What are the implications of myomas on fertility?

A need for a debate?

J. Donnez,1 and P. Jadoul

Department of Gynecology, Catholic University of Louvain, Cliniques Universitaires St-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
In order to evaluate the relationship between leiomyomas and infertility, which remains a subject of debate, we have tried to evaluate the impact of myomas on fertility and pregnancy outcome in different conditions where myomas are implicated. Medline research was conducted of publications appearing between January 1988 and August 2001 on the subjects of myomas and myomectomy and their impact on fertility and pregnancy outcome in infertile women. A total of 106 manuscripts were consulted. The incidence of myomas in infertile women without any obvious cause of infertility is estimated to be 1–2.4%. The relationship between leiomyomas and infertility remains a subject of debate. The question is: do myomas influence fertility? We are obliged to conclude that the question remains. The absence of an answer to this crucial question is probably due to the fact that we have not yet conducted the appropriate prospective studies required to obtain any clear results.

Key words: fertility/hysteroscopy/laparoscopy/myomas


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
Leiomyomas of the uterus are the most common solid pelvic tumours found in women and are estimated to occur in 20–50% of women with increased frequency during the late reproductive years (Verkauf, 1992Go). The incidence of myomas in infertile women without any obvious cause of infertility is estimated to be between 1 and 2.4% (Robert et al., 1974Go; Buttram and Reiter, 1981Go; Verkauf, 1992Go). The relationship between leiomyomas and infertility remains a subject of debate. To address this issue, we have tried to evaluate the impact of myomas on fertility and pregnancy outcome in different conditions where myomas are implicated. In an era of evidence-based medicine, we need a clear analysis of the literature. Can we draw any conclusions from what has been published or do we need to reconsider the whole problem?


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
A Medline search was conducted for publications appearing between January 1988 and August 2001 on the subjects of myomas and myomectomy and their impact on fertility and pregnancy outcome in infertile women. A total of 106 manuscripts were consulted. All were included, even if the methodology was questionable. In our opinion, including and scrutinizing questionable articles is necessary to have total perspective on the debate.


    Myomas and infertility
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
The central question in this debate is the following: `Do women with myomas suffer from decreased fertility?' To put it in more practical terms we should ask: `If we find a myoma in a woman with an infertility problem, can we conclude that there is a direct link between the myoma and the infertility and can we hope to improve fertility by removing the myoma?'

Different theories have been proposed to explain the effects of myomas on fertility. What are the mechanisms involved? It is generally accepted that the anatomical location of a fibroid is an important factor, with submucous, intramural and subserosal fibroids implicated, in decreasing order of importance, in causing infertility. Myomas may cause dysfunctional uterine contractility which may interfere with sperm migration, ovum transport or nidation (Hunt and Wallach, 1974Go; Buttram and Reiter, 1981Go; Vollen-Hoven et al., 1990Go). Myomas may also be associated with implantation failure or gestation discontinuation due to focal endometrial vascular disturbance, endometrial inflammation, secretion of vasoactive substances or an enhanced endometrial androgen environment (Deligdish and Lowenthal, 1970Go; Buttram and Reiter, 1981Go).

Ideally, to prove a relationship between fibroids and infertility, prospective randomized studies should be performed comparing women desiring pregnancy with and without myomas, in order to compare pregnancy rates and possibly the time needed to achieve pregnancy. Such studies were not encountered in our review. Another possibility would be to compare pregnancy rates between infertile women with and without myomas in whom other infertility factors have been excluded.

There is only one publication (Bulletti et al., 1999Go) that compares spontaneous conception in infertile women with and without myomas in whom andrological and tubal infertility factors have been excluded. The authors found a significant difference (P < 0.002) in pregnancy rates between infertile women with and without myomas (11 versus 25%). It is the only randomized prospective study to date and if it is to be believed, infertile women with myomas have better pregnancy rates after myomectomy (42%) than infertile women without myomas (25%), who in turn have better pregnancy rates than infertile women with untreated myomas (11%).

