The patient is broadly counseled regarding the options for management of uterine fibroids, which include expectant management, medical management with monthly injectable gonadotropin-releasing hormone agonists (GnRHa), uterine artery embolization (UAE), MRI-guided high-intensity focused ultrasound, laparoscopic-guided myolysis (using thermal energy, cryoablation, and radiofrequency ablation [RFA]), and laparoscopic, robot-assisted laparoscopic or abdominal myomectomy [2–4].

Hysterectomy is specifically discussed as a method that would provide a definitive cure for this uterine pathology, with the understanding that this is never a first-line management in a patient desiring future fertility. Due to the fact that leiomyosarcomas are a possible finding even in reproductive-aged women (see full discussion below), it is imperative that the decision of not removing the uterus en bloc be made by the patient, not by the surgeon. As a result, a clear discussion about hysterectomy should be had (and should be duly documented) with every reproductive-aged patient.

Expectant management avoids all procedure-related risks and confers the added benefit of not requiring waiting or recovery time before attempting fertility treatments. The presence of an intramural fibroid (over 4–5 cm) may, however, negatively affect implantation rates. Small retrospective studies (approximately 100 patients) have inconsistently shown reduced implantation, ongoing pregnancy, and live birth rates in patients with intramural fibroids [5–8]. A comprehensive meta-analysis confirmed the lower implantation (relative risk [RR] = 0.684; 95% confidence interval [CI], 0.587–0.796), clinical pregnancy (RR = 0.81; 95% CI, 0.696–0.941), and ongoing pregnancy and ongoing pregnancy/live birth rate (RR = 0.703; 95% CI, 0.583–0.848) in women with intramural fibroids not encroaching on the uterine cavity as compared to women without fibroids [9]. A meta-analysis focused on in vitro fertilization (IVF) outcomes in patients with non-cavity-distorting intramural fibroids as compared to patients without fibroids similarly reported a significant decrease in the live birth (RR = 0.79; 95% CI, 0.70–0.88; P < 0.0001) and clinical pregnancy rates (RR = 0.85; 95% CI, 0.77–0.94; P = 0.002) [10]. Please refer to the section on myomectomy below for data regarding comparison of expectant management and operative interventions.

Fewer studies have attempted to identify size thresholds for the potentially negative effect of intramural fibroids on pregnancy rates. A retrospective review including 130 women undergoing IVF with intramural fibroids reported that pregnancy rates were lower in women with intramural fibroids over 4 cm in diameter: 29%, as compared to 51% in women with fibroids measuring 2–4 cm and 53% in women with fibroids less than 2 cm (p < 0.05) [11]. Conversely, a prospective study of 119 women with intramural fibroids less than 5 cm in diameter and matched controls undergoing IVF demonstrated no significant difference in pregnancy rates and live birth rates [12]. Ultimately, the size of intramural fibroids warranting removal for fertility reasons remains undetermined, and the decision to intervene or proceed expectantly must be individualized and based on patient’s age, past reproductive history, associated pathology, and the degree of invasiveness of the tools available to treat the pathology.

The presence of fibroids in pregnancy is also associated with a variety of complications in the antepartum period and at delivery. Expectantly managed intramural fibroids in pregnancy have been associated with a higher rate of pregnancy loss; a meta-analysis of studies of intramural fibroids in early pregnancy (mean diameters of 1.8 cm to over 5 cm) reported a cumulative first trimester spontaneous abortion rate of 20.4% as compared to 12.9% in patients without fibroids (odds ratio [OR], 1.6; 95% CI, 1.30–2.0) [9, 13]. The presence of fibroids in later pregnancy has been associated with preterm premature rupture of membranes, preterm labor, placental abruption, intrauterine growth restriction, malpresentation, and pain due to fibroid degeneration [14]. Large submucosal and retro-placental fibroids confer the greatest risk of pregnancy complications [14]. Fibroids greater than 200 mL in volume, in particular, have been associated with fetal growth below the tenth percentile [15]. In a review of 190 women with singleton gestations, those with fibroids over 5 cm in diameter delivered at a mean gestational age of 36.5 weeks, compared to 38.4 weeks in women with fibroids less than 5 cm (p = 0.002) [16]. Finally, intrapartum issues associated with the presence of fibroids include dysfunctional labor, increased risk of cesarean section, hemorrhage, and retained placenta [14].

