Fibroids, Infertility and Pregnancy Wastage

Uterine ®broids are often found in women of reproductive age. Different types of ®broids may affect reproductive outcome to a different extent, with submucous, intramural and subserosal ®broids being (in decreasing order of importance) a cause of infertility and pregnancy wastage. Fibroids may also produce a number of complications during pregnancy. Women who are scheduled for assisted conception should be advised to have submucous and possibly intramural ®broids removed prior to IVF. Large ®broids (>5 cm), wherever their location, should be considered individually, with the reproductive history being an important consideration. Miscarriage rates are signi®cantly reduced following myomectomy. Open myomectomy should be the route of choice when there are large subserosal or intramural ®broids, multiple ®broids or entry into the uterine cavity is to be expected. Proper assessment of the bene®ts and risks of surgery for individual patients should be carefully considered before offering a procedure. Introduction Classi®cation of ®broids Fibroids and infertility Fibroids and reproductive outcome Impact of ®broids on assisted conception Factors affecting conception and reproductivity outcome following myomectomy Open myomectomy Hysteroscopic myomectomy Laparoscopic myomectomy Patient selection and counselling Conclusions References


Introduction Classi®cation of ®broids Fibroids and infertility
Fibroids and reproductive outcome Impact of ®broids on assisted conception Factors affecting conception and reproductivity outcome following myomectomy

Introduction
Uterine ®broids (leiomyomata, myomata) are a fairly frequent occurrence in a woman in the reproductive age group.Various prevalence rates have been quoted in literature ranges from 20± 50%, based on post-mortem studies (Novak and Woodruff, 1979).Therefore, it is not surprising to detect uterine ®broids in women with a history of infertility or reproductive wastage from time to time.Whether this represents an incidental ®nding or a cause of reproductive failure will be discussed in this article.

Classi®cation of ®broids
Different types of ®broids may affect reproductive outcome to a different extent and the results of surgical intervention for each type of ®broid may vary.Fibroids may be classi®ed as submucous, intramural or subserous (Tindall, 1987).
Unfortunately, there is a lack of consensus in the literature as to exactly how these categories are de®ned.A suggested classi®cation for ®broids, according to location in the uterus is as follows:

Submucosal
The European Society of Hysteroscopy has agreed on a classi®cation for submucous ®broids (Wamsteker et al., 1993).A submucous ®broid is one that distorts the uterine cavity.It is further divided into three subtypes: type 0 = pedunculated ®broid without intramural extension, type I = sessile with intramural extension of ®broid <50% and type II = sessile with an intramural extension of b50%.The degree of intramural extension can be assessed by ultrasonography, or by hysteroscopy by observing the angle between the ®broid and the endometrium at the attachment to the uterine wall.

Intramural
A ®broid which does not distort the uterine cavity and with <50% of its protruding into the serosal surface of the uterus is considered to be an intramural ®broid.

Subserosal
A ®broid is considered subserosal if >50% of the ®broid protrudes out of the serosal surface of the uterus.A subserosal ®broid may be sessile or pedunculated.

