Prognostic factors of reproductive outcome after myomectomy in infertile patients

Arnaud Fauconnier1,2, Jean-Bernard Dubuisson1, Pierre-Yves Ancel2 and Charles Chapron1

1 Service de chirurgie gynécologique (Pr. Dubuisson), Clinique universitaire Baudelocque, CHU Cochin – Saint Vincent de Paul, 123 Bd Port-Royal and 2 Inserm U 149, Unité de Recherches Epidemiologiques sur la Santé des Femmes and des Enfants (Docteur G.Breart), 123, Bd De Port-Royal, 75014 Paris


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The objective of this study was to identify the prognostic factors for conception after myomectomy carried out in cases of infertility. A total of 91 infertile patients presenting at least one subserous or intramural myoma measuring >2 cm underwent myomectomy. The characteristics of the patients, myomata and associated infertility factors were collected in a uniform and systematic way. A postal questionnaire was sent to patients. For each of the various factors studied, the specific cumulative probability of spontaneous intrauterine conception was estimated using the Kaplan–Meier method. Multiple regression analysis was then carried out using Cox's proportional hazards model. The cumulative probability of spontaneous intrauterine conception at 2 years follow-up was 44% (95% confidence interval: 32–56%). The cumulative probability of conception was less after removal of a posterior or intramural myoma, after a sutured hysterotomy, and when accompanied by a male factor, associated tubal or ovulation pathology. The cumulative probability of conception was greater after ablation of myomata responsible for menometrorrhagia. The size, deforming effect on the cavity and age played no role in our sample. Our results indirectly suggest that post myomectomy adhesions could have an adverse effect on fertility. Myomata responsible for menometrorrhagia are also the cause of infertility. In the presence of an associated male, tubal or ovulatory factor, the results were poor and it was not possible to determine if a myomectomy should be performed in these cases in order to enhance fertility.

Key words: adhesion/infertility/leiomyomata/myomectomy/multiple regression


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
It has long been common for a uterine myoma to be discovered during the work-up for infertility and for which myomectomy has been recommended (Bonney, 1931Go; Miller and Tirone, 1933Go). Although the efficiency of myomectomy in restoring fertility has never been proved by a randomized clinical trial, there are several lines of evidence indicating that myomata bear some responsibility for infertility: (i) there is a lower pregnancy rate in women presenting a myoma (Ross et al., 1986Go; Parazzini et al., 1988Go); (ii) the association between myoma and infertility has been reported by two observational surveys (Parazzini et al., 1996Go; Marshall et al., 1998Go); (iii) the rate of implantation for pregnancy obtained by IVF is lower in women with intramural myomata (Eldar-Geva et al., 1998Go; Stovall et al., 1998Go).

Myomectomy carried out in the context of infertility has been shown to adversely affect the reproductive function; for example, postoperative adnexal adhesions (Dubuisson et al., 1998Go; Tulandi et al., 1993Go; Ugur et al., 1996Go), uterine rupture after myomectomy carried out by laparotomy (Palerme and Friedman, 1966Go; Georgakopoulos and Bersis, 1981Go; Golan et al., 1990Go; Ozeren et al., 1997Go), by laparoscopy (Harris, 1992Go; Dubuisson et al., 1995Go; Friedmann et al., 1996Go), or by hysteroscopy (Abbas and Irvine, 1997Go) have been reported. Systematic use of myomectomy in infertility cases is a subject of debate, in particular in cases of intramural or subserous myoma, those of medium size or without symptoms (Berkeley et al., 1983Go; Vollenhoven et al., 1990Go; Paulson, 1993Go). Certain authors recommend that it should be carried out when no other infertility factor has been found (Buttram and Reiter, 1981Go; Verkauf, 1992Go; Vercellini et al., 1998Go; Dubuisson et al., 2000Go) but do not state which characteristics of the myomata (size, number, depth of penetration into the myometrium) justify operation. When there are infertility factors associated with the presence of myomata, the benefit observed after myomectomy remains unclear (Vercellini et al., 1998Go; Dubuisson et al., 2000Go). Knowledge of the prognostic factors which influence the rate of conception after myomectomy could be helpful for the decision. These factors are unknown at present (Vercellini et al., 1998Go).

