General issues

Uterine fibroids are the most common tumors in women and are almost always benign . Moreover, they are highly dependent on the ovarian steroids. Although their cellular origin remains unknown, they are considered to be monoclonal tumors, arising from the mutation of a single myometrial somatic stem cell after multiple cycles of growth followed by involution under hormonal influence .

According to recently published data, approximately 7–8 out of 10 women will have a fibroid during their lifetime . Pathological examination of hysterectomy specimens also revealed prevalence of >75% . Nevertheless, their overall rate does not seem to exceed 8–10% in 30–40 years .

It is worth noting that the prevalence of fibroids is higher in patients with infertility . Thus, among women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), more than one out of four women do have fibroid(s), although it is estimated that if all other causes of infertility are excluded, fibroids might be responsible for only 2–3% of the cases . Therefore, fibroids are the most common benign uterine condition, and their location and size determine their clinical presentation, if any.

Classification

Fibroids represent a heterogeneous disease, varying from a single small lesion to multiple extra large lesions that may fill the whole peritoneal cavity having different location characteristics. Similarly, the reproductive prognosis and clinical presentation of women with fibroids are variable, from totally asymptomatic to symptomatic requiring treatment.

There is no widely accepted classification system to categorize fibroids. Fibroids are generally classified according to their anatomical relationship with the myometrium and endometrium. Thus, at present, the fibroid location is the only basic criterion for classification, while additional parameters such as the size or the number are not taken into account, although they could have a prognostic role for their clinical significance. Thus, any correlation effort makes the assessment and any comparisons difficult .

Usually, they are divided into three topographic categories: the submucosal, the intramural, and the subserosal fibroids. According to the needs of hysteroscopic treatment, the submucosal category is further divided into type 0 (the fibroid is inside the endometrial cavity), type I (>50% of the fibroid protrudes into the endometrial cavity), and type II myomas (<50% of the fibroid protrudes into the endometrial cavity) ( Table 1 ).

Aiming to provide a more universal and detailed classification, Federation of Gynecology and Obstetrics (FIGO) proposed the classification of fibroids into seven types, that is, from type 0, where the subserosal part is totally inside the uterine cavity, to type 7, where the pedunculated fibroid is inside the pelvis ( Table 1 ) . This new classification represents an extension of the submucosal subclassification, including subcategories for the intramural and subserosal fibroids, also depending on the extent of their occupancy of the muscle and serosa layer of the uterus . However, the prognostic role as well as the utility of this new system of classification requires further investigation.

Classification

Fibroids represent a heterogeneous disease, varying from a single small lesion to multiple extra large lesions that may fill the whole peritoneal cavity having different location characteristics. Similarly, the reproductive prognosis and clinical presentation of women with fibroids are variable, from totally asymptomatic to symptomatic requiring treatment.

There is no widely accepted classification system to categorize fibroids. Fibroids are generally classified according to their anatomical relationship with the myometrium and endometrium. Thus, at present, the fibroid location is the only basic criterion for classification, while additional parameters such as the size or the number are not taken into account, although they could have a prognostic role for their clinical significance. Thus, any correlation effort makes the assessment and any comparisons difficult .

Usually, they are divided into three topographic categories: the submucosal, the intramural, and the subserosal fibroids. According to the needs of hysteroscopic treatment, the submucosal category is further divided into type 0 (the fibroid is inside the endometrial cavity), type I (>50% of the fibroid protrudes into the endometrial cavity), and type II myomas (<50% of the fibroid protrudes into the endometrial cavity) ( Table 1 ).

Aiming to provide a more universal and detailed classification, Federation of Gynecology and Obstetrics (FIGO) proposed the classification of fibroids into seven types, that is, from type 0, where the subserosal part is totally inside the uterine cavity, to type 7, where the pedunculated fibroid is inside the pelvis ( Table 1 ) . This new classification represents an extension of the submucosal subclassification, including subcategories for the intramural and subserosal fibroids, also depending on the extent of their occupancy of the muscle and serosa layer of the uterus . However, the prognostic role as well as the utility of this new system of classification requires further investigation.

Do fibroids affect reproductive potential?

An important question is what is the level of evidence and the significance of the available data to determine the impact of fibroids on fertility.

In 2007, Somigliana et al. performed a meta-analysis, the first serious attempt in this direction, studying the effect of fibroids on the reproductive outcome of women. They observed that childbearing was associated with decreased likelihood of fibroid existence . However, the explanation for this observation was not clear: fibroids negatively affect fertility or pregnancy “per se” protects against the development of fibroids. Therefore, meta-analysis of 13 studies including assisted reproduction patients showed a statistically significant negative effect on clinical pregnancy rates mainly of submucosal (common odds ratio (OR) = 0.3; 95% confidence interval (CI): 0.1–0.7) and to a lesser extent of intramural fibroids (common OR = 0.8; 95% CI: 0.6–0.9). A similar effect of those two types of fibroids was also observed on delivery rates. Conversely, the impact of subserosal myomas was not significant (common OR = 1, 95% CI: 0.7–1.5), and, consequently, these lesions did not seem to play a significant role in this aspect .

