Dr Morin is a Fellow in Reproductive Endocrinology and Infertility at Thomas Jefferson University/Reproductive Medicine Associates of New Jersey in Basking Ridge, New Jersey. He has no conflicts of interest to report in respect to the content of this article.
Dr Schlaff is Professor and Chair of the Department of Obstetrics & Gynecology at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania. He reports performing contracted research for AbbVie Pharmaceuticals.
Fibroids are extremely common in women of reproductive age. One large study reported that 70% of Caucasian and 80% of African-American women had at least one ultrasound- or pathology-confirmed fibroid by the end of their reproductive years.1 While many of these women experience no negative effects of fibroids on their reproductive function, a significant number are at increased risk of infertility, miscarriage, or poor obstetric outcomes. As a result, the average ob/gyn is confronted with a variety of clinical scenarios and decisions regarding management of fibroids in the context of reproduction. Furthermore, the frequency with which clinicians encounter these issues will only increase as the trend toward delaying childbearing coincides with an increased incidence of fibroids in women later in their reproductive years.
Here we synthesize the complex literature on fibroids into evidence-based, pragmatic clinical recommendations for contemporary fibroid management.
The reproductive implications and therapeutic options for uterine fibroids are largely a function of their location. Classically, fibroid location has been divided into 3 categories: submucosal, intramural, and subserosal, though these terms are not universally consistent. Many fibroids lie in a gray area between these 3 distinct categories, which further complicates our ability to analyze existing data. Any discussion of management of fibroids and reproduction must start with a detailed description of the location of the fibroid in relation to the endometrial cavity. We feel that the FIGO classification scheme is the most useful organizational system published to date.2 This system is based on describing the proportion of the fibroid that is distorting the endometrial cavity because that is the single most important factor that affects the clinical implications and the type of treatment offered to the patient.
Submucosal fibroids are divided into 3 types. Type 0 are completely intracavitary (often described as “intracavitary myomata” rather than submucosal to distinguish them from other submucosal myomata that are partially or almost completely intramural). Type I fibroids have an intramural component, but >50% of the fibroid is located within the endometrial cavity. Type II fibroids also have an intramural component, but <50% is intracavitary. Intramural fibroids do not distort the endometrial cavity and have <50% of their mass protruding through the serosa. Fibroids extending >50% out of the serosal surface are considered subserosal.
Use of the FIGO classification scheme requires accurate delineation of the anatomic relationships as described, reinforcing the importance of optimal imaging techniques. Transvaginal ultrasound (TVUS) has been demonstrated to be a rapid and cost-effective means of evaluating uterine fibroids but may be limited by a variety of factors including the size and number of myomas as well as the acoustic shadowing they produce.
While initial studies reported high sensitivity and specificity for diagnosing endometrial cavity distortion in submucous myomas, more recent studies have demonstrated positive predictive values as low as 47%,3 thereby underscoring the need to utilize other, more effective imaging approaches including saline infusion sonography (SIS). SIS enhances the diagnostic accuracy of traditional ultrasound by creating a fluid interface through the instillation of saline into the uterine cavity. The degree to which the fibroid is contained within or distorts the cavity is usually more easily diagnosable; other pathology such as endometrial polyps may also be diagnosed more effectively.4
Although data are lacking, SIS may be further enhanced by 3D ultrasound. If the patient has multiple myomas or the uterus is quite large, ultrasound and/or SIS may not be effective in providing an accurate assessment of fibroid location. In these cases, magnetic resonance imaging (MRI) is the technique of choice for providing detailed mapping of the location and anatomic relationships of the fibroids.5
Fibroids and fertility
Many hypotheses have been proposed to explain the mechanisms by which fibroids affect fertility. Some of these theories include a reduction in perfusion of the endometrium, local inflammatory changes that inhibit implantation, and alterations in normal uterine contractility that limit gamete and embryo migration.6-8 However, fibroids alone are often not the only identifiable cause of infertility. Indeed, one recent analysis suggested that when all other causes of infertility are excluded, fibroids are found in only 1-2% of remaining patients.9