In patients desiring future fertility, uterine artery embolization, MRI-guided focused ultrasound (MRgFUS), and laparoscopic-guided myolysis are not currently recommended. The most data have been published regarding pregnancy after UAE, which is performed by interventional radiology specialists and involves the cannulation of the femoral artery followed by catheter-guided delivery of embolic particles to the uterine arteries to induce fibroid necrosis. Risks include pain, infection, and nontarget embolization (including the lower extremities and ovaries) [17]. UAE may also result in endometrial atrophy and scarring or pelvic infection, all of which are potentially devastating complications in a patient desiring fertility [18, 19]. Benefits include avoidance of surgery and resultant fibroid shrinkage of 20–50% [20]. While series of successful pregnancies after UAE have been reported, UAE has also been associated with decreased anti-Müllerian hormone levels (presumed to be due to nontarget embolization of the ovaries), which would be highly detrimental to a patient seeking fertility (particularly in the age range of 35–45 years, which is precisely when most uterine fibroids are found) [21]. In a series of 53 pregnancies conceived after UAE as compared to 139 pregnancies conceived following laparoscopic myomectomy, patients with prior UAE were at increased risk for preterm delivery (odds ratio [OR] 6.2; 95% confidence interval [CI] 1.4–27.7) [22]. Series have also reported that UAE may be associated with an increased risk of miscarriage and abnormal placentation (such as placenta previa or accreta) [23, 24].

MRgFUS entails the targeting of ultrasound waves on fibroids to produce tissue destruction; risks include skin or visceral thermal injury [25, 26]. Small series have reported uncomplicated term deliveries after MRgFUS, but data are currently lacking to support use of this method in women planning pregnancy, while better studied alternatives are available [27]. Data are similarly few regarding pregnancy following laparoscopic myolysis, which involves the introduction of an energy source directly into a fibroid under laparoscopic guidance, to produce thermal damage and involution. While uncomplicated term pregnancies have been reported following myolysis using RFA and bipolar energy, reports of gravid uterine ruptures following myolysis with bipolar energy have also been published [28, 29].

In the age of widespread access to minimally invasive myomectomy (made possible by the many technological improvements in the fields of laparoscopy and robot-assisted laparoscopy), any technique that can only provide partial removal of intramural fibroids, but offer risk and recovery profiles comparable to minimally invasive surgery, lack true value proposition and should only be considered as a possible alternative to invasive surgery (open myomectomy).

Medical management with GnRHa alone may result in fibroid shrinkage by 35% or more within 3 months [30]. Patients may also report vasomotor symptoms, and prolonged use (greater than 6 months without progesterone add back) may result in decreased bone mineral density. The further limitation of this treatment modality is that the treatment effect is only sustained as long as the medication is continued [31]. This medication, by disrupting gonadotropin release from the pituitary, is also incompatible with spontaneous conception and may dampen ovarian response to ovulation induction. Furthermore, the myometrium would eventually be exposed to large concentrations of estrogen and progesterone during fertility treatment and even more so in pregnancy, which may counteract pre-pregnancy treatment effect [15]. At the present time, the use of GnRH agonists in reproductive-aged women with fibroids should be limited to preoperative treatment in order to shrink fibroids to a size more amenable to minimally invasive surgery (a decision that depends on the technical skills and preference of the surgeon) and to address preoperative anemia in women with fibroid-related abnormal uterine bleeding [32–35].

