Uterine fibroids & infertility: which fibroids should be removed?—a narrative review

Introduction

Fibroids are the most common gynecological tumor in women of reproductive age. By the age of 50 years old, cumulative incidence of fibroids reaches 70% in white women and 80% in black women (1,2). Black women present with fibroids at a younger age and their fibroids are usually larger and/or more in number (1). Similarly, fibroids are more frequent in nulliparous women (3). While many women with fibroids are asymptomatic, those with symptoms may report heavy and/or prolonged menstrual bleeding, pelvic pain, pressure-related symptoms such as urgency or constipation, and difficulties in conceiving (3).

Fibroids are detected in up to 27% of women who present with infertility (4). Their incidence is reported to be 1–2.4% in women with unexplained infertility (5).

Clinicians consulting women with fibroids who try or plan to conceive must answer two questions. First, is it possible that the present fibroid impairs fertility? If it does, would its surgical correction improve the women’s chance of achieving pregnancy and live birth? In spite of the high incidence of fibroids and improvements in diagnostic and therapeutic methods, it is not possible to answer these questions with solid evidence. Several reasons hinder our efforts to provide high-quality evidence about the potential link between infertility and fibroids.

The first problem is the overlapping risk factors for both infertility and fibroid development. For instance, nulliparity itself is a risk factor for fibroid development and it is difficult to determine whether these women are infertile because they have fibroids or their fibroids caused by infertility (6,7). Similarly, incidence of both fibroids and infertility increase with age (6).

Second, as only some fibroids tend to grow continuously and others stop at a certain point, anticipating their natural progress is not possible to predict (8).

Third, studies on fibroids are subject to a number of methodological challenges. Since fibroids are present in varying sizes, locations, and numbers, diverse combinations are possible (Figure 1). Every single fibroid itself and its combination can have varying effects on fertility, and it is difficult to reach sound conclusions from such heterogeneity. If studies implemented more specific inclusion criteria to overcome this problem, then recruitment problems may arise, and the study may never be completed. Another problem with the studies performed is that fibroids are not always uniformly defined or classified in most studies and their managements vary greatly, decreasing their internal and external validity.

Figure 1 Ultrasound image of a uterus with a submucosal and subserosal fibroid.

In addition to these factors, there is the impossibility of performing an appropriately sized clinical trial in a homogenous population with long enough follow-up time. Thus, it is very likely that there never will be a conclusive study that will demonstrate the relationship between fibroids and fertility, or the role of surgery on fertility. Therefore, the current evidence comes from studies which are mostly observational and are prone to a number of biases. Moreover, these studies are highly heterogeneous as they use varying classifications, diagnostic-therapeutic methods and endpoints, and are performed on different populations.

Nonetheless, we will discuss whether fibroids affect fertility or whether myomectomy improves reproductive outcomes, based on the best available evidence. We present this article in accordance with the Narrative Review reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-22-29/rc).

Methods

We have searched PubMed from 1980 to September 1^st, 2022 for publications in English, using various combinations of keywords “fertility”, “infertility”, “fibroid”, “myoma uteri”, “myomectomy”, and “surgery”. There were no limitations regarding study type. Since this is a narrative review, we have only included publications that we believed were solid and relevant to our questions of interest. The search strategy is summarized in Table 1.

Do fibroids affect fertility?

Disturbance in the uterine peristalsis, increase in the endometrial blood flow, possible detrimental effect of endometrial inflammation, reduction in endometrial HOXA10, and HOXA11 gene expression, blockage of cervix or the tubal ostia are some of the proposed mechanisms fibroids interfere with implantation and successful pregnancy (9-12).

In one of the landmark publications on the subject, Pritts et al. performed a meta-analysis of 23 studies on fibroids and infertility (13). They reported that clinical pregnancy rates were 63% lower in women with submucous (SM) fibroids [International Federation of Obstetrics and Gynecology (FIGO) type 0-1-2] compared to those with no fibroids [risk ratio (RR) 0.36; 95% confidence interval (CI): 0.18–0.74, P=0.005] (Figure 2) (14). Furthermore, there was an increase in miscarriage rates by 68% (RR 1.68; 95% CI: 1.37–2.05, P=0.022). In accordance, ongoing pregnancy/live birth rates were significantly lower in the SM group as well (RR 0.32; 95% CI: 0.12–0.85, P<0.001). Thus, it was concluded that SM fibroids have significant adverse effects on fertility and pregnancy outcomes.