Furthermore, many patients with fibroids achieve pregnancy without difficulty. Thus, counseling an individual patient about how her fibroids may affect reproduction can be challenging. The literature, however, does provide clear answers in some clinical scenarios. An abundance of data demonstrate that patients with submucosal myomas are less likely to become pregnant (RR 0.363, 95% CI 0.179-0.737, P=0.005) and more likely to experience spontaneous abortion (RR 1.678, 95% CI: 1.373-2.051, P=0.22) than are women who have intramural or subserosal fibroids.10 Conversely, many studies have demonstrated that patients with subserosal fibroids are not at increased risk of infertility or pregnancy loss.11 Controversy still exists, however, regarding the effect on fertility of intramural myomas that have no impact on the uterine cavity. The majority of studies comparing patients with intramural fibroids and those without fibroids have demonstrated no difference in pregnancy rates. However, 2 recent meta-analyses both observed that after pooling the results of individual studies, patients with non-cavity-distorting intramural fibroids were less likely to become pregnant (RR 0.88, 95% CI 0.77–0.94, P=0.002)12 and more likely to miscarry (RR 1.891, 95% CI 1.473–2.428, P<0.001).10
While fibroid location has received significant scrutiny in the literature, fibroid size and number have received relatively less attention. The limited expert opinion that does exist generally supports the notion that only intramural myomas >4 cm significantly affect pregnancy rates.13 However, the available literature does not provide data regarding whether 10-cm fibroids produce similar untoward effects on pregnancy rates and outcomes as 4-cm fibroids. While it seems logical that larger fibroids and an increased number of intramural fibroids would be more likely to cause poor outcomes, more data addressing these questions are needed.
While information comparing the likelihood of a pregnancy between women with and without fibroids is helpful from a counseling standpoint, it does not address whether treating those fibroids improves outcomes. Multiple studies compare the outcomes of patients with submucosal fibroids who underwent myomectomy to those who did not. Only one of these studies was performed prospectively and demonstrated that hysteroscopic myomectomy improved the chances of pregnancy over no treatment (43% vs 27%, P<0.05) in patients with submucosal myomas.14 A meta-analysis of the remaining retrospective studies also found an apparent benefit of hysteroscopic myomectomy for submucosal myomas (RR 2.034, 95% CI 1.081–3.826, P=0.028).10
The picture for non-cavity-distorting fibroids is less clear. Pooled data from multiple observational studies have reported post-myomectomy pregnancy rates for infertile patients with intramural myomas that approach 50%.15 However, there are relatively few studies that have prospectively compared pregnancy rates in patients with non-cavity-distorting fibroids after myomectomy versus expectant management. Those studies have produced conflicting results. Bulletti et al. found that myomectomy prior to in vitro fertilization (IVF) for patients with at least one non-cavity-distorting myoma >5 cm improved delivery rates over expectant management (25% vs 12%, P<0.05).16
Conversely, Casini et al. observed no significant difference in pregnancy rates whether myomectomy for non-cavity-distorting fibroids was performed or not.14 An important distinction between these 2 studies was that pregnancy was attempted via IVF in the Bulletti study. This bypasses one potential side effect of abdominal myomectomy—pelvic adhesions—which may affect a patient’s ability to naturally conceive following surgery.
Additionally, when considering this literature, it is especially important to note that all studies that reported a negative effect of intramural myomas on fertility and all studies that demonstrated an improvement in outcomes following myomectomy for intramural myomas utilized traditional TVUS to establish the diagnosis, an approach known to be limited in its accuracy. In fact, the only study that confirmed a lack of cavity involvement of intramural myomas via hysteroscopy found no negative impact of intramural myomas on IVF outcomes.17 Thus, it is possible that studies observing a negative impact of intramural myomas on fertility may have missed a submucosal component to those fibroids.18
Thus, given that 1) the evidence to support myomectomy for non-cavity-distorting myomas is debatable and 2) the implications of abdominal surgery (risk of adhesions, surgical risk of bleeding or infection, increased likelihood of requiring a cesarean section) are significant, it seems prudent to allow patients to attempt pregnancy on their own without surgery before offering intervention for intramural fibroids. For patients who do not conceive after a reasonable amount of time and whose workup has yielded no other likely source for infertility, it is reasonable to offer myomectomy for large intramural myomas with adequate counseling regarding the associated risks and implications for future pregnancies.
