Introduction
Uterine fibroids or leiomyomas are the most common benign tumor in reproductive-age women, consisting of smooth muscle cells and fibroblasts. When symptomatic, they typically cause pain or pelvic pressure, abnormal uterine bleeding and potential reproductive effects, such as infertility or adverse pregnancy outcome.
Ultrasound evaluation reveals an incidence of fibroids as high as 60% by the age of 35 years old in African-American women and 40% in Caucasian women. Parity may influence the development of fibroids; one or more pregnancies extending beyond 20 weeks decrease the risk of uterine fibroids. Although the epidemiology of leiomyomas is parallel to the ontogeny and life cycle changes induced by estrogen and progesterone, the growth of these tumors is not necessarily influenced by them, studies showing a presence of about 5% up to 10% in infertile women(1). The prevalence of fibroids increases with age during reproductive years, but only occasionally is noted in adolescents and for most patients it shows a decline after menopause.
Other factors associated with the development of fibroids include elevated Body Mass Index (BMI), positive family history, personal history of myoma, early menarche, smoking, alcohol consumption and genetics(2).
Regarding pregnancy, the potential effects of fibroids on pregnancy and vice versa are of intense concern, with controversial studies providing information about potential unfavorable obstetric outcome and assessing myomectomy as the most suitable surgical treatment for preserving fertility.
Clinical aspect and types
Uterine leiomyomas are suspected by symptoms or discovered incidentally on ultrasound (US) evaluation. The majority are small and asymptomatic, but the ones significant in size present with symptoms which are classified in three categories: heavy menstrual bleeding, bulk-related symptoms and reproductive dysfunction(3).
Fibroids are typically confirmed by US and are identified by their hypoechoic appearance and circular flow with Doppler. Location (intracavitary, submucosal, intramural, or subserosal) and size can be determined by US, with importance for providers in counseling patients on treatment options.
According to the classification system of the International Federation of Gynecology and Obstetrics (FIGO), there can be described several types of fibroids: intramural – located inside the myometrium, that can grow up in size and distort the cavity or serosal surface, submucosal – derived from myometrial cells, extending to the endometrium, subserosal, that may have a broad or pedunculated base, and the cervical myomas(4). Intracavitary and submucosal fibroids are involved in decreasing implantation and pregnancy rates(5).
There are a number of potential mechanisms whereby leiomyomas may adversely affect implantation. These include abnormally increased uterine contractility and disturbances in endometrial cytokine expression, as well as abnormal vascularization and chronic endometrial inflammation. All these modifications could adversely affect blastocyst implantation. The process of implantation requires coordinated and synchronous development of the embryo and an endometrium that is receptive to implantation.
Uterine fibroids and pregnancy
Influence of pregnancy on fibroids
The incidence of uterine leiomyomas in pregnancy ranges from 0.1% up to 10.7%(6,7). They can be encountered more frequently in women of 35 years of age and older, in nulliparous and in Afro-American women. Although changes in estrogen and progesterone and uterine blood flow may affect the fibroid size, there is evidence that antepartum they remain stable in approximately 50 up to 60 percent of the cases, only 20 up to 30 percent showing an increase(8-10). Usually, large fibroids over 5 cm in diameter may experience growth in size, while the smaller ones remain stable, with a growing process occurring more often in the first trimester. Regarding the postpartum period, most of the women experience regression after birth, with a 50% reduction in volume three to six months postpartum, with little results for women using progestins(11).
Influence of fibroids on pregnancy
Fibroids can obstruct the tubal ostia or the cervix and cause changes in the uterine contour, impairing the mobility of the egg, sperm or the implantation. Fibroids can also diminish the subendometrial artery blood flow, leading to worsened implantation rates and in vitro fertilization (IVF) outcomes.
During pregnancy, uterine leiomyomas are usually asymptomatic. Despite this fact, some women may experience pain, more in those with large fibroids or increasing in size, associated with nausea, vomiting, leukocytosis and fever(12,13).
Complications and obstetric outcome
Complications occur in 10-40% of pregnancies, due to the presence of fibroids(14). Depending on the stage of pregnancy, they can be classified as antepartum complications, intrapartum and postpartum complications, and fetal complications. The most frequent antepartum complications are pregnancy loss, preterm labor, premature rupture of membranes, placental abruption, pain, intrauterine growth restriction and malpresentations. Regarding the intrapartum and postpartum difficulties, there are to mention the dysfunctional labor, caesarean delivery, adherent placenta, postpartum hemorrhage and postpartum sepsis. At last, fetal complications include a low Apgar score and fetal abnormalities.