The conservative surgical approach to intramural fibroids is determined by fibroid number, size, and surgeon and patient preference. Options include abdominal (open), laparoscopic, and robot-assisted laparoscopic myomectomy. Any myomectomy is not without risk; perioperative complications include blood loss and infection; adhesions may develop, leading to pain and tubal occlusion [36]. Hospital length of stay, blood loss, and complication rates, however, can be significantly reduced with the adoption of a minimally invasive approach (laparoscopic, with or without robotic assistance) instead of an abdominal approach [37]. Minimally invasive approaches can be achieved even in patients with numerous or large fibroids, at a surgeon’s discretion; robot-assisted myomectomy has been reported as safe and feasible for fibroids exceeding 9 cm [38].

In the last decade, robot-assisted laparoscopic myomectomy has gained acceptance as an alternative to conventional laparoscopic myomectomy. Hospital stay, postoperative pain, complication rate, and blood loss are comparable between laparoscopic and robot-assisted myomectomy [37, 39, 40]. Robotic surgery, with its stereoscopic view and articulated instruments, allows for microsurgical uterine dissection and careful suturing of hysterotomies in multiple layers, reducing tissue trauma [34]. This gentle handling of reproductive structures is well suited to an infertility population. Most importantly, recent evidence that surgeons can perfect their robotic surgical technique on a digital simulator presents a significant advantage, particularly for patient safety, in the adoption of this minimally invasive approach to myomectomy [41].

Minimally invasive approaches to myomectomy require fragmentation of the enucleated fibroids, for removal through small incisions. A very small percentage of uterine tumors presenting clinically as fibroids will be malignant, most commonly leiomyosarcoma. Currently, no clinical testing can reliably differentiate between a fibroid and a leiomyosarcoma in a low-risk patient population [42]. Patients undergoing myomectomy should be specifically counseled regarding the possibility of occult malignancy, particularly as the disruption of the fibroid capsule and tumor enucleation within the abdomen is implicit in any myomectomy. It is unknown whether the disease-free survival is affected by the spread of cells and tissue fragments in the abdominal cavity that occurs universally during myomectomy. However, extrapolation from hysterectomy data suggests that en bloc removal of a uterus with leiomyosarcoma (as in open hysterectomy) confers longer disease-free interval, but no overall survival advantage, as compared to patients whose uteri were morcellated [43, 44]. An en bloc myomectomy, however, is a surgical impossibility. As a result, every patient who desires a conservative surgical approach to their fibroids must voluntarily assume a certain degree of risk. The patient’s active decision to proceed with conservative surgery for solid uterine masses should be documented in every informed consent that is signed before surgery.

Reproductive-aged patients who do not want a hysterectomy can be helped in their decision-making by offering an estimate of risk of occult malignancy. An FDA advisory in 2014 reported an incidence of occult sarcoma of 1 in 350 hysterectomies (following a methodologically questionable and arguably biased analysis of the literature) [45]. However, the risk of occult leiomyosarcoma was reported as less than 1 in 8000 hysterectomies in the only complete meta-analysis in the current literature [44, 46].

In spite of their exaggerated report of the prevalence of malignant uterine tumors, the FDA advisory specifically allows open morcellation in adequately counseled premenopausal women [45]. However, many surgeons and hospitals fear opportunistic lawsuits and have abandoned open morcellation, resulting in a surge in open pelvic surgery—associated with higher complication rates than minimally invasive approaches—rather than in the adoption of alternative tissue extraction techniques for enucleated fibroids [47, 48]. As an alternative to open morcellation —while novel-contained tissue extraction devices await approval by the FDA—enucleated fibroids can be placed within a containment bag in the abdomen and brought up to a laparoscopic incision that has been extended to 2–3 cm in length to allow for manipulation of the fibroids; the fibroids are then serially incised using a scalpel and removed. The use of intra-abdominal containment bags for tissue extraction may limit fragment spread while allowing patients to enjoy the benefits of a minimally invasive approach [49, 50]. Studies of these containment devices are ongoing.