Fibroids and infertility
The degree to which ®broids contribute to infertility is controversial.Fibroids were implicated as the sole factor of infertility in <10% of infertility cases (Wallach and Vu, 1995).It is well accepted that the anatomical location of the ®broid is an important factor, with submucous, intramural and subserosal ®broids being in decreasing order of importance, in causing infertility.Fibroids of >5 cm and, those located near the cervix or near the tubal ostia, are more likely to pose a problem (Ubaldi et al., 1995).Submucous or intramural myomata may cause dysfunctional uterine contractility which may interfere with sperm migration, ovum transport or nidation (Hunt and Wallach, 1974;Buttram and Reiter, 1981;Vollenhoven et al., 1990).In addition, uterine myomata may be associated with pre-conception (implantation) failure or gestation discontinuation due to focal endometrial vascular disturbance as well as endometrial in¯ammation, secretion of vasoactive substances, or an enhanced endometrial androgen environment (Deligdish and Lowenthal, 1970;Buttram and Reiter, 1981) Fibroids and reproductive outcome It has been observed that ~1±4% of pregnancies are associated with ®broids (Muram et al., 1980;Rice et al., 1988;Exacoustos and Rosati, 1993).Overall, 80% of uterine ®broids observed during pregnancy remain the same size or become smaller during the course of pregnancy (Muram et al., 1980;Lev-Toaff et al., 1987).Fibroids may produce a number of complications during pregnancy.Firstly, it may result in a miscarriage.The miscarriage rate is likely to be higher if implantation occurs over a submucous ®broid.Fibroids in close proximity to the placenta are more likely to be associated with early pregnancy bleeding and spontaneous miscarriage.The location of a ®broid in relation to the placenta appears to be more important than the size (Muram et al., 1980;Rosati et al., 1989).Intramural and subserosal ®broids of <3 cm are often considered to be not clinically signi®cant (Rice et al., 1988;Rosati et al., 1989).However, we have observed a ®rst trimester miscarriage rate of 40% and a second trimester miscarriage rate of 17% with intramural and subserosal ®broids (Li et al., 1999).
A recent study suggested that a previous myomectomy increased the incidence of ectopic pregnancy following IVF (Strandell et al., 1999).Apart from miscarriage and ectopic pregnancy, ®broids may also produce a number of other complications during pregnancy: preterm labour, abdominal pain due to degeneration, abruption, intrauterine growth retardation, obstructed labour and post-partum haemorrhage.
Several mechanisms have been postulated to explain the pregnancy wastage associated with ®broids (Te Linde, 1985;Wallach and Vu, 1995).In a study which examined the ultrastructure of the host myometrium of ®bromyomatous uteri (Richards et al., 1998), the sacrolemmal dense bands of host myometrial myocytes were found to be of signi®cantly greater length than that of normal myometria with a corresponding decrease in the number of caveolae, making the host myometria structurally abnormal.This speci®c abnormality may affect calcium metabolism in these tissues, which in turn may cause abnormal contractions leading to reproductive wastage or infertility.

Impact of ®broids on assisted conception
There are altogether ®ve retrospective cohort studies that examined the impact of ®broids on the results of assisted conception.The results for each type of ®broid are separately analysed in Table I.The pregnancy rate per embryo transfer in submucous, intramural and subserosal ®broids were 9, 16 and 37% respectively, compared with an average of 30% in control subjects.The results are consistent with the commonly held view that submucous ®broids have the most detrimental effect on pregnancy rate, intramural ®broids a modest impact and subserosal ®broids have the least impact on pregnancy rate.
The miscarriage rate in the various types of ®broids were: submucous, 40% (two out of ®ve cases), intramural, 33% (three out of nine cases), and subserosal, 33% (eight out of 24 cases) compared with a total of 183/1115 (16.4%) among all the control subjects in all ®ve series.Whilst it appears to show, once again, a trend similar to that of pregnancy rate, i.e. in descending order of importance: submucous, intramural and subserosal ®broid, the numbers are too small on the whole for a ®rm conclusion to be made.
It is not possible, from the available literature data, to analyse the impact of the size and number of ®broids on the outcome of assisted conception because the information was not clearly described in the reported series.
From the above data, it appears that patients should be advised to have submucous and possibly intramural ®broids removed prior to IVF, whereas those with subserosal ®broids may be reassured that it is unlikely to have an adverse impact on the implantation rate and live birth rate.However, large ®broids (>5 cm) should be considered individually, with the reproductive history, e.g.miscarriage, being an important consideration (Li et al., 1999).

Age of patient
Age was found to have a clinically signi®cant impact on pregnancy rate, with a lower spontaneous or assisted conception pregnancy rate when the woman is >35 years (Ramzy et al., 1998;Li et al., 1999).It is well accepted that older women are less likely to conceive when compared with younger women (Berkeley et al., 1983;Acien and Quereda, 1996).

History of infertility
Some authors (Acien and Quereda, 1996;Li et al.., 1999) have found that a history of infertility negatively affected the conception rate following myomectomy.The pregnancy rate was reduced by as much as 20% in the presence of additional infertility factors (Vercellini et al., 1998).

Miscarriage
Whilst uterine ®broids are associated with an increased rate of ®rst and mid-trimester pregnancy loss, this rate is signi®cantly reduced following a myomectomy (Li et al., 1999;Vercellini et al., 1999a).