Reassuring ovarian reserve testing and an active plan for pursuing pregnancy is also a prerequisite in these patients prior to undergoing myomectomy for fertility optimization given the controversy surrounding the value of surgery in improving a patient’s chances of pregnancy.
A number of less-invasive treatment approaches are available, such as uterine artery embolization (UAE) and MRI-guided thermal ablation. In addition, patients may desire medical management exclusively. However, very little data are available regarding the effects of these strategies on fertility and reproductive outcomes.
Studies on the effects of UAE on fertility and outcomes are mostly small, observational reviews with low-quality data. While results are inconsistent, an increased incidence of infertility, preterm birth, cesarean section, and postpartum hemorrhage has been reported.19-21 Only one prospective trial comparing myomectomy to UAE has been conducted and demonstrated a lower delivery rate and high miscarriage rate in patients treated with UAE.22
Until higher-quality data are available to clarify these associations, UAE should be avoided in patients wishing to preserve fertility. Magnetic-resonance-guided focused ultrasound surgery (MRgFUS) is a thermal ablation technique that directs ultrasonic energy to a fibroid, resulting in tissue necrosis with limited surrounding damage. Only 35 pregnancies have been reported following MRgFUS. Thus, the experience is currently too small to draw conclusions regarding the safety of pregnancy following this method.23
Several medical treatments have been shown to reduce the size of fibroids. These include gonadotropin-releasing hormone agonists, danazol, and mifepristone. Although these therapies may reduce myoma volume by 50%, all must be discontinued before pregnancy and the uterus usually returns to pretreatment size upon stopping treatment.24 Thus, there is no evidence that fertility improves with medical management and these strategies may delay the initiation of more efficacious approaches.
Fibroids and pregnancy
Fibroids are significantly associated with multiple morbidities in pregnancy, although significant misconceptions about this continue. The most common is that pregnancy will result in fibroid growth and an increased risk of adverse symptoms. Data show that the course of fibroid growth during pregnancy is variable. Approximately 85% patients experience no significant growth during pregnancy and those fibroids that do grow are rarely clinically significant.25,26 However, pelvic pain is significantly more common in patients with fibroids (12.6% vs. 0.1%, P<0.001) and is the most common fibroid-related pregnancy complication.
The association of fibroids with more serious untoward pregnancy outcomes has been evaluated in many studies. While most studies are observational and limited by small numbers of adverse events, consistent associations exist in the literature for some poor outcomes in pregnancy27 (Table 1). Fibroids are associated with an increased risk of preterm birth, placental abruption, and postpartum hemorrhage. Placentation overlying large fibroids increased the risk for these morbidities. Fibroids are also associated with an increased incidence of malpresentation and cesarean delivery.
Most women with fibroids do not experience fibroid-related complications during pregnancy.28 Furthermore, performing a myomectomy for a patient without symptoms in the preconception period also exposes her to a number of additional risks: surgical risk of myomectomy and future cesarean sections, pelvic and intrauterine adhesion formation, and uterine rupture. Thus, it is not advisable to perform preconception myomectomy for the prevention of pregnancy complications. However, if a patient experiences a pregnancy complication that is suspected to be related to her fibroids, myomectomy is a logical approach.
The evidence upon which to base recommendations for contemporary fibroid management is challenging to interpret. Furthermore, each patient’s individual presentation provides additional nuances that complicate clinical decision making. However, it is clear that imaging techniques that accurately define a fibroid’s relationship to the endometrial cavity are essential when determining the optimal course of action.
There is little doubt that cavity-distorting myomas are associated with infertility and miscarriage and that removing these fibroids improves outcomes. Whether the same conclusions can be drawn about truly intramural myomas is debatable, but large myomas are most likely to be associated with poor outcomes.
While fibroids do increase the incidence of certain untoward obstetric outcomes, the vast majority of pregnancies are uncomplicated despite the presence of fibroids. Thus, prophylactic myomectomy is not indicated to prevent poor pregnancy outcomes but rather only to prevent their recurrence.
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