Antepartum
Pregnancy loss
Submucosal fibroids increase the risk of spontaneous abortion and might be a cause for recurrent pregnancy loss by damaging the uterine cavity. Subserosal and intramural myomas have little effect on implantation and fertility. The mechanisms involved are: the compression produced by the leiomyoma on the endometrium, resulting in an endometrial dysfunction, the alteration of vascularization at some site and prejudice on the embryo implantation, affecting the normal placentation and the development of future uteroplacental circulation, and the degeneration of fibroids with release of prostaglandins(15). Another explanation for spontaneous abortion is that a rapid growth in size might increase the uterine contractility and disrupt the placenta.
Preterm labor and premature rupture of membranes
There is cited a small increase in preterm labor and preterm birth(16-19). The cause that might explain this fact relates to the deformities produced on the uterine cavity, especially by leiomyomas of 3 cm or larger. Fibroid uteri are less susceptible to enlarge while the gestation is growing and this mechanism can initiate labor and even preterm birth. Not all studies present the correlation between uterine fibroids and preterm labor(20). Decreased oxytocinase activity in the gravid fibroid uterus increases the oxytocin level and produces premature contraction with the same result(21).
Similar to premature labor, there is cited a double risk for premature rupture of membranes for women with fibroids, particularly for fibroids in direct contact with the placenta(22). The risk is growing with large fibroids and multiple intramural ones, but there is no indication for performing cervical length measurements during pregnancy(23).
Placental abruption
Most often, the retroplacental and submucous fibroids can produce placental abruption. The increased risk comes from the impaired placental perfusion, several studies demonstrating a significant reduction of blood flow in fibroids and adjacent myometrium(24). Hence, the implantation in the endometrium beside a fibrotic site may produce placental ischemia and decidual necrosis, leading to abruption.
A mention should be made about placenta praevia, which seems to be related to the presence of large fibroids that lead to lower uterine segment implantation(25).
Pain
Pain is one of the most frequent complications of leiomyomas. It is associated with fibroids larger than 5 cm. Pain is mainly encountered during late first trimester and early second one, corresponding to the period of fibroid greatest growth. Pain results from torsion, mainly in the first trimester, when there is enough space in the abdominal cavity for twisting, obstruction of vessels supplying the leiomyoma, or red degeneration. The last one involves histological changes due to reduced blood supply of the rapid growing fibroid, leading to ischemia, necrosis and release of prostaglandins(26,27). Clinically, it manifests with localized tenderness over the fibroid, nausea, vomiting, mild fever and leukocytosis(28). The treatment includes rest, hydration and analgesics. In case of refractory pain, it is recommended the use of NSAIDs or antepartum myomectomy. Regarding the use of NSAIDs, it is advisable to avoid them beyond 32 weeks of gestation, due to the possibility of premature closure of ductus arteriosus, neonatal pulmonary hypertension or platelet dysfunction.
Intrauterine growth restriction
There is little implication on fetal growth. A study made by Rosati et al. showed the influence of large submucosal (more than 200 mL) and retroplacental fibroids (more than 4 cm) that interfere with normal placentation, producing small-for-gestational-age infants(29). For this reason, it is recommended to have the pregnant woman monitored by a maternal-fetal medicine specialist along this period.
Myomectomy during pregnancy
Generally, myomectomy during pregnancy must be avoided, given the potential risk of heavy bleeding, uterine rupture, miscarriage or preterm delivery. The exceptions are represented by acute abdomen caused by torsion of pedunculated fibroma, red degeneration fibroma, or intractable pain, when exploratory surgery cannot be safely delayed.
Intrapartum/postpartum
Dysfunctional labor
In case of vaginal delivery, large myomas might obstruct labor. Using the ultrasound examination, one can establish earlier the diagnosis of obstruction if the leiomyoma is located between the fetal head and the internal os, interfering with cervical dilatation and fetal descent.