Size of ®broid
An earlier review (Buttram and Reiter, 1981) suggested that a uterine size of >10 weeks prior to the operation was associated with a poorer reproductive outcome after myomectomy.One group (Sudik et al., 1996) found that the pregnancy rate after myomectomy for ®broids with a volume of >100 ml (~8 cm Fibroids, infertility and pregnancy wastage diameter) were signi®cantly higher than those of smaller ®broids.They suggested that larger ®broids are more likely to interfere with fertility than smaller ones, hence removal of a large ®broid could result in restoration of fertility.A more recent review of 27 studies (Vercellini et al., 1998) could ®nd no conclusive evidence either way on whether number, size or location of ®broids prior to myomectomy in¯uenced post-operative pregnancy rates.Uterine size was not considered to be a factor in determining reproductive outcome in two other studies (Rosen®eld, 1986;Smith and Uhlir, 1990).

Number of ®broids
The pregnancy rate was signi®cantly lower in women when more than ®ve ®broids were removed (Sudik et al., 1996).This reduction may be attributed to the increased number of incisions and subsequent adhesions.In a study of 50 patients desiring pregnancy (Berkeley et al., 1983), it was found that women who had multiple ®broids removed had dif®culty in conceiving postoperatively.On the other hand other authors (Rosen®eld, 1986;Li et al., 1999;Vercellini et al., 1999a), noted no difference in pregnancy rate after myomectomy, irrespective of the size or number of ®broids removed.

Location of ®broids
The location of the ®broid did not appear to affect the pregnancy rate after the operation, whether or not it was submucous in location and regardless of whether or not the uterine cavity was entered (Berkeley et al., 1983;Rosen®eld, 1986;Acien and Quereda, 1996;Sudik et al., 1996).

Operation to conception interval
Most women who conceive, do so within 1 year after a myomectomy (Berkeley et al., 1983;Rosen®eld, 1986;Sudik et al., 1996).This is an important consideration when the clinician has to decide whether to operate on an asymptomatic woman who is not considering a pregnancy in the immediate future.

Open myomectomy
Open myomectomy, i.e. removal of ®broid via laparotomy should be the route of choice when there are large subserosal or intramural ®broids (>7 cm), when multiple ®broids (more than ®ve) are to be removed and when entry into the uterine cavity is to be expected.The pregnancy rate after myomectomy reported in various retrospective studies (Table II) was 50±68%, with a spontaneous miscarriage rate of 6±40%, and a live birth rate of 57±93%, calculated as a percentage of the total number of pregnancies, rather than the number of subjects.Caesarean section was the mode of delivery in nearly 50% of women following a myomectomy (86/177).Two comprehensive reviews (Verkauf, 1992;Vercellini, 1998) suggest that >50% of women with infertility/reproductive wastage conceive after myomectomy.The short interval time between surgery and conception suggests that myomectomy has an important value in treatment of patients with ®broids and otherwise unexplained infertility (Verkauf, 1992).
Compared with myomectomy via laparotomy, hysteroscopic myomectomy is associated with a lower risk of scar rupture during subsequent pregnancy and vaginal delivery, as any scar resulted does not involve the whole thickness of the uterine wall.Pelvic adhesions, which is a common occurrence following open myomectomy, is avoided.
The results of seven retrospective studies on the outcome of hysteroscopic myomectomy are summarized in Table III.The overall results, including conception rate (55%) and live birth rate (80%) are very similar to those of myomectomy via laparotomy.A signi®cantly higher pregnancy and live birth rates were found when ®broids >2 cm were resected, compared with women who had ®broids <2 cm resected or women with normal uterine cavity (Varasteh et al., 1999).In addition, a shorter interval from treatment to conception was noted in women with larger ®broids.No difference in spontaneous miscarriage rate was noted after treatment in these two groups.The pregnancy rate (10/22) was found to be highest when pedunculated submucous ®broids (Type 0) were resected (Vercellini et al., 1999b).Large ®broids take longer to resect, require a very experienced surgeon and frequently require more than one operation to completely remove the ®broid.In their study, only one of six women with Type II submucous ®broids conceived (Vercellini et al., 1999b).They suggested that an open myomectomy may be preferable to hysteroscopic resection when a predominantly intramural ®broid is to be removed.
Hysteroscopic myomectomy is a safe, effective and relatively simple surgical procedure for the restoration of fertility.However, large (>5 cm) Type II submucous ®broid may not be suitable for hysteroscopic surgery.If hysteroscopic surgery is considered in Fibroids, infertility and pregnancy wastage this situation, laparoscopic control and the availability of a very experienced hysteroscopic surgeon is essential.