During both abdominal and minimally invasive myomectomy, intraoperative techniques can be used to minimize myometrial damage and provide an optimal myometrial repair, theoretically limiting later risk of gravid uterine rupture [51]. These intraoperative measures include avoiding electrocautery in favor of less destructive energy tools such as the carbon dioxide (CO₂) laser and the Harmonic^® scalpel (Ethicon, Somerville, NJ), thereby limiting thermal damage to the myometrium [51, 52]. Additionally, closing the full depth of myometrial incisions in multiple layers avoids hematoma formation, which results in healing by second intention [53].

The utility of myomectomy in improving delivery rates in women with intramural fibroids continues to be debated because the definitive study—i.e., a randomized study to compare myomectomy with expectant management in IVF cycles—has never been done. Such a study has likely not been undertaken as the evidence for a negative impact of fibroids on IVF outcomes is substantial, and patients (and their clinicians) are likely to resist randomization to a nontreatment group. MRI studies of uterine peristalsis suggest utility of myomectomy for reproductive function. Uterine quiescence, which has been demonstrated to be vital for implantation, has been found to be abnormal in women with intramural fibroids, who have increased luteal phase uterine peristalsis by MRI [54]. In a series of 51 patients with intramural fibroids, those with rare uterine peristalsis had a pregnancy rate of 34% compared to 0% in the high peristalsis group. This abnormal peristalsis may be due to increased estrogen resulting from increased aromatase activity within the fibroids [55]. Altered production of neuropeptides involved in peristalsis in the pseudocapsule, and various growth factors may also play a role [56, 57]. Uterine peristalsis has been shown by MRI to return to normal in a majority of patients after myomectomy for intramural fibroids, associated with increased delivery rates following IVF [58, 59].

Few studies have specifically focused on the utility of myomectomy in improving pregnancy outcomes in patients with intramural fibroids. Of note, studies of intramural fibroids and pregnancy outcomes are variable in their methods of assessing fibroid location and encroachment on the uterine cavity (by ultrasound, MRI, hysteroscopy, or other imaging), which complicates comparison among them. A review of 41 patients with intramural and subserosal fibroids who underwent either laparoscopic or open myomectomies reported significantly improved pregnancy rates after myomectomy (34.1% pre-myomectomy vs. 60.9% post-myomectomy) [60]. Patients who were significantly more likely to conceive after myomectomy were younger and had had intramural fibroids (OR, 12.38) or significantly larger fibroids removed (5.80 cm vs. 4.28 cm; P = 0.0274), via laparoscopic myomectomy. Conversely, in their meta-analysis, Pritts and colleagues reported no differences in clinical pregnancy rate, live birth rate, or spontaneous abortion, when comparing women with intramural fibroids who underwent myomectomy when compared to those who did not [9]. In the only prospective study on the subject, Bulletti and colleagues enrolled 168 women with fibroids greater than 5 cm in diameter that did not deform the intrauterine cavity; patients elected whether or not to have laparoscopic myomectomies before IVF treatment [61]. Delivery rates were significantly different between the two groups, who were similar in age (<35 years): 25% in patients who underwent myomectomy as compared to 12% in women who declined myomectomy.

Preoperative treatment with GnRHa (for 3 months) or misoprostol (immediately preoperatively) may decrease surgical morbidity. Pretreatment with GnRHa may reduce intraoperative blood loss and operative time: A prospective study of 91 women with cumulative fibroid diameter of over 10 cm, treated with 3 months of an injectable GnRHa prior to laparoscopic myomectomy, showed a reduction in blood loss, operative time, and need for blood transfusion [62]. Studies have not consistently reported this finding, particularly as many studies included patients with smaller fibroids [32]. Ultimately, the benefit of GnRHa pretreatment is likely in patients who might otherwise not be eligible for a minimally invasive approach due to fibroid size [34, 35]. Additionally, preoperative treatment with rectal misoprostol has been associated with decreased blood loss and is a prudent, low-risk intervention immediately before myomectomy [63, 64].