The methodology of this article is questionable as the follow-up is limited to 9 months. Moreover, the different groups are too small to draw any conclusion and the influence of the location and size of the myoma cannot be evaluated.

Myomas and IVF
Another way to approach the issue of the relationship between myomas and infertility is to assess the influence of myomas on implantation rates. IVF provides a good model to assess this influence, excluding other factors such as tubal or andrologic factors and allowing investigation of the influence of myomas on embryo implantation for embryos of the same `quality'. One should note that IVF cannot assess the impact of myomas on sperm migration and ovum transport.

Seven manuscripts (Farhi et al., 1995Go; Eldgar-Geva et al., 1998Go; Ramzy et al., 1998Go; Stovall et al., 1998Go; Healy, 2000Go; Jun et al., 2001Go; Surrey et al., 2001Go) have compared the results of IVF in women with untreated myomas and without myomas. They showed a significant decrease in pregnancy rates in patients with a distorted uterine cavity (9% pregnancy rate) compared with patients without distortion of the cavity (29.1%) and patients without myomas (25.1%).

In a retrospective comparative study of patients with uterine fibroids and those without fibroids, Eldar-Geva et al. and Healy concluded that pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine cavity (pregnancy rate: 16.4 and 10% respectively versus 30% in the control group), but pregnancy and implantation rates were not influenced by the presence of subserosal fibroids (Eldar-Geva et al., 1998; Healy, 2000Go).

In a non-randomized prospective case–control study, Stovall et al. concluded that myomas had a negative effect on implantation and pregnancy rates (37 versus 53%) (Stovall et al., 1998Go).

Ramzy et al. concluded that the presence of a myoma up to 7 cm, which does not distort the uterine cavity, does not affect pregnancy rates in IVF (39 versus 34%) (Ramzy et al., 1998Go).

Jun et al. found no significant differences in implantation rates and pregnancy outcome between women with myomas measuring <7 cm not distorting the uterine cavity and women without myomas (30.5 versus 41.6%) (Jun et al., 2001Go). Surrey et al. concluded from their retrospective case–control study that live birth rates were not affected by the presence of intramural leiomyomas in IVF patients with hysteroscopically normal endometrial cavities (Surrey et al., 2001Go).

When we compare these results, we can see that authors come to opposing conclusions. For some authors, myomas do not influence pregnancy rates if they have no repercussions on the uterine cavity (Farhi et al., 1995Go; Ramzy et al., 1998Go; Jun et al., 2001Go; Surrey et al., 2001Go). For others, the presence of a myoma, even one not distorting the cavity, decreases pregnancy rates (Edgar-Geva et al., 1998; Stovall et al., 1998Go; Healy, 2000Go).

How can we explain these differences? First of all, one should note the differences in pregnancy rates in the control groups between the different teams. Secondly, in our opinion, retrospective studies of small series have no medical value. If we conduct a meta-analysis of these studies (Table IGo), the pregnancy rate in women with fibroids distorting the cavity is 9%, while it is respectively 33.5 and 40% in women with fibroids not distorting the cavity and the control groups. Thirdly, the important differences observed between the different series raise the question of proper evaluation of the cases. In some series, the classification and the exact location of myomas is not clearly defined, casting doubts on the true value of the studies. Nevertheless, it seems reasonable to conclude that submucosal and intramural myomas distorting the uterine cavity impair implantation and pregnancy rates in women undergoing IVF.


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Table I. Pregnancy rate (PR) in women with fibroids distorting the cavity, in women with fibroids not distorting the cavity and in a control group (women without myomas)
 
Myomectomy and fertility outcome in infertile patients
The impact of fibroids on fertility was mainly evaluated indirectly by assessment of fertility after myomectomy. Does myomectomy improve pregnancy rates? Forty-six studies on fertility outcome after myomectomy in infertile patients have been published (Table IIGo). Most of them are retrospective analyses. Some focus on a particular location of the myoma, while others do not distinguish the type of myoma. The global pregnancy rate after myomectomy in infertile women, regardless of the kind of surgery undertaken, varies between 9.6 and 76.9%.