Caesarean delivery
The risk of caesarean section (CS) is increased in case of uterine myoma, especially when myoma is large and located at the level of the lower uterine segment. Uterine myoma could influence the mode of delivery before labor by its praevia position or abnormal presentation. Once labor started, CS could be indicated because of dystocia. Uterine fibroma is not an indication for CS per se, but many obstetricians in current practice decide in this way(30). The association of uterine myoma (multiples or large one) and pregnancy could double the risk of CS. Because there is a well-known danger for postpartum hemorrhage, it is recommended for a patient to have at least a 9.5-10 mg/dL hemoglobin level.
Caesarean myomectomy
Elective myomectomy at caesarean delivery should be limited to pedunculated fibroma or fibroma that make difficult or impossible the closure of hysterotomy incision. There is a clear recommendation to avoid intramural myomectomy due to the risk of severe bleeding(31,32).
A meta-analysis including 2301 caesarean myomectomies (women who had myomectomy after the delivery of the baby) revealed a higher incidence of anemia and high need of transfusion compared with those of women who had CS alone (OR 1.41 versus 0.96). A weak point of the study was that there was not a stratification of the study according to the type and location of the fibromas and the correlation of these localization with the risk of hemorrhage.
Delivery after preconceptional myomectomy
The mode of delivery depends on the type and size of fibroma. In case of a pedunculated or subserosal myoma operated on, the mode of delivery will be based on obstetric indications. In case of myomectomy for a deep large intramiometrial myoma, with or without opening of uterine cavity, the best mode of delivery would be an elective CS performed at 38 weeks. In case of myomectomy for a medium-size myoma, with subserosal or intramyometrial location, in case of cephalic presentation, vaginal delivery will be encouraged. The risk of uterine rupture in labor after myomectomy is not significantly higher as compared to vaginal birth after CS. The overall rate of uterine rupture after myomectomy is 0.93% (0.47% in cases of trial of labor after myomectomy and 1.52% before the onset of labor)(33).
Postpartum hemorrhage
Several studies showed an increased risk for postpartum hemorrhage for women with uterine fibroids, especially for those larger than 3 cm and for retroplacental ones, the higher risk being reported in relation with caesarean delivery.
Adherent placenta
Due to the fact that the uterine cavity might be distorted or the uterine wall might present with abnormalities, it is imperative to investigate for adherent placenta or abnormal placentation. It is more often associated with submucosal fibroids. Ultrasound examination offers the possibility to visualize the placenta overlying an anterior fibroid, while MRI is better for posterior fibroids(34). For pregnancies diagnosed with adherent placenta, birth should be carried out in a tertiary center.
Fetal complications
Extremely rare, large intramyometrial or submucosal myoma could be associated with fetal abnormalities such as congenital torticollis, head deformities, arthrogriposis or hypomobility syndrome(35-37).
Myomectomy – management and implications
Asymptomatic fibroids found incidentally on clinical or US examination require periodic monitoring.
Myomectomy is the standard of care for treating symptomatic fibroids (abnormal uterine bleeding, recurrent pregnancy loss and infertility) in women desiring fertility preservation. The different efficacy profile on pregnancy outcome of different techniques is, however, still open to debate.
For symptomatic patients desiring fertility and presenting with a submucosal fibroid or fibroids (FIGO type 0, type 1, or some type 2), it is recommended to perform hysteroscopic myomectomy both for optimizing fertility rate and for improving distressing symptoms (heavy bleeding)(38).
The advantages of hysteroscopic myomectomy are: minimal recovery time, minimal need for analgesia and postoperative restrictions, decreased perioperative morbidity, and minimal scarring on the myometrium. The complication rate for the hysteroscopic procedure is low. The risk for uterine perforation increases with extensive resection, but it is usually uncommon. There is a small risk of excessive fluid absorption, which may cause hyponatremia, and excessive bleeding in patients requiring blood transfusions that was reported in a few studies. The outcome of hysteroscopic myomectomy provides good results on fertility rate, patients being more likely to conceive after the removal of distorting cavity myomas. However, there is still the risk of miscarriage and other obstetric complications (placenta accreta spectrum).
