myomata >2 cm in diameter is warranted if all ather factors have been evaluated [9]. Morover, Kolankaya et al. also suggested that there is no consensus for intramural myomas that do not enroach upon the cavity; however, most surgeons would agree to remove them if they are larger than 7 cm or are associated with multiple failed IVF cycles [19]. Only a few reports showed the significant detrimental effect of intramural myoma on ART outcome as detailed in Table 3[5, 6, 20]. However, meta-analysis results of all reported studies showed the negative effect of fibroid on pregnancy rates (Figure 1, odds ratio 0.737, 95% confidence interval 0.647-0.840, p = 0.000).

In contrast, according to systematic review of the evidence reported by Pritts et al. [3] those women with only intramural fibroids had relative risks of pregnancy, implantation and delivery of 0.94 (95% CI 0.73–1.20), 0.81 (95% CI 0.60–1.09) and 1.01 (95% CI 0.73–1.34), respectively, when compared with their infertile counterparts without fibroids in in vitro fertilization cycles [3]. Furthermore Surrey et al. [28] recommended that submucosal leiomyomas and intramural leiomyomas which distort the endometrial cavity would have deleterious effects on implantation and IVF cycle outcome. However, the effect of intramural leiomyomata which do not distort the cavity is much more difficult to evaluate. Conflicting conclusions from various investigators made difficult to recommend routine myomectomy for all intramural lesions before IVF/ICSI cycle [28]. Many retrospective and only a few prospective matched control studies failed to reveal significant detrimental effect of intramural myoma on IVF/ICSI outcome as detailed in Table 3[8‐10, 12‐16]. The failed significant detrimental effect of myoma on reproduction may be explained with the lack of better classification system of myoma. The wide use of new FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding and leimyoma subclassification system [29] in the world may help to elucidate the effect of leoimyoma not distorting endometrial cavity on pregnancy and implantation rates.

The effect of intramural fibroids not distorting endometrial cavity was also investigated in oocyte donation cycles in order to rule out the effect of ovarian stimulation on endometrial receptivity as well as the detrimental effect of age on oocyte quality. The authors failed to reveal detrimental effect of myoma on clinical pregnancy and implantation rates, although they reported alteration in the expression pattern of some endometrial genes [30]. The effect of submucosal myoma on endometrial gene expression was also investigated and the recent study reported that submucosal myomas adversely affect reproduction by decreasing endometrial HOX gene expression [4].

The mechanisms by which myomas may affect reproductive outcome are as follows: interference with sperm transport or access (by anatomic distortion of the cervix, enlarging or deforming the endometrial cavity, altering the uterine contractility, and obstructing tubal ostia) or implantation failure (by physically changing the shape of the endometrium, preventing discharge of intrauterine blood or clots, and altering the normal endometrial development (endometrial vascular disturbances, inflammation, ulceration, thinning, and atrophy and altered biochemical environment)) [4, 19]. Intramural myomas particularly <7 cm in size may alter myometrial contraction during ET procedure and cause negative effect on implantation, pregnancy and abortion rates following ICSI/ET cycles, even they do not impinge the endometrial cavity.

Ng et al.[13] reported that the presence of fibroids resulted in significantly reduced uterine artery pulsatility and resistance index [13]. Based on this study it may be suggested that the blood flow towards the endometrium may be compromised because of drainage of blood towards fibroids. This effect may explain the detrimental effect of myoma on implantation and pregnancy rates in ICSI/ET cycles.

In this retrospective controlled study, the effect of single intramural myoma (<7 cm) not distorting endometrial cavity was investigated and we found that the fibroid group had lower implantation ad pregnancy rates. This may suggest the detrimental effect of myoma on reproduction. As seen in Table 3, the significant detrimental effect of such size myoma on reproduction has not been reported previously. However, the main limitations of this study are the limited size of groups and the retrospective study design. In order to make a certain conclusion regarding intramural fibroids below 7 cm in size not distorting intrauterine cavity, a randomized controlled trial (RCT) of myomectomy versus no therapy should be performed in ICSI/ET cycles. Furthermore, the best study to determine the effects of intramural fibroids on the ART outcome would be a prospective cohort study and then a RCT would best demonstrate any possible benefit of myomectomy to mitigate these potentially detrimental effects.

Based on our preliminary results of this study, although significant results were obtained in terms of implantation and pregnancy rates, it is not easy to advocate removal of intramural fibroids to improve fertility before ART cycles, since there are many potential complication associated with myomectomy, such as infection, bleeding, possibly blood transfusion, damage to abdominal or pelvic organs, formation of intraabdominal adhesions and anesthesia related complications and possible subsequent pregnancy complications [9]. However, the current study significant results in terms of implantation and pregnancy rates may suggest the possible positive effect of myomectomy on ICSI/ET outcome for only particular myoma size.