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Table II. Pregnancy rates (PRs) after myomectomy
 
How can we explain this discrepancy? Considerable differences in results persist even when the different kinds of surgery are considered separately. After hysteroscopic myomectomy, pregnancy rates are between 16.7 and 76.9% and after laparoscopic or laparotomic myomectomy, between 9.6 and 75%.

On the other hand, the global pregnancy rate found in these 46 studies is 48% (783 pregnancies in 1631 subjects). The pregnancy rate after hysteroscopic myomectomy is 45% (168/376) and after laparoscopic or abdominal myomectomy, 49% (615/1255). The differences found with the same surgical approach show the influence of different factors on pregnancy rates: (i) age and other infertility factors; (ii) factors related to the myoma(s); and (iii) technical factors.

Age and other infertility factors
Factors not directly related to the technique used could interfere with pregnancy rates. Age >35 years and an association with other infertility factors decrease pregnancy rates (Ramzy et al., 1998Go; Li et al., 1999Go; Vercellini et al., 1999aGo; Fauconnier et al., 2000Go; Zollner et al., 2001Go). In Fauconnier's study, fertility was found to be reduced in women who had associated tubal pathology, male or ovulatory factors (Fauconnier et al., 2000Go). In this study, fertility only slightly declined in the group of women aged >=40 years. Other authors found no relationship between age and fertility after myomectomy (Gatti et al., 1989Go; Gehlbach et al., 1993Go). Vercellini et al. showed decreased pregnancy rates after myomectomy in women >35 years of age and when the duration of infertility before myomectomy exceeded 2 years (Vercellini et al., 1999aGo).

Factors related to the myomas (number, volume, location)
With regard to the number of myomas, some authors showed a lower pregnancy rate when more fibroids were removed (Sudik et al., 1996Go; Dessolle et al., 2001Go), while others noted no difference (Vercellini et al., 1999aGo; Fauconnier et al., 2000Go; Rossetti et al., 2001Go). For Sudik et al. pregnancy rates were better after removal of myomas with a volume of >100 ml (±8 cm diameter) (Sudik et al., 1996Go). However, others found no difference according to myoma size (Vercellini et al., 1999aGo; Fauconnier et al., 2000Go; Rossetti et al., 2001Go).

Ancien and Querada, and Sudik et al. demonstrated no influence of myoma location (Ancien and Querada, 1996Go; Sudik et al., 1996Go). Fauconnier et al. found a lower pregnancy rate with posterior myomas (Fauconnier et al., 2000Go). Dessolle et al. showed better results when there was distortion of the uterine cavity before myomectomy (Dessolle et al., 2001Go). According to Fauconnier et al. prior deformation of the cavity did not influence pregnancy rates after myomectomy, but the presence of menometrorrhagia before myomectomy seemed to be associated with better results of myomectomy on fertility outcome (Fauconnier et al., 2000Go).

Altogether, the conclusions on the influence on pregnancy rates of the number, size and location of myomas and their capacity for distorting the cavity are somewhat contradictory. These contradictions and the influence of a patient's age and associated fertility factors, together with the probable role of technical factors, can lead us to question the real impact of myomas on fertility.

When we analyse the global results, the pregnancy rate after myomectomy in these 46 studies is 48%, without any significant difference between hysteroscopic myomectomy (45%) and laparoscopic and abdominal myomectomy (49%). In order to be able to interpret these figures, we need control groups of infertile women with myomas, to whom surgery was not proposed. Such groups were not found in these 46 manuscripts. Another important factor required to interpret these figures is the duration of infertility before myomectomy and the time taken to achieve pregnancy after myomectomy. Pregnancies seem to occur quite soon after myomectomy, 7.5 ± 2.6 months in Dessolle's review (Dessolle et al., 2001Go). No extensive figures on pregnancy rates relating to infertility duration were encountered.

Technical factors
Technical factors, such as the surgeon's skill and experience and the material and techniques used surely play a role. We tried to analyse the impact of the different surgical techniques on pregnancy rates.

