Abstract
The growing body of evidence concerning the safety and efficacy of uterine artery embolization (UAE) has led to increasing confidence amongst gynecologists and interventional radiologists that UAE can be used safely to treat women with symptomatic fibroids. UAE is clearly preferable for certain subgroups of patients, for example those with increased risks of complications of general anesthesia, those with religious objection to blood transfusion and those wishing to avoid surgical risk. This review of the available literature demonstrates the paucity of information concerning safety and efficacy of UAE for those wishing to conceive. Case reports and series are largely positive. However, there are continuing concerns over the effects of UAE on ovarian and uterine function, and on subsequent pregnancy outcome. More long-term data and randomized controlled trials are required to address these issues. Women who undergo embolization should be told that the effects on pregnancy and the resulting child are uncertain and that there may be long-term implications for the health and development of the offspring. Hence, it is inadvisable to try to conceive following the procedure. Given the available evidence, concern must remain that UAE may lead to significant damage to fertility, with higher risk of miscarriage and adverse pregnancy outcome when compared with open or laparoscopic myomectomy.
There is a considerable body of literature supporting the contention that uterine fibroids are a cause of subfertility, but a direct causal effect relationship is yet to be established. It is clear that subfertility resulting from fibroids is not absolute, as many patients conceive without any intervention. Hence, before any treatment is offered, other causes of infertility should be sought and, if found, treated accordingly. Couples should be advised to try natural conception in the absence of other causes of infertility.
If a fertility problem seems likely to be the result of uterine fibroids, management options now include uterine artery embolization (UAE) of fibroids. It is an attractive option because it is minimally invasive compared with traditional surgical approaches such as myomectomy. The aim of UAE is to deliver particulate material into both uterine arteries to produce ischemic changes in the fibroids without the surgical complications associated with myomectomy. Although UAE is an attractive treatment option, major complications do occur in an estimated 1–5% of cases [1,2]. Complications reported include chronic vaginal discharge occurring in up to 7% of patients, serious infections in 1–2%, particularly in patients with large fibroids, and hysterectomy in 1%. Although uncontrolled trials reported lower complication rates with UAE, a randomized trial (Embolization versus Hysterectomy [EMMY] trial) from The Netherlands showed a comparable overall major and minor complication rate in both UAE and hysterectomy, but minor complications in the first 6 weeks postprocedure were significantly higher in the UAE group [2,3].
Different types of fibroids respond differently to UAE. Interstitial fibroids respond best to embolization, with a 60% shrinkage rate in 6 months and 70% shrinkage within 12 months [16]. Very large and pedunculated subserosal fibroids respond less well, have a higher rate of complications and, as such, are considered a relative contraindication. Submucous fibroids tend to respond well to embolization but complications such as septicaemia have being reported [4]. Until the efficacy of UAE for submucous fibroids is proven, hysteroscopic resection of submucous fibroids is the preferred approach as it is a minimally invasive outpatient procedure with nearly 50% of patients becoming pregnant after hysteroscopic resection of submucous fibroids [29].
Like medical treatment for fibroids, recurrences after UAE have been reported and correlate with the size and number of fibroids [5].
Although more than 150,000 procedures have been performed worldwide, the role of UAE in women with fibroids who wish to conceive is controversial as little is known of its long-term effect on reproductive function and pregnancy outcomes [3]. Before UAE can be recommended for routine use in women wishing to conceive, information is required with regards to patients' chance of having a healthy child after UAE and their obstetric risk when compared with myomectomy. The chance of conception in these patients is in turn dependent on UAE's effect on ovarian and endometrial function. The aim of this article is to review current evidence on the impact of UAE on ovarian–endometrial function and pregnancy outcome.
Ovarian function
The negative effect of fibroid embolization on ovarian function has been reported in the literature. Possible mechanisms for ovarian dysfunction include inadvertent embolization of uteroovarian anastomoses, overaggressive embolization and effect of ionizing radiation exposure on the ovaries [6,7]. While these mechanisms are plausible, it is as yet not possible to ascertain the real impact of UAE on ovarian function as studies are limited by small numbers of patients, short-term follow up and involve predominantly older women.