Figure 2 Three-dimensional ultrasound image of a submucosal fibroid.

In contrast, subserosal (SS) fibroids are acknowledged to have no effect on fertility or live birth rates (Figure 3) (13). It is noteworthy that in the last two decades, almost all research on the effect of SS fibroids in fertility has been dropped. The most recent meta-analysis that investigates the relationship on SS fibroids and infertility was published 15 years ago and it reported odds ratio (OR) for clinical pregnancy as 1.2 (95% CI: 0.8 to 1.7) and OR for live birth as 1.0 (95% CI: 0.7 to 1.5) (15).

Figure 3 Ultrasound image of a subserosal cavity.

Thus, in the last decade, almost all the studies and meta-analyses on the relationship of fibroids and fertility have focused on intramural (IM) fibroids.

In 2010, Sunkara et al. performed the first meta-analysis focusing on the in vitro fertilization (IVF) outcomes of non-cavity disturbing IM fibroids (16). They included 6,087 IVF cycles from 19 observational studies in their meta-analysis. It should be noted that, although majority of studies included IM fibroids, a few also included SS fibroids, as they are not cavity disturbing as well. Analysis of eleven studies comprising 3,981 cycles showed 21% relative reduction in live birth rates in women with non-cavity disturbing fibroids compared to those with no fibroids (RR 0.79; 95% CI: 0.70–0.88, P<0.0001). The association remained statistically significant when eight studies with mean women age less than 37 (RR 0.75; 95% CI: 0.62–0.89, P=0.001), and four studies that included women undergoing their first IVF cycle only were analyzed (RR 0.77; 95% CI: 0.59–1.00, P=0.05). Clinical pregnancy rates were reported in 18 studies (n=5,588) and showed a relative reduction of 15% in women with fibroids compared to those without (RR 0.85, 95% CI: 0.77–0.94, P=0.002). Last of all, miscarriage risk was 24% increased relatively in women with fibroids compared to women with no fibroids, but this difference was not statistically significant (RR 1.24; 95% CI: 0.99–1.57, P=0.07). The authors warned against the heterogeneity in patients and diagnostic methods, and the observational nature of the studies included.

In 2018, Wang et al. published a systematic review and meta-analysis investigating the effect of fibroids that do not disturb the cavity on IVF results (Figure 4) (17). Live birth rates (RR 0.82; 95% CI: 0.73–0.92, P=0.005) and clinical pregnancy rates (RR 0.86; 95% CI: 0.80–0.93, P=0.0001) were significantly reduced in women with fibroids compared to those with no fibroids according to their analyses as well.

Figure 4 Ultrasound image of a non-cavity disturbing intramural fibroid.

Most recently, in 2020, Rikhraj et al. performed a meta-analysis on the impact of non-cavity disturbing IM fibroids in IVF cycle outcomes (18). Unlike Sunkara et al., they excluded studies without IM fibroids. Results from 15 observational studies with a total of 5,029 women were analyzed. A total of 8 studies reported live birth rates in 2,876 women, and women with non-cavity distorting fibroids were found to have 44% lower odds for live birth when compared to those without any fibroids (OR 0.56; 95% CI: 0.46 to 0.69). When data on only IM fibroids and “IM and SS” fibroids were analyzed separately, once more a significant association was observed. Fifteen studies reported clinical pregnancy rates and similarly, when compared with women with no fibroids, women with non-cavity distorting fibroids had significantly lower odds for clinical pregnancy (OR 0.68; 95% CI: 0.56 to 0.83). Once more, the association was still significant when IM and “IM and SS” fibroids were analyzed separately. It is worth mentioning that clinical pregnancy rates were not statistically significant when only the five prospective studies were analyzed (OR 0.78; 95% CI: 0.58–1.06). According to data from 10 studies comparing women with IM fibroids and those who do not, miscarriage rates were marginally similar (OR 1.38, 95% CI: 0.98–1.95). The authors of the meta-analysis underlined that while non-cavity disturbing IM fibroids seem to have adverse effects on live birth and clinical pregnancy rates after IVF, the data are heterogeneous and originate primarily from retrospective observational studies. Thus, they advocate caution when interpreting these results.