Hysteroscopic myomectomy
For submucosal myomas, transhysteroscopic removal is the standard approach (Donnez et al., 1996Go). Different techniques can be used such as the resectoscope or the Nd:YAG laser (Donnez and Nisolle, 1993Go). Depending on the size of the intramural part of a submucosal myoma, one- or two-step surgery is required (Donnez et al., 1989Go, 1995Go, 2001Go). GnRH agonists have proved useful in reducing myoma size and expelling the myoma inside the uterine cavity (Donnez et al., 1992Go; Nisolle et al., 1994Go).

After hysteroscopic myomectomy in infertile women, pregnancy rates vary from 16.7 to 76.9%, with a mean value of 45% (Brooks et al., 1989Go; Donnez et al., 1990Go; Loffer, 1990Go; Corson and Brooks, 1991Go; Valle, 1991; Hucke et al., 1992Go; Cravello et al., 1995Go; Goldenberg et al., 1995Go; Hallez, 1995Go; Preutthipan and Theppisai, 1998Go; Giatras et al., 1999Go; Varasteh et al., 1999Go; Vercellini et al., 1999bGo; Bernard et al., 2000Go; Fernandez et al., 2001Go).

Only one study (Varasteh et al., 1999Go) included a control group of infertile women with a normal uterine cavity at hysteroscopy, and showed a significant benefit of removing submucosal myomas of >2 cm in size. Fernandez et al. also described better pregnancy rates after the removal of larger myomas, although the difference was not statistically significant (Fernandez et al., 2001Go). Indeed, the pregnancy rate after the removal of myomas >5 cm in size was 57%, while it was 23% for myomas <5 cm. Besides myoma size, no other myoma characteristics were examined to explain the differences in pregnancy rates.

Laparoscopic and laparotomic myomectomy
For intramural and subserosal myomas, laparoscopic and abdominal removal can be considered. The pregnancy rates after laparoscopic myomectomy vary between 16.7 and 73.1% and after abdominal myomectomy between 9.6 and 75%.

Are there any indications that one of these two techniques should be preferred? Seracchioli et al. published the only randomized study comparing pregnancy rates after laparoscopic and laparotomic myomectomy (Seracchioli et al., 2000Go). The authors showed no statistically significant difference between the cumulative pregnancy rates after 2 years (41.75% in the laparoscopy group and 47.07% in the laparotomy group). The myoma recurrence rate did not differ in the two groups (21.4 versus 20.3%).

Studies on the risks of adhesions (Mais et al., 1995Go; Bulletti et al., 1996Go; Diamond et al., 1996; Dubuisson et al., 2000aGo) and the risks of recurrence (Nehzat et al., 1998Go; Fauconnier et al., 2000Go) have tried to find arguments in favour of one of the two techniques. Unfortunately, they only compared the severity of adhesions evaluated by second-look laparoscopy and the number of recurrences, but we have no idea of their true impact on pregnancy rates.

Other techniques: embolization and myolysis
Ravina et al. first proposed uterine artery embolization as an alternative to surgical treatment of uterine fibroids (Ravina et al., 1995Go). However, this technique is still very young, so follow-up with respect to pregnancy rates after embolization is limited and few conclusions can be drawn. Can embolization be considered when pregnancy is desired? In Forman's series, only 17 women out of 192 who wished to become pregnant after embolization, conceived (Forman et al., 1999Go). After treatment, significant complications occurred in six patients, which were expected to reduce fertility. Other reports of pregnancies after fibroid embolization remain anecdotal (Bradley et al., 1998Go; Hutchins et al., 1999Go; Nicholson and Ettles, 1999Go; Pron et al., 1999Go). We agree with Forman that embolization should be avoided in women who desire pregnancy. Fertilization and delivery rates after uterine fibroid embolization are a matter of speculation for the moment.

In the late 1980s, techniques of laparoscopic myolysis were developed. Nd:YAG laser (Goldfarb, 1992Go; Nisolle et al., 1993Go; Donnez et al., 1999Go), bipolar needles (Goldfarb, 1995Go; Phillips, 1995Go), diathermy (Chapman, 1993Go) and cryomyolysis (Zreik et al., 1998Go) were proposed. More recently, myoma interstitial thermo-therapy (Donnez et al., 2000Go) was described. No data are available on pregnancy rates after this technique.