Studies on ovarian function to date have produced contradictory results, from no effect on ovarian function to ovarian failure [8–10]. The risk of ovarian dysfunction is higher with increased age and various studies report up to 15% of patients experience ovarian dysfunction based on pre- and post-embolization serum follicular stimulating hormone (FSH) levels [10–13]. Ovarian failure is reported to occur in 1–2% of patients based on cessation of their period [7]. Although the EMMY study did not show any significant difference in early menopause at 2 years after UAE compared with hysterectomy, Jim Reekers, at a recent Joint RCOG/RCR meeting on fibroid embolization 2007 in London, reported a lower serum level of anti-mullerian hormone (AMH) post UAE in the EMMY study [3]. As AMH is a regulator of primordial follicle recruitment, serum AMH is likely to reflect the size of the primordial pool. Therefore, lower serum AMH may reflect ovarian dysfunction in these patients.
Despite contradictory results, the potential adverse effect on ovarian function is a great concern to women who wish to preserve their reproductive function. Even if future fertility is not an issue, possible iatrogenic premature ovarian failure will raise serious medical questions especially in younger patients. Future studies investigating the effects of uterine artery embolization on ovarian function should include sequential measurements of early follicular phase AMH and inhibin B, and ultrasound assessment of ovarian volume and blood flow pre-embolization and post-embolization. An attempt should be made to determine the age of menopause in these patients [14]. As current data are based mostly on women over 40 years of age, the long-term effects of UAE on ovarian reserve in younger women are unknown.
Endometrial function
UAE may compromise the vascularity of the uterine myometrium and endometrium, resulting in suboptimal embryo implantation. Both animal and human studies after UAE have shown myo-metrial necrosis at the embolization site, accompanied by acute and severe inflammatory reaction with foreign body granulomas [15–17]. Postembolization transient and permanent amenorrhoea in the absence of any apparent change in ovarian function have been reported after the procedure [13,18]. The likely mechanism of amenorrhoea is endometrial atrophy due to endometrial necrosis following fibroid embolization [11,13,19]. As with ovarian failure, endometrial dysfunction after UAE is age dependent, being more frequent in older women (7–14%) compared with younger women (3%) [7].
Pregnancy outcome
Data pertaining to fertility and pregnancy outcome after UAE are scarce. The literature is limited to case reports and case series investigating the safety and effectiveness of fibroid reduction and symptom relief following UAE. UAE may have negative effects on placental blood supply leading to pregnancy complications such as preterm labor, intrauterine growth restriction and postpartum hemorrhage. To date, there are no randomized, controlled trials comparing the effect of UAE and conventional myomectomy on improving fertility or pregnancy outcome. Based on retrospective observational studies, live birth rates after UAE have been reported to range from 7–25% compared with 40% after laparoscopic myomectomy [20,24,32].
Most large case series show a significant increase in pregnancy complications when compared with the general obstetric population. Reported pregnancy complications include increased miscarriage rate, preterm delivery, antepartum hemorrhage, malpresentations, cesarean section and postpartum hemorrhage [20–24]. Significant intrauterine growth retardation has not been observed in the reported case series. Data on pregnancy outcome published from a recent randomized trial comparing UAE versus surgery for symptomatic uterine fibroids (REST study) reported four miscarriages from a total of seven pregnancies and one intrauterine fetal death at 33 weeks after UAE [25]. Currently, there are no data on the long-term sequelae to children born after fibroid embolization. From these observation studies, UAE is associated with lower pregnancy rates and higher miscarriage rates leading to lower live birth rates. UAE also appears to be associated with higher risk of obstetric complications. However, when interpreting these findings, it must be remembered that this population is not typical of the general obstetric patients, as they are generally older with known pregnancy risks such as increased aneuploidy, miscarriage and pre-eclampsia. One should also consider the potential confounding effect of fibroids is cases where there is persistence or regrowth of fibroids.
Myomectomy
Myomectomy remains a sensible option for women with fibroids who wish to conceive. Surgery should be performed in a specialist center by an experienced surgeon, and should use microsurgical techniques to reduce postoperative adhesion formation. The likelihood of pregnancy after myomectomy is reported to be between 40 and 76.9%. The various studies have reported on heterogeneous populations, and there is a shortage of randomized trials in this field [26–30].