Since 1989, we have made continuous assessment with prospective collection of data concerning the patients operated in our department for myomectomy by laparoscopy (LM). The reproductive outcomes after LM for infertility were published previously (Dubuisson et al., 2000Go). These data were analysed in order to identify the prognostic factors affecting fertility after myomectomy carried out in the context of infertility, and to clarify the indications for myomectomy for infertility.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
All 91 infertile patients presenting a subserous or intramural myoma measuring >=20 mm and operated by LM between March 1989 and July 1996 were included in the study. Infertility was defined as the absence of all conception (whatever the outcome or location of the pregnancy) after at least 12 months attempting pregnancy. The technique for LM was described previously (Dubuisson et al., 1997Go). LM was performed most often by two surgeons (J-B.D. and C.C.) with occasional operations also performed by five other surgeons. Concerning the laparoscopic closure of the myoma's bed we most often used a sero-muscular plane with separate stiches of vicryl 2/0 (Polyglactine 910; Ethicon, Neuilly, France). When the myoma was located deeply or the uterine cavity had been opened, we sutured along a deep plane with a few single stitches deep in the myometrium, and a superficial plane taking in the serosa and the superficial part of the myometrium. For five patients the uterine suture was difficult to carry out and we had to use a minilaparotomy to achieve the suture. For each patient operated by LM in a context of infertility, a preoperative work-up was performed systematically including study of ovarian function (monthly temperature curve; FSH, LH, oestradiol and prolactin concentrations); partner's semen analysis; transvaginal ultrasonography; examination of the uterine cavity by diagnostic hysteroscopy or hysterosalpingography. The following peroperative data were systematically collected: characteristics of myomata; existence of adnexal adhesions; tube appearance, permeability, and aspect of the mucosa; existence and extent of endometriosis.

Variables
The variables used for analysis were the following: age, duration of infertility, primary or secondary infertility; existence of menometrorrhagia preoperatively, existence of uterine cavity deformation; total number of myomata; type (pedunculated, sessile or intramural), size (greatest diameter) and location (anterior, posterior or at the fundus) of the largest myoma; existence of a male factor defined by the presence of spermogram anomalies according to World Health Organization criteria (number >=20x106; percentage with normal motility >=40%; percentage normal forms >=30%) (WHO, 1987); existence of an ovulatory factor (anovulatory cycles on the monthly temperature curve with low or normal FSH, or hyperprolactinaemia, or polycystic ovary); existence of tubal pathology (hydrosalpinx, phimosis, proximal anomalies); tubo-ovarian adhesions (whatever the degree of severity); existence of endometriosis according to the revised American Fertility Society classification (AFS, 1985); record of surgery for infertility associated with the myomectomy and if so, what type.

Follow-up and outcome event of interest
In July 1997 a postal questionnaire was sent to the women in the study. If no reply was received contact was made by telephone after checking for any change of address. When a patient was lost to follow-up, the patient's doctor was contacted. The questionnaire included: how long attempts at pregnancy had lasted; any attempts at medically assisted procreation together with the result; and, for each pregnancy obtained after the myomectomy, the date it began and how it was achieved (e.g. IVF, stimulation, insemination, spontaneous) and its outcome (e.g. spontaneous miscarriage, therapeutic abortion, voluntary abortion, birth). When pregnancy had been ongoing, a questionnaire was sent to the attending obstetrician.

The analysis criterion selected was the occurrence of spontaneous intrauterine pregnancy whatever the outcome of this pregnancy. Intrauterine pregnancies obtained by IVF together with ectopic pregnancies were excluded from analysis and the patients who obtained these pregnancies were censored at the point where their pregnancy began. Pregnancies obtained by stimulation, and those obtained by insemination, were included with the spontaneous pregnancies.

Statistical analysis
The cumulative probabilities of conception and their confidence interval at 95% (95% CI) were estimated using the Kaplan–Meier method (Kaplan and Meier, 1958Go). Initially the influence of each of the variables on postoperative fertility was analysed separately using the log-rank test (Mantel, 1966Go). In order to determine what the independent prognostic factors for fertility were after LM, we then carried out a multiple regression analysis using Cox's proportional hazards model (Cox, 1972Go; Christensen, 1987Go). Variables with a significance threshold below 0.15 by univariate analysis were included in the regression. For the selection of the final model we used a backward stepwise elimination method. Adjusted conception rate ratios (RR) and their 95% CI were derived from the regression coefficients of the final model. During the final phase of analysis the existence of interaction between the posterior nature of myomata and certain other variables was examined in order to test the hypothesis that adnexal adhesions have an effect on fertility after myomectomy (Tulandi et al., 1993Go; Ugur et al., 1996Go; Dubuisson et al., 1998Go).