For symptomatic patients who desire pregnancy and have fibroids that are not amenable to hysteroscopic resection, abdominal myomectomy via either laparoscopy or open surgery is the alternative solution. The selection for laparoscopic or open technique is determined by the number, size, location of the fibroids and the surgeon’s experience, and does not appear to impact the live birth rate. Bearing in mind that the relapse is frequent and the rate of new fibroid formation is high following uterine-sparing interventions, fibroids are ideally treated when they are symptomatic or there is a reasonable causative relation to infertility.
The abdominal myomectomy is the classic approach and remains the routine approach for most surgeons faced with multiple or large fibroids. The average blood volume loss is approximately 200-800 mL, with the possibility of severe blood loss that may require blood transfusion. Fever within 48 hours after surgery and infection occur with the same rates as in hysteroscopic version. There is also cited the possibility for adhesions, especially in case of posterior fibroids or prior sutures, which may impact tubal fertility.
As regards fertility and pregnancy after myomectomy, the risk of uterine rupture is much lower (0.002%) than after prior classical caesarean section (3.7%)(39). Patients undergoing myomectomy are advised to wait three to six months before attempting to conceive.
When performing laparoscopic myomectomy, the location and the size of uterine fibroids are of the outmost importance. Many surgeons find anterior or fundal myomas easier to remove than those that are on the posterior face of the uterus. Performing laparoscopic myomectomy in patients with large or numerous myomas is likely to be time consuming, particularly since morcellation is usually required. In addition, the removal of such fibroids may lead to increased blood loss, which is better prevented and controlled during open myomectomy. The most serious complications are hemorrhage (0.68%), fever and infection, bowel or bladder injuries (0.04%) and emergency hysterectomy (0.09%). Laparoscopic myomectomy has lower overall morbidity and a shorter recovery time than open myomectomy.
The risk of occult leiomyosarcoma dissemination associated with fibroid morcellation was exaggerated and would not be taken as a contraindication.
As for long-term outcome, there is no significant difference in the rate of recurrent myomas, but a decreased rate in postprocedural adhesions, particularly near annexes, which affects fertility. Patients who undergo myomectomy with significant uterine disruption should wait three to six months before attempting to conceive. If they have delays in conceiving, a hysterosalpingogram is recommended. A birth plan should be performed and clearly explained to the future mother, advising caesarean delivery as a conservative approach. However, patients who had myomectomy for pedunculated or subserosal fibroids (types 5, 6 or 7) might be considered for a trial of labor.
Conclusions
Pregnancy has little impact on uterine leiomyomas, most of them remaining stable, with a small percentage increasing in size in the first and second trimesters, and more than 50% decreasing in three to six months after birth. On the other hand, leiomyomas have an important impact on pregnancy, from symptoms like severe pain, nausea and fever, to producing future adverse obstetric outcomes such as miscarriage, anomalies of placental implantation, growth restriction, association with caesarean delivery.
Asymptomatic myomas should be follow-up, while symptomatic fibroids should be removed by hysteroscopy, laparoscopy or by open surgery. Submucosal myomas are associated with infertility and hysteroscopic myomectomy is beneficial, while subserosal and pedunculated fibroids do not have a negative impact on infertility, and myomectomy is not beneficial.
Intramural fibroids are not clearly associated with infertility and their surgical removal has not clear benefits. Further studies are needed.
Large uterine myomas of the lower segment are associated with an increased risk of CS due to the fetal malposition or previa position of the myoma.
Myomectomy during pregnancy must be avoided, except for cases with acute abdomen (suspicion of necrosis, torsion, red degeneration) or when surgery could not be safely delayed.
Myomectomy at CS should not be encouraged, except for cases of large pedunculated myoma of the anterior face of the uterus, or myoma that impede hysterotomy closure. In well-individualized cases of large myoma of the lower segment, myoma complications (necrosis), difficulties of uterine closure or lack of interest for future fertility, hysterectomy could be an option.
Vaginal delivery should not be an indication for CS in case of uterine myoma, except for cases of myoma praevia. Vaginal delivery should not be an indication for CS after a preconceptional myomectomy, except for well-documented cases of deep large intramyometrial myoma with the opening of uterine cavity.
There is an excess of myomectomies, especially subserosal or intramural, by laparoscopy or open procedures. Gynecologists and surgeons have the professional duty to pled for decreasing the excess of unproved beneficial interventions. This attitude will decrease the number of CS and of the associated obstetrical complications.
Conflict of interests: The authors declare no conflict of interests.