Minimally invasive laparoscopic myomectomy has gained popularity in recent years and the proponents of this surgical technique have argued that it has shorter postoperative recovery and produces equal results compared with laparotomy. However, there are concerns regarding the long-term strength of the uterine repair, particularly after removal of large fibroids. There are four randomized, controlled trials comparing laparoscopic with abdominal myomectomy. These found that laparoscopic myomectomy was associated with shorter postoperative recovery, but with no significant difference in recurrence of fibroids or pregnancy rates between groups [31–35]. Hence, although there is increasing evidence of its effectiveness, laparoscopic myomectomy remains more time consuming, is technically more challenging and may not be the best approach in all cases.
Unlike UAE, we have ample data on pregnancy outcome after myomectomy. Hence, before UAE can be recommended routinely in patients who desire to preserve their fertility, there should be a multicenter, randomized trial of embolization versus microsurgical or laparoscopic myomectomy that is properly powered, with livebirth as primary outcome, studying patients under 40 years of age with a complete infertility workup, including pretreatment and serial post-treatment assessment of ovarian reserve.
Conclusion
The growing body of evidence concerning the safety and efficacy of UAE has led to increasing confidence amongst gynecologists and interventional radiologists that UAE can be used safely to treat women with symptomatic fibroids. UAE is clearly preferable for certain subgroups of patients, for example those with increased risks of complications of general anesthesia, those with religious objection to blood transfusion and those wishing to avoid surgical risk. UAE is relatively contraindicated for women with pedunculated subserous fibroids and those patients with submucous fibroids who are best treated hysteroscopically. This review of the available literature demonstrates the paucity of information concerning safety and efficacy of UAE for those wishing to conceive. Case reports and series are largely positive. However, there are continuing concerns over the effects of UAE on ovarian and uterine function, and on subsequent pregnancy outcome.
The joint Royal College of Obstetricians and Gynaecologists/Royal College of Radiologists (RCOG/RCR) committee on fibroid embolization (2000) concluded in its report that women who undergo embolization should be told that the effects on pregnancy and the resulting child are uncertain, and that there may be long-term implications for the health and development of the offspring. Hence, they should not try to conceive following the procedure. Given the available evidence, concern must remain that UAE may lead to a high risk of damage to fertility, with higher risk of miscarriage and adverse pregnancy outcome when compared with open or laparoscopic myomectomy.
Future perspective
UAE is growing in popularity as a minimally invasive alternative to surgery for uterine fibroids. Obstetricians and gynecologists are likely to see an increasing number of women who have undergone this procedure, and need to be aware of its possible short- and long-term consequences. Although firm evidence is lacking, UAE appears to have negative impact on ovarian reserve and may lead to loss of fertility potential. We may see improvement in means of targeting embolization to fibroid vessels to reduce this risk. Equally, there appears to be an increased incidence of pregnancy loss and pregnancy complications, including ante- and post-partum hemorrhage following UAE. Pregnancies following UAE should be designated as ‘high risk’ and such cases will become a regular feature of antenatal clinics and labor wards in years to come.
Executive summary
There is a growing body of evidence concerning the safety and efficacy of uterine artery embolization (UAE). This has led to increasing confidence amongst gynecologists and interventional radiologists that UAE can be used safely to treat women with symptomatic fibroids.
UAE is clearly preferable for certain subgroups of patients, for example those with increased risks of complications of general anesthesia, those with religious objection to blood transfusion and those wishing to avoid surgical risk.
There is a lack of good quality evidence concerning safety and efficacy of UAE for those wishing to conceive.
There are continuing concerns over the effects of UAE on ovarian and uterine function, and on subsequent pregnancy outcome. There appears to be higher risk of miscarriage, premature birth and other adverse pregnancy outcomes when compared with open or laparoscopic myomectomy.
We recommend that women who undergo embolization should be told that the effects on pregnancy and the resulting child are uncertain and that it is therefore inadvisable to plan to try to conceive following the procedure. Surgical treatments for fibroids are preferable for women who wish to retain their fertility.