Fibroids and fertility: a review of the evidence

Abstract

The role of uterine fibroids (leiomyomata) in infertility has been the subject of debate for many years. Its importance as a topic of research has further increased as women delay childbirth into their 30s and 40s, when the incidence of fibroids is significantly increased. This article reviews the evidence for mechanisms by which fibroids may decrease fertility and the diagnostic and therapeutic options available to clinicians faced with a couple with fertility problems where fibroids are present. The majority of studies have looked at the location of fibroids within the uterus (submucosal, intramural and subserosal) to help determine their impact on fertility and spontaneous abortion rates. These studies have underlined the importance of location and distortion of the uterine cavity for fertility, although meta-analysis has highlighted a number of study design issues with suboptimal localization of fibroid position being a common problem in interpreting the exact role of intramural fibroids. Apart from physical location, other mechanisms have also been explored, including impaired uterine peristalsis, vascular changes and disruption of the uterine intracavity biochemical milieu.

Keywords::

• fertility outcomes
• fibroid
• infertility
• location
• mechanism
• surgery

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journals/expertob; (4) view/print certificate.

Release date: 13 December, 2011; Expiration date: 13 December, 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Distinguish the best imaging modalities for uterine fibroids

• • Identify the type of uterine fibroid most associated with infertility

• • Analyze adverse events associated with the use of uterine artery embolization for fibroids

• • Assess surgical options for the treatment of fibroids and the effect of surgery on fertility

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure:CP Vega, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Andrew Knox, MD

Ulster Hospital, Upper Newtownards Road, Dundonald, Belfast, BT16 1RH, UK.

Disclosure:A Knox has disclosed no relevant financial relationships.

Neil McClure, MRCOG

Royal Jubilee Maternity Hospital, Grosvenor Road, Belfast, BT12 6BA, UK.

Disclosure:N McClure has disclosed no relevant financial relationships.

Uterine fibroids are benign tumors that vary greatly in number, size, location and symptoms. It has been estimated that the incidence of fibroids ranges from 5.4 to 77% in premenopausal women, with a fibroid being the only detected abnormality in 1–2.4% of infertile women [1,2]. The main risk factors for development of fibroids are: African–American ethnicity (almost three-times as likely as white women), increasing age, nulliparity, obesity, cigarette smoking and a prolonged menstrual cycle [3].

Mechanisms by which fibroids cause infertility

The traditional mechanisms by which fibroids are thought to be related to fertility problems are associated simply with their physical presence in the uterus. Fibroids may impede sperm or egg transport through displacement of the cervix or obstruction of the fallopian tubes and pouch of Douglas. Implantation may be affected by deformity of the cavity but increased contractility of the myometrium and a chronic inflammatory response by the endometrium to underlying fibroids may also be important [4–7]. Many studies look at a single mechanism but it is most probably a combination of factors that contributes to any associated fertility difficulties.

Ben-Nagi et al. examined the effect of submucous (SM) fibroids on concentrations of glycodelin, insulin-like growth factor binding protein-1 (IGFBP-1), IL-6, IL-10, TNF-α and osteopontin in uterine flushings: these cytokines are thought to promote early pregnancy. Premenopausal women with a diagnosis of a SM fibroid, confirmed on 3D saline infusion sonohysterography, were recruited into the study. The control group was women with no ultrasonic evidence of any uterine or endometrial pathology. Uterine flushings were taken to measure the levels of these substances. They found that women with SM fibroids had significantly lower concentrations of glycodelin and IL-10 in mid-luteal phase uterine flushings than controls and speculated that this may be a significant factor in the reduced fertility seen in these women [8].

Rackow et al. looked at the genes HOXA10, HOXA11 and BTEB1, which are essential for proper adult endometrial development and receptivity during each menstrual cycle. Their study found a significant reduction in the three genes in the presence of SM fibroids. These reductions were not just localized to the endometrium overlying the fibroid but occurred throughout the cavity. They did not demonstrate a significant decrease for intramural (IM) fibroids, although a trend to lower levels was noted [7].