Nevertheless, in the same study, the authors concluded that the design of a clear strategy and formulation of guidelines for the management of subfertile women with fibroids seems to be very difficult due to the lack of large randomized controlled trials (RCTs). Moreover, they suggested that physicians should explain to the patients the possible complications of fibroids or myomectomy during pregnancy, taking into account their age, as well as the number, size, and location of fibroids. Notably, after 2006, the practice committee of the American Society of Reproductive Medicine (ASRM) has already adopted this suggestion.

Two years later, in 2009, Pritts et al. attempted answer the same questions through their meta-analysis. Based on data from 18 studies, they found that the presence of fibroids in general, regardless of localization, led to a statistically significant decrease in fertility, regarding clinical pregnancy (risk ratio (RR) = 0.85; 95% CI: 0.73–0.98) and birth rates (RR = 0.69; 95% CI: 0.59–0.82) and, simultaneously an increase in miscarriage rates (RR = 1.68; 95%CI: 1.37–2.05) . They also showed that the greatest negative statistical correlation was observed with the submucosal fibroids, thereby reducing the clinical pregnancy rates up to 70% (RR = 0.36; 95% CI: 0.18–0.74) . Interestingly, even fibroids not interfering with the intrauterine cavity architecture resulted in significantly lower birth rates (RR = 0.78; 95% CI: 0.69–0.88) and higher miscarriage rates (RR = 1.89; 95% CI: 1.47–2.43) .

When all studies were included in the meta-analysis, they further observed that the intramural fibroids had the same effects on clinical pregnancy, (RR = 0.81; 95%CI: 0.70–0.94), live birth (RR = 0.70; 95% CI: 0.58–0.85), and miscarriage rates (RR = 1.75; 95% CI: 1.23–2.49). Narrowing the analysis to only prospective studies, although they failed to find a significant decrease in clinical pregnancy rates, they still observed impaired implantation (RR = 0.55; 95% CI: 0.39–0.78) and live birth rates (RR = 0.46; 95% CI: 0.29–0.74) as well as higher abortion rates (RR = 2.38; 95% CI: 1.11–5.12) .

Based on these findings, the authors concluded that both patients with fibroids affecting the endometrial cavity and those with fibroids located in the muscular layer, even not affecting the endometrial cavity architecture, have poorer reproductive outcomes compared to patients without fibroids. However, subserosal fibroids do not seem to generate any obvious fertility issue .

In 2010, Sunkara et al. published another meta-analysis on this subject, focusing only on the “gray” zone fibroids. It was almost unanimously accepted that the submucosal fibroids are mostly detrimental to fertility, while the subserosal ones do not harm or interfere with fertility, when of reasonable sizes.

However, with regard to intramural fibroids, the authors meta-analyzed 19 trials including 6089 patients, of which five were prospective studies with 1127 patients; these patients had intramural fibroids of size ranging, between 0.7 and 5 cm, which do not interfere with the intrauterine cavity. The authors tried to investigate if the existence of fibroid affected the outcomes of IVF . When all studies were taken into account, they found that in women undergoing IVF, the fibroids not reaching the endometrium and not disrupting the endometrial cavity at all are associated with significantly lower clinical pregnancy (RR = 0.85; 95% CI: 0.77–0.94) and live birth rates (RR = 0.79; 95% CI: 0.70–0.88) . However, when they included the five prospective studies, then a significant decrease in live birth rates was observed (RR = 0.6; 95% CI: 0.41–0.87) . Thus, they concluded that the presence of non-cavity-distorting intramural fibroids was associated with adverse pregnancy outcomes by reducing expected live birth rates, although they acknowledged that well-designed RCTs were necessary to address this question .

Although intramural location of fibroids seems to interfere with fertility potential, additional parameters such as the size and number could also play a critical role. Somigliana et al. compared patients with asymptomatic intramural or subserosal fibroids of size < 5 cm with controls and found similar live birth rates in both groups, thereby concluding that the presence of asymptomatic small fibroids did not affect assisted reproductive technique (ART) outcomes . By contrast, Oliveira et al. found that patients with intramural fibroids of size >4 cm had statistically lower pregnancy rates than those with intramural fibroids of size <4 cm . Furthermore, in a recent study, Yan et al. reported that patients with intramural fibroids with the largest diameter (>2.85 cm) had significantly lower delivery rates when compared with matched controls without fibroids (adjusted OR = 0.86; 95% CI: 0.74–0.99) . It seems, therefore, that size is probably a critical independent variable for the intramural fibroids not affecting the architecture of endometrial cavity. Apparently, the fibroids could play a significant role in the fertility potential of the woman only if their size was >3–4 cm .