Somigliana et al. aimed to perform a systematic review of studies that focus on the effect of fibroids on spontaneous conception (7). However, 7 of the 11 studies examined if infertility was a risk factor for fibroids, not if fibroids had an effect on conception. When the other 4 studies were analyzed, common odds ratio of fibroid presence in subfertile women was found to be 3.54 (95% CI: 1.55 to 8.11). The authors concluded that evidence on natural fertility was scarce and the subject was underinvestigated.

While the three meta-analyses by Sunkara, Wang and Ri̇khraj show mild differences in methodology and included studies, it can be concluded that non-cavity disturbing IM fibroids are likely to have negative impact on clinical pregnancy and live birth rates following IVF (16-18). However, the heterogeneity in the methodology and fibroid location/size should not be overlooked. Bias and confounding factors arising from the mostly retrospective nature of the studies included should be noted. Most importantly, even if the association was true, surgery may not be necessarily beneficial.

Does surgical treatment of fibroids improve fertility outcomes?

Even if we accept that some fibroids have detrimental effects on fertility, their surgical removal may not result in restoration of fertility. Myomectomy carries risks such as hemorrhage, infection, adhesions, scar tissue, uterine perforation, and increased risk of uterine rupture, if pregnancy is achieved (19). Furthermore, it is not known if the regenerated tissue following surgery accommodates functions of the healthy myometrium, partially or fully. Hence, prior to offering myomectomy, its potential benefits, risks, and costs should be analyzed and discussed.

Myomectomy for SM fibroids is commonly practiced with the conviction that their removal increases fertility. However, there is only one very low-quality randomized clinical trial (RCT) on the subject (20). In this study in 2006, 181 infertile women were recruited. Fifty-two had SM and 42 had SM and IM fibroids. They were randomized to surgery and expectant management groups and monitored for a year. Clinical pregnancy rates were 43.3% vs. 27.2% for surgery and expectant arms, respectively, in the SM groups (P<0.05); and 36.4% vs. 15% for surgery and expectant arms, respectively, in the SM and IM group (P<0.05). Live birth was not reported in this study.

In their Cochrane review on the subject, Bosteels et al. found only the RCT by Casini et al. fit their criteria (20,21). After combining data for SM and “SM and IM”, OR was 2.44 (95% CI: 0.97 to 6.17, P=0.06) for clinical pregnancy and 1.54 (95% CI: 0.47 to 5.00, P=0.47) for miscarriage, when surgery was compared to expectant management (21). They concluded that the evidence was of “very low-quality” and the benefit of hysteroscopy in SM and “SM and IM” groups was uncertain.

Still, surgical removal of SM fibroids and IM fibroids that distort endometrial cavity is generally recommended for women seeking spontaneous or assisted fertility. American Society for Reproductive Medicine (ASRM) and Society of Obstetricians and Gynaecologists of Canada (SOGC) declare that there is fair amount of evidence to offer myomectomy to these women (22,23).

The greatest debate about the role of myomectomy for fertility involves non-cavity distorting fibroids. There are only relatively small-sized observational studies on the subject, and the results are usually conflicting. They are heterogeneous as some studies chose women with no fibroids as control, while others chose women with fibroids that are left in situ.

In a prospective cohort study, 63 infertile women with IM fibroids (19 of which underwent myomectomy) were compared with 100 age-matched controls undergoing IVF (24). Clinical pregnancy rates were similar at 36%, 29% and 36% (P=0.25) in the myomectomy, fibroid left in situ, and control groups, respectively. Another study compared 47 women who underwent myomectomy with 11 women whose fibroids were left in situ prior to IVF (25). Clinical pregnancy rates were comparable at 16.9% in the myomectomy vs. 20.8% in the control group. It should be noted that, the study was not limited to IM fibroids, and 10% of women who underwent myomectomy had SM and 50% had SS fibroids. Thus, the small size and the heterogeneity of the fibroid locations decreases the quality of evidence considerably.