With regard to IM fibroids, it has been postulated that they may be associated with decreased fertility by interfering with uterine contractility. Studies have examined uterine peristalsis in relation to the menstrual cycle and have found that the direction is cervix to fundus during the periovulatory phase, and fundus to cervix during the menstrual phase. However, during the luteal phase, uterine peristalsis is barely observed. These results support the concept that uterine peristalsis is related to uterine function, namely such activities as sperm transport, embryo implantation and discharge of menstrual blood [9]. Yoshino et al., using MRI, aimed to determine if IM fibroids increased peristalsis and thereby possibly decreased fertility. Their results showed that less than half of the patients with IM fibroids exhibited abnormal uterine peristalsis during the mid-luteal phase. Interestingly, in the high-frequency peristalsis group, no patients achieved pregnancy, while a-third of the patients in the low peristalsis group achieved pregnancy (significance p < 0.005). In the high-frequency group, 12 out of 22 patients had cavity distortion, which is a possible confounding factor [10]. Further studies looking at peristalsis following myomectomy for IM fibroids not distorting the cavity would help support this theory.

Role of location

The location of uterine fibroids has been the most widely examined factor in studies hoping to explain the role fibroids play in infertility. The main outcome of these studies has been to demonstrate that SM fibroids appear to have a definite detrimental effect, IM fibroids have a role not yet fully understood and that subserosal fibroids, unless very large and disrupting fallopian tube function or distorting the pouch of Douglas, have little bearing on fertility [11].

In reaching these conclusions, one of the assumptions that had to be made was that fibroid location has been accurately assessed by the investigators. The assessment of fibroid location has traditionally been performed either by transvaginal ultrasound (TVS) or by hysterosalpingography (HSG), as it was felt that these were both adequate in demonstrating fibroid location and, critically, endometrial cavity distortion. The evidence now available suggests that these methods are inadequate to evaluate the cavity fully for distortion [12–17]. In 2001, Dueholm et al. compared MRI, TVS, hysterosonographic examination (HSE) and hysteroscopy in evaluating uterine cavity pathology, along with histopathology specimens, in 106 women who underwent hysterectomy for benign pathology. They found the sensitivity for identification of SM myomas was MRI 1.0, TVS 0.83, HSE 0.90 and hysteroscopy 0.82; the specificity was MRI 0.91, TVS 0.90, HSE 0.89 and hysteroscopy 0.87. They concluded that for exclusion of abnormalities in the uterine cavity, MRI, HSE and hysteroscopy were equally effective and slightly superior to TVS [18]. The superiority of HSE to TVS and HSG has been confirmed by a number of studies, including Ragni et al., who demonstrated that HSE yielded higher diagnostic accuracies than TVS for intrauterine pathology. Compared with hysteroscopy, the sensitivity and specificity of saline infusion sonography were 98 and 94%, respectively, whereas those of TVS were 91 and 83%, respectively [19,20]. Despite this evidence, TVS and HSG have been used in the majority of studies to determine cavity distortion and therein lies the problem that fibroids classified as IM may well have an unrecognized SM component and so are wrongly classified. Thus, the significance of IM fibroids may have been over-represented.

With the limitation of study quality regarding imaging technique borne in mind, the question of fibroid location affecting fertility has been assessed in a large number of trials. In three reviews in 2001, 2009 and 2010, Pritts et al. identified the relevant published studies that had addressed the presence of fibroids and their impact on clinical pregnancy rate, implantation rate, live birth rate and spontaneous abortion (SAB) rate. They initially included 23 studies – one randomized controlled trial, nine prospective and 13 retrospective studies. They applied the Meta-analysis of Observational Studies in Epidemiology guidelines for systematic reviews of observational studies and found an overall significant adverse effect for fibroids on implantation rate (relative risk [RR]: 0.821), live birth rate (RR: 0.697) and SAB (RR: 1.678) rates when compared with infertile women without fibroids [21]. When they looked at fibroids by location their analysis revealed that SM fibroids had the most significant effect reducing implantation rate (RR: 0.283), live birth rate (RR: 0.318) and SAB rate (RR: 1.678). The analysis of IM fibroids was more complicated as they initially looked at all studies addressing this issue and then proceeded with a further subanalysis of the studies that include those that only used hysteroscopy to evaluate the cavity. They found that the initial analysis of IM fibroids demonstrated a significant reduction in implantation rate (RR: 0.684), live birth rate (RR: 0.703) and SAB rate (RR: 1.747). However, the subanalysis of trials using only hysteroscopy showed a loss of significance in all outcomes apart from implantation rate (RR: 0.714). The loss of significance highlights the difficulty of using studies that do not use optimal methods for evaluating the uterine cavity when describing IM fibroids, as there may well be a degree of unrecognized cavity distortion [22,23].