Laparoscopic myomectomy
It is now possible to carry out laparoscopic myomectomy for subserosal or intramural ®broids.Whilst it is suggested that the laparoscopic approach is appropriate for pedunculated or subserosal ®broids (Nezhat, 1996), other authors (Wallach and Vu, 1995) commented that removal of asymptomatic pedunculated subserosal ®broids may not be justi®ed, as these may not necessarily be the cause of infertility or recurrent miscarriage.Adequate closure of the myometrium is essential, to avoid the risk of uterine rupture in a future pregnancy (Dubuisson et al., 1995).Laparoscopic myomectomy of an intramural ®broid requires a very experienced laparoscopic surgeon, otherwise intramural ®broids may be better removed via laparotomy.In addition, uterine indentations at the sites of laparoscopic removal of intramural or deep subserosal myomata at second look laparoscopy have been reported (Nezhat et al., 1991).Uterine ®stulae have also been reported, in some cases, during follow-up of these patients (Nezhat et al., 1992).This raised concerns about the potential compromise in the integrity of the uterine wall during subsequent pregnancies following laparoscopic myomectomy in infertile patients.There have been at least two reported cases of uterine rupture during the third trimester of pregnancy following the procedure (Harris, 1992;Dubuisson et al., 1995).The reproductive outcome following laparoscopic myomectomy has been examined in six studies (Table IV).Pregnancy and live birth rates (47 and 76% respectively) are comparable with those after open and hysteroscopic myomectomy procedures.Once again, the majority (>80%) of women who conceive do so in the ®rst year after myomectomy.

Patient selection and counselling
It is important to carefully assess the bene®ts and risks of surgery before offering any procedure to a patient.A proper assessment of the patient is essential.A thorough work-up of the infertility/ recurrent miscarriage problem should be carried out prior to the surgery.A detailed reproductive history and examination needs to be followed by investigations such as ultrasonography, laparoscopy, hysteroscopy and/or a hysterosalpingogram.This will help to ascertain the size, number and location of the ®broids in order to be able to arrive at the correct management option, including the choice of operation.
Women with infertility or a poor obstetric history are often desperate to consider any measure that may improve their reproductive outcome.Women should be thoroughly counselled and be fully informed about the various treatment options.Patient information lea¯ets should be readily available, to help reinforce verbal discussions.Clinicians should be able to discuss the expected success rates as well as possible complications.

Conclusions
Fibroids are a fairly frequent occurrence in the reproductive age group and are exclusively responsible for both infertility and pregnancy wastage in a small (5%) but signi®cant proportion of patients.Of women with infertility and uterine myomata, ~50% conceive after myomectomy.A slightly higher proportion of women with a history of recurrent pregnancy loss, conceive following myomectomy.More importantly, there is a highly signi®cant reduction in early and mid trimester miscarriage rates.Evidence suggests that most women who wish to conceive are able to do so in the ®rst year, with pregnancy rates dropping sharply after this time.If possible, therefore, the surgery should be timed to take place when a woman is ready to start a family.The site, number and size of the myomata as well as the expertise of the surgeon along with patient preference may all in¯uence the management option.A submucous ®broid or an intramural ®broid distorting the uterine cavity, ®broids >5 cm and multiple ®broids are all indications for intervention in a woman considering a pregnancy.For relatively small (<5 cm) intramural or subserosal ®broids, the reproductive history is an important consideration in counselling the patient regarding the need for surgical intervention.Open myomectomy, i.e. removal of ®broid via laparotomy should be the route of choice when there are large subserosal or intramural ®broids (>7 cm), when multiple ®broids (>5) are to be removed and when entry into the uterine cavity is to be expected.

Table I .
Outcome of assisted conception treatment in women with ®broids PR = pregnancy rate; LB = livebirth rate (per pregnancy); NS = not specified; MR = miscarriage rate.*Statistically different from controls.

Table III .
Reproductive outcome after hysteroscopic myomectomy in women with infertility/pregnancy wastage

Table IV .
Laparoscopic myomectomy: reproductive outcome in infertile women a Prospective study.b Retrospective study.