In conclusion, data available in the literature do not allow us to propose the techniques to young women with myomas because of the absence of evidence in the results, in terms of fertility, for those who wish to become pregnant. So far, we have no idea about adhesions or subsequent infertility. In the absence of conclusive data, it seems logical to propose uterine embolization or myolysis to women who do not desire pregnancy.


    Myomectomy and pregnancy outcome
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
Do myomectomy and the resulting uterine scars impair pregnancy outcome? According to Li et al. and Vercellini et al. miscarriage rates are significantly reduced after myomectomy (Li et al., 1999Go; Vercellini et al., 1999aGo). Uterine scars are associated with a risk of vicious placental implantation (acreta, increta, percreta, praevia) and a risk of uterine rupture. In Seracchioli's randomized study comparing laparoscopic and abdominal myomectomies, no uterine rupture occurred (Seracchioli et al., 2000Go). There were no significant differences between the percentages of vaginal births (35 versus 22%) and Caesarean sections (65 versus 78%).

Of the 145 pregnancies in Dubuisson's follow-up after laparoscopic myomectomy, 38 (26.2%) resulted in miscarriage, 58 in vaginal deliveries and 42 in Caesarean sections (Dubuisson et al., 2000cGo). Dubuisson describes three uterine ruptures, all occurring before labour, one attributed to the laparoscopic myomectomy.

A few case reports were found in the literature on uterine rupture after laparoscopic myomectomy (Harris, 1992Go; Mecke et al., 1995Go; Friedman et al., 1996Go; Pelosi and Pelosi, 1997Go; Dubuisson et al., 2000cGo; Foucher et al., 2000Go; Hockstein, 2000Go). However, they do not allow us to draw any conclusions on the relative risk compared with abdominal myomectomy. Moreover, we found no recent reports at all on the risk of uterine rupture after abdominal myomectomy.

For some authors, the presence of a uterine scar is an indication for Caesarean section (Friedman et al., 1996Go; Seineira et al., 1997); for others, it is not systematically required (Darai et al., 1997Go; Ribeiro et al., 1999Go; Dubuisson et al., 2000cGo). Reports remain anecdotal, especially reports on the risks for the newborn.


    Conclusion
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
The role of uterine fibroids in infertility remains unknown. A causal relationship between fibroids and infertility has not been definitively demonstrated. Ideally, a comparison of pregnancy rates should be made between women with known fibroids and women without fibroids. Such studies have not been conducted, so our knowledge of the relationship between infertility and myomas results from indirect studies. The IVF model appears to indicate that pregnancy rates only decrease when myomas are submucosal.

The only study comparing infertile women without tubal and andrological infertility factors, with and without myomas and after myomectomy, seems to suggest that the presence of myomas decreases pregnancy rates, while their removal increases pregnancy rates.

The favourable pregnancy rates obtained after myomectomy lead us to believe that myomas influence fertility. Surprisingly, the global pregnancy rates are the same after hysteroscopic, laparoscopic and abdominal myomectomy. However, we have no control groups of women who did not undergo surgery.

So the question remains: do myomas influence fertility? The absence of response to this crucial question is probably due to the fact that we have not yet conducted the appropriate prospective studies required to obtain any clear answers. Meanwhile, every situation has to be judged separately and efforts must be made to develop the best technique, that is to say, the technique with the least risk of impairing fertility or causing complications during pregnancy. At the same time, more fundamental research must be carried out to detect the mechanisms of infertility and understand the genetic basis for fibroid development and the molecular and hormonal mechanisms of myometrial proliferation (Nisolle et al., 1999Go). In the future, this approach will allow the development of an effective prevention strategy in genetically predisposed individuals and provide strategies to slow the growth of myomas.


    Notes
 
1 To whom correspondence should be addressed. E-mail: donnez{at}gyne.ucl.ac.be Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Myomas and infertility
 Myomectomy and pregnancy outcome
 Conclusion
 References
 
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