A further meta-analysis by Sunkara et al. evaluated the role of non-cavity-distorting IM fibroids in women undergoing assisted reproductive technology. They included 19 studies (over 6000 IVF cycles) and their primary outcome measure was live birth rate. They found a statistically significant (21%) relative reduction in live birth rate in women with non-cavity-distorting IM fibroids compared with women without fibroids (RR: 0.79; 95% CI: 0.70–0.88; p < 0.000). The secondary outcome measure showed a statistically significant (15%) reduction in clinical pregnancy rate in women with non-cavity-distorting IM fibroids, following IVF treatment (RR: 0.85; 95% CI: 0.77–0.94; p = 0.002) [24].

These results have been replicated by other authors, including Klatsky et al. who reported their findings with a cumulative rate odds ratio (OR) from 19 studies looking at the effect of IM fibroids. Their findings for implantation rates, clinical pregnancy rates and SAB rates demonstrated an OR of 0.79, 0.84 and 1.82, respectively. They did not subanalyze the data for sole use of hysteroscopy [25].

The above analyses demonstrate the difficulty in drawing conclusions from the available studies. There initially appears to be a negative impact on fertility with IM fibroids but Metwally et al. demonstrated that when only the highest quality studies are included, this impact loses significance. They concluded that there is no compelling evidence to suggest that IM fibroids have a significant effect on fertility when taking into account the existing study designs and biases. Their review highlighted the need for new high-quality studies that fully assess confounding variables that will enable clinicians to decide how best to counsel patients prior to designing their individual management strategy [26].

The size of fibroids has been reported in most of the studies mentioned above but there is no strong evidence to suggest that larger fibroids have a more detrimental effect than smaller fibroids. Oliveira et al. found lower pregnancy rates with fibroids larger than 4 cm compared with those less than 4 cm but their study did not demonstrate any difference in live birth rate between those with and without fibroids [27]. Klatsky et al. demonstrated that subjects with fibroids measuring 4–8 cm had a pregnancy rate of 67%, which was not significantly different from their controls and women with smaller fibroids [28]. To date there is no study that clearly demonstrates a relationship between size and pregnancy outcome.

The association between fibroid number and fertility outcomes has not been fully assessed in most of the studies. In 2002, Check et al., as part of their study on IM fibroids and IVF outcomes, reported the pregnancy rates with respect to the number of fibroids diagnosed by TVS. They were able to show a nonsignificant fall in pregnancy rate as the number of fibroids increased from one to a maximum of seven [29]. This does suggest that the higher the number of fibroids the more likely they are to be detrimental to fertility. However, it is unclear if this is because of increased aggregate fibroid volume within the uterus, or if it is specific to the number present. The methodical approach used by Check et al. could be usefully employed in a larger prospective study to help clarify the relationship between number of fibroids and reproductive outcome.

Surgery for fibroids

Given that the evidence appears to demonstrate a negative impact for SM fibroids on fertility, it is a logical extension of reasoning that by their removal one would expect an improvement in pregnancy rates.