Statistical analyses were carried out using the StatView 5.0 software program (SAS Institute Inc., Cary, NC, USA).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The main characteristics of the 91 patients in the sample population are given in Table IGo.


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Table I. Characteristics of the study population (n = 91)
 
Among the 91 operated patients, 81 (89%) were finally assessed for reproductive outcome. Seven patients were excluded from the follow-up: three because they no longer desired pregnancy after the LM; four because they had no chance of spontaneous conception (two cases of untreated bilateral tubal obstruction; one case of azoospermia; one case of anovulation with high FSH concentration). Three patients had no follow-up after myomectomy.

During the follow-up period 43 patients became pregnant after myomectomy. After exclusion of pregnancies obtained by IVF (n = 8) and ectopic pregnancies (n = 1), the number of pregnancies taken into account in our analysis was 34, of which seven were obtained by stimulation and two by intrauterine insemination. The median duration of follow-up for patients who did not conceive was 23 months and the median time-lapse prior to conception was 8 months. The cumulative probability of spontaneous intrauterine conception was 34% (95% CI: 22 – 45) at 1 year, and 44% (95% CI: 32–56) at 2 years (Figure 1Go).



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Figure 1. Cumulative probability of spontaneous intrauterine conception (CPC) after myomectomy using the Kaplan and Meier method (time 0 is the date of the myomectomy).

 
The specific cumulative probabilities of conception for each of the factors studied and associated threshold of significance are given in Tables II and IIIGoGo.


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Table II. Univariate analyses: specific cumulative probability of conception (SCPC) at 2 years according to patient and infertility characteristics using the Kaplan–Meier method. n = 81 patients assessed for reproductive outcome and 34 spontaneous intrauterine pregnancies
 

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Table III. Univariate analysis: specific cumulative probability of conception (SCPC) at 2 years according to characteristics of the myomata using the Kaplan–Meier method. n = 81 patients assessed for reproductive outcome and 34 spontaneous intrauterine pregnancies
 
The variables included in the regression model are those for which the threshold of significance was <0.15 at univariate analysis: i.e. the duration of infertility; existence of menometrorrhagia, the type and location of the largest myoma and the existence of an associated tubal pathology, male, or ovulatory factor. Factors associated independently with fertility after myomectomy are given in Table IVGo. Fertility was higher in women who suffered from menometrorrhagia, due to their myomata, was lower in women whose largest myoma was intramural, in a posterior location, and who had an associated tubal pathology, male, or ovulatory factor. The association observed at univariate analysis between the duration of infertility and postoperative fertility disappeared once the other variables were taken into account, in particular the male and ovulatory factors. There was indeed an association between these two factors and the duration of infertility (P = 0.007 and P = 0.13 respectively).


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Table IV. Multiple regression analysis of prognostic factors of fertility after myomectomy using Cox's proportional hazards model. Values are given as adjusted conception rate ratio (aRR) with 95% confidence interval (CI).n = 81 for 34 spontaneous intrauterine conceptions; {chi}2 model = 30.379 ; P model = 0.0002
 
The variable `myomectomy with uterine suture' was strongly associated with the type of myoma (P < 0.0001), since all the defects after removal of intramural myomata had been sutured, so this variable was not included in the model. The result of multivariate analysis was similar when this variable replaced the `type of myoma' variable (result not shown).

If the largest myoma was intramural, this had an adverse effect on postoperative fertility only when it was in a posterior location (Table VGo), and the test for interaction was close to the threshold for significance (P = 0.06). Similar non-significant results were observed for the uterine suture, tubo-ovarian adhesions before myomectomy and tubal pathology factor variables.


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Table V. Effect of other prognostic factors according to the location of myoma. Specific conception rate ratio (RR)
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Postoperative fertility after myomectomy for infertility was lower when there was a posterior or intramural myoma, or one which had been sutured. It was higher after ablation of myomata responsible for menometrorrhagia. When there was an associated male factor, tubal pathology or ovulatory factor postoperative fertility was lower.

Our study, covering 91 patients and 34 spontaneous first pregnancies, is one of the largest series published in terms of sample population, and specifically addressing the prognostic factors for myomectomy for infertility. Furthermore our study is the only one to take into account only those pregnancies which occurred spontaneously, excluding those obtained by IVF. Finally, data collection was done in a uniform and systematic way, at least for the characteristics of the myomata and the infertility. This enabled the data to be standardized with the minimum of missing data ensured.