In a relatively larger study, Bulletti et al. included 168 infertile women with at least one fibroid at least 5 cm in diameter and no SM component (4). Half of these women underwent laparoscopic myomectomy prior to IVF, while the other half had no surgery prior to IVF. Cumulative clinical pregnancy rates were 34% vs. 15% (P<0.05), and live birth rates were 25% vs. 12% (P<0.05) in the surgery and no-surgery groups, respectively. While the results are encouraging, age of the control group was not reported, and other possible confounding factors were not accounted for by the non-randomized design.

Although there is no solid evidence, some researchers advocate removal of non-cavity distorting fibroids larger than 4–5 cm in diameter, due to the possibility that non-cavity distorting IM fibroids may interfere with fertility. Likewise, they suggest that for women with a history of failed IVF attempts, myomectomy may be considered for fibroids smaller in size (26). SOGC states that, regardless of their size, there is fair evidence to recommend against surgery for non-cavity distorting fibroids. However, after discussing the potential benefits and risks myomectomy may be offered to selected patients with no other options (23). Likewise, ASRM states that myomectomy is generally not advised for women with asymptomatic fibroids that do not distort the cavity, yet it can be considered if they complicate or hinder oocyte retrieval. They add that there is fair evidence to believe that myomectomy does not impair IVF outcomes (22).

Lastly, removal of SS fibroids is not offered as there is limited evidence on its benefit. Casini et al. expectantly observed 11 women with SS fibroids expectantly. This subgroup of patients were not randomized to undergo surgery or not (20). The pregnancy rate was 63.6% after twelve months. Removal of SS solely for fertility purposes is not recommended (7,13,22,23).

Studies in this section are summarized in Table 2.

Does the myomectomy method affect pregnancy rates?

There are only a few studies regarding the effect of different surgical approaches on fertility.

In a study in 2022, Wise et al. prospectively studied 1,095 women of reproductive age undergoing surgery for symptomatic fibroids for 36 months to see if route of myomectomy was associated with conception and live birth (27). Although the study has limitations such as study population not being limited to women with infertility as the primary symptom, tendency to prefer abdominal route for more severe cases, and lack of information on the use of infertility treatments, this is one of the few studies with prospective design, long follow-up period and acceptable size comparing different routes of myomectomy.

After adjusting for differences in demographics, symptoms, and fibroid characteristics, ORs for achieving pregnancy and live birth were respectively 1.27 (95% CI: 0.72–2.23) and 1.71 (95% CI: 0.81–3.65) for hysteroscopic myomectomy (n=273); 1.26 (95% CI: 0.77–2.04) and 1.49 (95% CI: 0.77–2.89) for laparoscopic myomectomy (n=434), when compared with abdominal myomectomy (n=388). Same analyses that were performed after excluding hysteroscopic myomectomy cases yielded similar results with adjusted ORs for achieving pregnancy and live birth after laparoscopy were respectively 1.25 (95% CI: 0.84–1.84) and 1.35 (95% CI: 0.80–2.25), compared to the abdominal route. According to Wise et al., route of myomectomy does not have substantial effect on the probability of achieving pregnancy and live birth.

In a Cochrane review in 2020, only two RCTs comparing laparoscopic myomectomy with myomectomy by laparotomy or mini-laparotomy were found (28). Palomba et al.’s and Seracchioli et al.’s studies included 62 (30 in laparoscopy an 32 in laparotomy groups) and 115 women (56 in laparoscopy an 59 in laparotomy groups), respectively (29,30). In the meta-analysis, live birth rates of both approaches were found to be similar (OR 0.8 (95% CI: 0.42–1.5).

Currently, there is only one RCT comparing the use of monopolar and bipolar resectoscopes in removing SM fibroids and their effects on reproductive outcomes (31). In this small-sized RCT, 34 women were assigned to each group and ongoing pregnancy/live birth rates were found similar between the monopolar and bipolar groups (26.5% vs. 29.4%, respectively; OR 0.8, 95% CI: 0.3–2.5).