Casini et al. studied the effect of fibroid location and myomectomy either abdominally or hysteroscopically. In the group of 52 women who had SM fibroids, 32 underwent surgical resection. They were able to demonstrate statistically significant improvements in pregnancy rates from 27.2 to 43.3% and a fall in miscarriage rate from 50 to 38.5% [5]. Surrey et al. showed in a retrospective case-controlled series of women receiving assisted reproductive technology compared with those who underwent hysteroscopic or open resection of fibroids prior to IFV and embryo transfer that those women who underwent hysteroscopic resection achieved a clinical pregnancy rate of 61% [30]. Pritts et al., in their meta-analysis, were able to draw the conclusion that those women who underwent hysteroscopic myomectomy had a significantly higher pregnancy rate than those women who had their fibroid left in situ (RR: 2.034). They also concluded that by removing SM fibroids women had comparable pregnancy rates to controls with no fibroids (RR: 1.545; nonsignificant) [23]. Hysteroscopic surgery has the benefits of a shorter hospital stay, less pain and, as the abdominal cavity is not opened, there is no risk of pelvic adhesion formation [31]. The procedure is not without complications and can be technically difficult, especially if the fibroid is located at the uterine fundus. The significant risks associated with hysteroscopic surgery were investigated by Propst et al., and they found an overall complication rate of 2.7% with an increased rate in resections of fibroids (OR: 7.4; 95% CI: 3.3–16.6). The complications reported included: uterine perforation, excessive glycine absorption (1 l or more), hyponatremia (less than 130 mEq/l), hemorrhage (estimated blood loss of 500 ml or more), blood transfusion, unplanned hospital admission directly related to hysteroscopy, bowel or bladder injury, inability to dilate the cervix, or inability to complete the surgery because of poor visibility or excessive fluid absorption [32]. A longer term complication that has the potential to impair fertility is the formation of uterine synechiae. The rate varies widely in the literature between 7.5 and 45.5% and this is possibly due to the differences between monopolar and bipolar energy modalities and the use of techniques to reduce their formation, such as intrauterine devices or gels [33].

Myomectomy & pregnancy rates with IM fibroids

There have been few high-quality studies that have focused on the role of myomectomy in improving fertility outcomes for women with IM fibroids. Casini et al., in the only prospective controlled trial, aimed to determine if myomectomy prior to conception improved pregnancy rates and pregnancy outcomes in 181 women. Their findings demonstrated that in women with IM fibroids there was no significant difference in pregnancy rates between those who had a myomectomy (56.5%) and those who did not (41%) [5]. This is currently the best study that has directly looked at IM fibroid location and myomectomy and it does not support surgical intervention to improve fertility outcomes.

The question of whether laparoscopy or laparotomy is a better approach for the removal of fibroids has been addressed by a number of studies. The increasing skill of gynecologists in laparoscopic surgery over recent years has made the use of minimal access techniques more widely available. The main issues in operating abdominally by either route are the risks of hemorrhage, the formation of adhesions, recurrence of fibroids and the presence of a uterine scar and its possible implications for future pregnancies.

In 2000, Seracchioli et al. published their comparison of outcomes between laparoscopic and abdominal myomectomy. The study included 131 women with a primary complaint of infertility who also had at least one fibroid measuring over 5 cm. They were able to demonstrate that laparoscopic myomectomy was associated with significantly less febrile morbidity, a smaller hemoglobin drop and a shorter hospital stay when compared with myomectomy at laparotomy [34].

The risk of adhesion formation reported by Dubuisson et al. after laparoscopic myomectomy was 35.6% [35]. Takeuchi et al. reported adhesions at the site of the uterine surgical wound in 141 patients (37.9%). They involved the anterior uterine wall in 30 patients (21.3%), the posterior wall in 97 patients (68.8%), and both in 14 patients (9.9%). Thus, adhesions tended to occur more frequently on the posterior wall [36]. Although studies have reported adhesions in as many as 88% of women following laparoscopic myomectomy, the majority of studies report similar findings to those of Dubuisson and Takeuchi – approximately 30–40%. This is in contrast to a rate of over 90% adhesion formation quoted by the myomectomy adhesion multicenter group following abdominal myomectomy [37].