There are several points in our study, however, which are open to criticism. (i) This was an observational study, and for certain patients preoperative assessment was not complete: for five patients the male factor was not investigated, and for these cases we considered that the results for the male factor were normal; the uterine cavity was not assessed preoperatively in six cases. (ii) Data on postoperative fertility were collected retrospectively with a postal questionnaire. (iii) Certain characteristics of the myomata were not taken into account in our study: when the myoma is located on the uterine horns this could play a part in the infertility associated with the myoma (Kessel et al., 1988Go; Gardner and Shaw, 1989Go; Ben-Ami et al., 1993Go) ; the preoperative volume of the uterus could also play a part (Sudik et al., 1996Go). (iv) Some of the factors studied were closely associated with each other: intramural nature and the need for uterine suture; the duration of infertility and associated infertility factors; the presence of tubo-ovarian adhesions and the existence of tubal pathology. All this needs to be taken into account when interpreting the results of the regression model.

The fact that the cumulative probability of conception after myomectomy was lower in the presence of a posterior myoma, an intramural myoma and/or uterine suture indirectly suggests the hypothesis that adhesions are responsible for the lower postoperative fertility. These situations were previously recognized as risk factors for adhesions after myomectomy: posterior myomata (Tulandi et al., 1993Go; Ugur et al., 1996Go; Dubuisson et al., 1998Go) and/or intramural myomata (Ugur et al., 1996Go); the use of uterine sutures (Elkins et al., 1987Go; Nezhat et al., 1991Go; Dubuisson et al., 1998Go). The reduced fertility is secondary to involvement of the adnexa in adhesions associated with the scarring due to posterior myomectomy. Indirect support for this can be found in the analysis of the interaction between the posterior and intramural nature of the myoma (Table VGo), which shows that myomectomy of intramural myomata is only responsible for reduced fertility in cases of posterior location. Several authors have postulated that adhesions might adversely affect fertility after myomectomy (Berkeley et al., 1983Go; Gehlbach et al., 1993Go; Tulandi et al., 1993Go; Ugur et al., 1996Go; Dubuisson et al., 1998Go). Our study provides indirect support for this by showing the role played in postoperative fertility, by factors known to increase the adhesion rate.

The relationship between menometrorrhagia associated with a myoma and fertility after myomectomy needs to be interpreted with caution, given the low number of cases on which this result is based (Table IIIGo). Moreover, this relationship has never been found in other studies addressing fertility after myomectomy (Berkeley et al., 1983Go; Starks, 1988Go; Smith and Uhlir, 1990Go; Gehlbach et al., 1993Go; Sudik et al., 1996Go). However, one other study (Buttram and Reiter, 1981Go) did find a link between infertility and the existence of menometrorraghia (50% for patients suffering from infertility compared with 15% of those without infertility). If this result is confirmed by other studies, it suggests that myomata responsible for menometrorrhagia are also responsible for infertility. Several physiopathological mechanisms can be suggested as an explanation for both infertility and menometrorraghia. (i) The existence of endometrial changes associated with the myomata could play a role (Stevenson, 1964Go; Deligdish and Loanthal, 1970Go; Hunt and Wallach, 1974Go) but in these cases they are related to submucosal myomata (Deligdish and Loanthal, 1970Go), which was not the case for the myomata in our sample. In fact, we did not look at the existence of this kind of endometrial change. (ii) Deformation of the uterine cavity is often quoted to explain the association between infertility and the presence of a myoma (Sehgal and Haskins, 1960Go; Ingersoll, 1963Go; Deligdish and Loanthal, 1970Go; Hunt and Wallach, 1974Go; Buttram and Reiter, 1981Go; Iosif and Akerlund, 1983Go). In our study (Table IIIGo), as in others (Babaknia et al., 1978Go; Berkeley et al., 1983Go; Starks, 1988Go; Smith and Uhlir, 1990Go; Gehlbach et al., 1993Go; Sudik et al., 1996Go; Vercellini et al., 1998Go), we did not find that deformation of the uterine cavity had any influence on fertility after myomectomy. This is consistent with the results of two cross-matched studies (Eldar-Geva et al., 1998Go; Stovall et al., 1998Go) which showed that an intramural myoma could impair implantation even when there is no deformation of the uterine cavity. (iii) The most likely explanation for the relationship between menometrorrhagia (when there is no deformation to the cavity) and infertility is vascular changes (ectasia of the submucosal venous plexus) associated with the presence of the myoma (Farrer-Brown et al., 1971Go) which could play a part in infertility. These vascular changes play an important role in the onset of menometrorraghia (Farrer-Brown et al., 1971Go; Buttram and Reiter, 1981Go).