The lack of significant difference of success between surgical techniques may be related to different surgical approaches as well. For example, some researchers suggest that preservation or non-preservation of the fibroid pseudocapsule during surgery may influence the outcome. Malvasi et al. studied the pseudocapsule at the ultrastructural level and reported that pseudocapsule was a part of myometrium compressing the fibroid and should be preserved as much as possible (32). Several following studies demonstrated that the preserved pseudocapsule containing many neuropeptides and angiogenic elements determined the regenerative capacity of the myometrium after the removal of the fibroid (33,34). Moreover, an immunohistochemical study revealed that pseudocapsule of removed fibroids of 6–11 cm showed increased signs of aging and loss of regenerative potential by changes in proportion of laminin and collagen IV. Thus, the authors proposed to remove fibroids remaining under 6 cm diameter before the loss of regenerative potential (35). As the surgical removal of fibroids larger than 5 cm has been the common clinical practice for many years and the studies focusing on the results of surgical removal of fibroids mostly include the cases with fibroids larger than 5 cm, the findings of this study may explain why surgical removal of some fibroids are not increasing the fertility rates.

In 2020, a systematic review compared pregnancy outcomes of myomectomy with non-surgical management options (36). Data from 68 studies included 1,575 pregnancies after myomectomy, 424 after uterine artery embolization (UAE), and 420 after fibroid ablation. Live birth rates and miscarriage rates for myomectomy, fibroid ablation, and UAE were 75.6%, 70.5%, 60.6% and 19.9%, 11.9%, 27.4%, respectively. UAE had significantly higher miscarriage and lower live birth rates compared to other methods (P<0.001) and it seems wiser to avoid for women who may conceive in the future. The authors’ personal impression is the same about UAE. Patients who underwent myomectomy following prior UAE seem to have a fragile, easily broken myometrial tissue in our experience.

ASRM declares abdominal, laparoscopic, or hysteroscopic approaches acceptable (22). Yet it is common and practical to prefer hysteroscopy for SM fibroids or IM fibroids that distort endometrial cavity (22,23,26). SCOG states SM fibroids should be smaller than 5 cm in diameter to be managed hysteroscopically, since larger ones often require repeat surgeries (23). They add that although reproductive outcomes of laparoscopic and abdominal routes for myomectomy produce comparable reproductive outcomes, laparoscopy provides quicker recovery, less febrile morbidity and less postoperative pain (23). The choice between the two approaches depends on the number, location and size of the fibroids, risk of malignancy women’s surgical history, costs, experience of the surgeon and patient preference.

Last of all, besides their potential impact on fertility, fibroids may increase risks for several obstetric complications, such as preterm labor, malpresentation and postpartum hemorrhage (37-39). Discussing the potential impact and risks of their fibroids with the patients on an individual basis, should they achieve pregnancy, is important and it can affect the joint decision-making process.

Conclusions

Although fibroids are frequent in the infertile population, their high heterogeneity and methodological problems hinder efforts to reach high-quality evidence on their impact on and surgery’s role in infertility.

SM and IM fibroids that distort the uterine cavity are likely to adversely affect fertility and surgical removal of these are recommended. On the contrary, SS fibroids are not thought to have an impact on fertility, therefore removal of these solely for fertility purposes is not recommended. The effect of non-cavity distorting IM fibroids on fertility is still a subject of debate, however, the evidence tends to suggest that their presence may lower a woman’s chance of achieving a live birth. Likewise, whether their surgical removal restores or improves this is a gray area and usually not recommended. However, it can be an option for women with large fibroids, a history of miscarriages, or failed IVF attempts in the absence of another factor explaining reproductive failure.

The route of myomectomy is also an underinvestigated area. SM and IM fibroids that distort endometrial cavity are best managed hysteroscopically, if not larger than 5 cm. For other fibroids, laparoscopy and laparotomy seem to yield similar reproductive results, but laparoscopy may be preferred for quicker recovery and reduced postoperative pain.

Finally, it should be noted that majority of data on the relationship between fertility, fibroids and their surgical correction are based on heterogenous observational studies, providing low-quality evidence that should be treated with caution.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Omer Lutfi Tapisiz and Sadiman Kiykac Altinbas) for the series “Uterine Fibroids: Various Aspects with Current Perspectives” published in Gynecology and Pelvic Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-22-29/rc

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-22-29/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-22-29/coif). The series “Uterine Fibroids: Various Aspects with Current Perspectives” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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