With limited evidence to suggest that myomectomy of IM fibroids is of actual benefit in improving a woman’s chance of achieving a pregnancy, the decision to subject her to an operation which has a high risk of adhesion formation, a risk factor for infertility in itself, needs to be carefully considered. To this end there are now a growing number of studies looking at methods to prevent adhesion formation using a variety of agents. These studies have shown that the use of adhesion barriers can reduce the risk of adhesion formation and thus associated morbidity [38,39].

Nonsurgical alternatives

Uterine artery embolization (UAE) and magnetic resonance-focused ultrasound (MRI-FUS) are the most commonly utilized alternatives to surgical treatment for uterine fibroids.

UAE has been successfully used for over a decade now to reduce the symptoms of fibroids but not specifically as a treatment for fibroids thought to be causing infertility [40]. It involves occlusion of the uterine vessels with a variety of agents including nonabsorbable polyvinyl alcohol spheres, coated gel spheres and temporary gelfoam. The aim is complete occlusion of the fibroid blood supply bilaterally with subsequent necrosis and reduction in fibroid mass. The issue of fertility following UAE was initially confined to case reports as it was advised that women wishing to conceive should not routinely be offered it as a treatment. However, as the number of post-treatment pregnancies has grown, researchers have looked more closely at their outcomes. The first review of pregnancies following UAE was published in 2004 by Goldberg et al. They compared outcomes between 51 women undergoing UAE and 139 undergoing laparoscopic myomectomy. Their results showed an increased risk of preterm delivery and malpresentation, with a nonsignificant increase in miscarriage and post-partum hemorrhage [41]. A more recent meta-analysis performed by Homer et al. included seven studies that looked at pregnancy outcomes after UAE. They identified 227 pregnancies and examined six pregnancy-related outcomes. The meta-analysis confirmed an increased rate of miscarriage of 35.2% compared with pregnancies matched for age and fibroid location of 16.5% (OR: 2.8; 95% CI: 2–3.8). They also found that women were more likely to deliver by cesarean section and to experience a post-partum hemorrhage (OR: 2.1 and 6.4, respectively). When compared with pregnancies with fibroids left in situ, the likelihood of preterm delivery, intrauterine growth restriction and malpresentation were similar. The control groups used were a pooled miscarriage rate from 1121 pregnancies with IM fibroids in situ, taken from 14 studies, and 4454 pregnancies from ten studies where fibroids were a complicating factor. The authors of this review commented on the limitations of their study, especially the heterogeneity of the population studied. However, they felt that such a large increase in miscarriage rate could not be entirely due to confounding factors such as age, obesity and parity [42]. An interesting study by Kuzel et al. may help explain why there is this increase. They undertook hysterscopic examination of the uterine cavity at 3–6 months postprocedure in 74 women who underwent UAE for IM fibroids. Their results identified 32 patients with evidence of intracavity necrosis, and five of these patients had a necrotic defect of the endometrium. Adhesion formation was identified in eight women and the majority of these were described as dense. Overall, after hysteroscopy and biopsy they could only classify 30 women as having a normal cavity or endometrium after UAE [43].

MRI-FUS is a more recent, noninvasive approach to the treatment of fibroids using MRI-FUS. It aims to ablate the fibroid tissue thermally by using ultrasound to heat the tissue to 65–85°C, thus inducing necrosis. It has a definite role for women in whom surgical management is undesirable. Since its introduction in 2000 it has been shown to be effective in the relief of symptomatic fibroids [44,45]. Like UAE it has not been specifically used for the treatment of fibroid-related infertility but pregnancies have now been reported as case series. Rabinovici et al. reported 54 pregnancies in 51 women. Live births occurred in 41% of pregnancies, with a 28% spontaneous abortion rate, an 11% rate of elective pregnancy termination, and 11 ongoing pregnancies (20%) beyond 20 gestational weeks. The mean birthweight was 3.3 kg and the vaginal delivery rate was 64% [46]. While these results are promising, a randomized controlled trial comparing MRI-FUS with myomectomy is currently in progress in the USA, and this will help clarify risks associated with this procedure (ClinicalTrials.gov identifier: NCT00730886 [101]).