Intramural myomata themselves are known to hamper fertility (Eldar-Geva et al., 1998Go; Stovall et al., 1998Go). However in this study, the fertility after myomectomy for intramural myomata was lower than that after other types of myomata (Tables III and IVGoGo). This result can be explained by the fact that these intramural myomata were associated with an increased risk of postoperative adhesions. Anterior myomata and those at the fundus were not associated with the occurrence of adnexal adhesions, and postoperative fertility was equivalent to that for other types of myomata (Table VGo).

An unexpected finding of this study is that postoperative fertility was not affected by maternal age (Table IIGo). In particular, the fertility only slightly declined in the group of women aged 40 years and over. In this group six women spontaneously conceived shortly after LM. It is well documented that fertility declines gradually over a woman's reproductive lifespan (Fédération CECOS et al., 1982Go; Tan et al., 1992Go). Two hypotheses could be used to explain this discrepancy. First, because of ageing, some of the oldest women of the study could have been referred sooner for IVF and thus prematurely censored. This could lead to some bias, but it is difficult to determine if such a bias would explain our result. Moreover, because the incidence rate of myoma increases widely with age (Marshall et al., 1997Go), infertility, when really caused by myoma should, therefore, appear later in a woman's lifespan. In our study women were selected by having a myoma and being infertile and it is likely that these women would differ from the population of infertile women in general. For some of the women in our study, the positive effect of the myomectomy might have compensated for the negative effect of age in general. In many studies addressing fertility after myomectomy (Garcia and Tureck, 1984Go; Rosenfeld, 1986Go; Gatti et al., 1989Go; Gehlbach et al., 1993Go), no relationship was found between age and fertility. However, in one study in which the design was similar, it was found that ageing was associated with a decrease of cumulative conception rate after myomectomy (Vercellini et al., 1999Go).

Although the presence of an associated infertility factor (tubal pathology, male, or ovulatory factor) was found to have an adverse effect on postoperative fertility, the design of our study does not allow any conclusions on the role of myomata per se as an infertility factor. Hence, it is not possible to determine if myomectomy has an influence in these cases. Several authors consider that myomata could hinder the travel of the spermatozoa (Ingersoll, 1963Go; Hunt and Wallach, 1974Go; Buttram and Reiter, 1981Go; Iosif and Akerlund, 1983Go) but fertility after myomectomy was poor in cases with an associated male factor (Tables II and IVGoGo) even after excluding one case with azoospermia. In cases with distal tuboplasty the rate of conception was low after myomectomy (Tables II and IVGoGo), but these rates differed little from those observed in series of distal tuboplasty without myomectomy (Hull, 1992Go; Dubuisson et al., 1994Go). Would fertility after tuboplasty have been different if we had not treated the myoma? Myomectomy could nevertheless impair the results of tuboplasty due to the adhesions generated by the uterine scar. The fact that in cases of myomectomy for a posterior myoma the probability of conception after tubo-ovarian adhesiolysis or tubal surgery was lower than when the myoma was located elsewhere (Table VGo) provides indirect support for this.

When the work-up for infertility reveals both a myoma and a major infertility factor (male, tubal or ovulatory), it is difficult to know whether the myoma itself has much to do with the infertility. The indication for myomectomy should then be evoked in only three circumstances: (i) when the myoma is large, meaning there is a considerable risk of complications for future pregnancies (necrobiosis, miscarriage, threatened preterm delivery) (Exacoustos and Rosati, 1993Go); (ii) when menometrorrhagia is associated with the myoma; (iii) when IVF is indicated. If the myoma does not deform the cavity, the indications are not so clear (Fernandez, 1997Go), but the results of two controlled studies suggest that there is an advantage if myomectomy takes place in cases of even moderate-sized intramural myomata (Eldar-Geva et al., 1998Go; Stovall et al., 1998Go). The expected benefits must be weighed against the risk of uterine rupture after myomectomy both by laparotomy (Ozeren et al., 1997Go) and by laparoscopy (Dubuisson et al., 1995Go).


    Notes
 
3 To whom correspondence should be addressed at: Service de chirurgie gynécologique, Clinique universitaire Baudelocque, CHU Cochin Port-Royal, 123 Bd Port-Royal, 75014 Paris, France.E-mail: arnaud.fauconnier{at}cch.ap-hop-paris.fr Back


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 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on October 18, 1999; accepted on May 4, 2000.