Expert commentary

This review has aimed to evaluate the evidence for the role fibroids do or do not play in infertility, and to highlight some of the key features that should influence management decisions by clinicians. The cornerstone of management, and the downfall of a number of these studies, lies in the accurate diagnosis of fibroid location within the uterine wall. The evidence shows that the best methods to determine cavity involvement include hysteroscopy, HSE and MRI, and future studies should aim to employ one of these modalities in the study design. More accurate assessment of cavity involvement would help either to support or refute the role that IM fibroids play in infertility, as the current evidence from existing trials using suboptimal imaging makes drawing firm conclusions difficult.

The literature, to date, would suggest that the removal of SM fibroids is of benefit to women and, if technically possible, this should be by hysteroscopic resection as this has the least surgical morbidity.

An individual approach to counseling women with IM fibroids needs to be adopted as the evidence for improving fertility is poor and there is a significant associated operative morbidity, not least the high risk of abdominal adhesion formation. These may be reduced by the use of laparoscopic approaches and adhesion barriers.

Five-year view

In the next few years additional studies are required to determine the exact role IM fibroids play, and if the surgical morbidity associated with their removal is balanced with the improvement of fertility outcomes. Alternative nonsurgical therapies are now gaining acceptance in women who are wishing to maintain their fertility. The use of UAE is increasingly widespread and is of use in symptom control. However, with reported high miscarriage rates its use should be individually tailored to those women in whom surgical management is not desirable. MRI-FUS is in its infancy in the UK, and whilst initial results are promising its routine use will likely be limited by cost and availability in the immediate future.

The genetics of fibroids are currently being explored in greater depth. A study in Finland has recently demonstrated altered genes in fibroids. They identified tumor-specific mutations in the mediator complex subunit 12 in 70% of fibroids studied from 80 patients [47]. This will not only help us understand how fibroids develop but may also open the door for potential targeted gene therapy in their prevention and treatment.

Key issues

• • The use of hysterosonographic examination, MRI and hysteroscopy are most accurate in determining fibroid location.

• • Impaired peristalsis, inflammatory response and physical deformity of the cavity may all play a role in reducing fertility outcomes.

• • Submucosal fibroids have a proven detrimental role in fertility outcomes.

• • Intramural fibroids and their removal have not been conclusively proven to improve outcomes.

• • Minimally invasive surgical techniques are superior as they have less associated morbidity.

• • The use of adhesion barriers at the time of surgery decreases adhesion formation.

• • Uterine artery embolization and magnetic resonance-focused ultrasound are gaining acceptance as treatment options, although long-term outcomes are not clear.

• • Future treatments may involve gene therapies as this field of medicine advances.

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Fibroids and fertility: a review of the evidence

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Your patient is a 32-year-old woman. She and her husband have failed to conceive a child during the past 15 months. You consider whether uterine fibroids may be contributing to this woman’s infertility. Which of the following imaging modalities is LEAST effective in identifying fibroids?

• □ A Transvaginal ultrasonography

• □ B MRI

• □ C Hysteroscopy

• □ D Hysterosonographic examination

2. The patient undergoes appropriate diagnostic testing. Which of the following type of fibroid is most associated with infertility?

• □ A Submucosal

• □ B Intramural

• □ C Subserosal

• □ D Both intramural and subserosal

3. The patient is diagnosed with intramural and submucosal fibroids, and she is interested in a less invasive means of treating her fibroids. Which of the following outcomes is a serious adverse event during pregnancy related to the previous use of uterine artery embolization?

• □ A Uterine rupture

• □ B Intrauterine growth restriction

• □ C Miscarriage

• □ D Shoulder dystocia

4. What can you tell this patient regarding surgical management of her fibroids?

• □ A Excision of submucosal fibroids appears to improve fertility rates

• □ B Excision of intramural fibroids appears to improve fertility rates

• □ C Hysteroscopic surgery is best for fibroids located in the fundus

• □ D Laparoscopic myomectomy is associated with higher rates of adhesion formation compared with abdominal myomectomy