Environmental Health Perspectives Volume 108, Supplement 5, October 2000
Impact of Uterine Fibroids on ART Outcome
David L. Healy
Department of Obstetrics and Gynaecology, Monash Medical Centre, Monash University, Melbourne, Victoria, Australia
Abstract
Our objective was to investigate the effect of subserosal (SS), intramural (IM), and submucosal (SM) fibroids on the outcome of assisted reproductive technology (ART) treatment. A retrospective comparative study at a tertiary referral center for infertility was designed. The treatment outcome of 106 ART cycles in 88 patients with uterine fibroids (33 SS, 46 IM without cavity distortion, 9 SM) was compared with that of 318 ART cycles in age-matched patients without fibroids. The main outcome measure(s) were the findings on transvaginal uterine ultrasonography performed before the initiation of treatment and pregnancy and implantation rates. The pregnancy rates per transfer were 34.1, 16.4, 10, and 30.1% in the patients with SS fibroids, IM fibroids, SM fibroids, and no fibroids, respectively. The implantation rates were 15.1, 6.4, 4.3, and 15.7%, respectively. Both rates were significantly lower in patients with IM fibroids than in those with SS fibroids or no fibroids. We conclude that pregnancy and implantation rates were significantly lower in the groups of patients with IM and SM fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of SS fibroids. Surgical or medical treatment should be considered in infertile patients who have IM and/or SM fibroids before resorting to ART treatment.
Key words: assisted reproductive technology, infertility outcomes,
in vitro fertilization, leiomyomata, uterine fibroids. --
Environ Health Perspect 108(suppl 5):845-847 (2000).
http://ehpnet1.niehs.nih.gov/docs/2000/suppl-5/845-847healy/abstract.html
This article is based on a presentation at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research held 7-8 October 1999 in Research Triangle Park, North Carolina, USA.
Address correspondence to D.L. Healy, Dept. of Obstetrics and Gynaecology, Monash Medical Centre, Level 5, Monash University, 246 Clayton Rd., Clayton 3168, Melbourne, Victoria, Australia. Telephone: 0011 61 3 9594-5488. Fax: 0011 61 3 9594-5389. E-mail: david.healy@med.monash.edu.au
Received 23 February 2000; accepted 23 June 2000.
Uterine fibroids (leiomyomata) are the most common tumors found in women. Their occurrence increases with age; they occur in 20-50% of women over the age of 30 years (
1,2). The clinical features of these benign tumors are variable, and most are asymptomatic. The symptomatology and severity usually depend on the size, position, and number of fibroids present (
1).
The influence of uterine fibroids on reproduction is expressed in several ways. Uterine fibroids, especially the submucosal (SM) type, are associated with increased risks of spontaneous abortion, preterm delivery, abnormal presentation in labor, pelvic outlet obstruction, postpartum hemorrhage, and puerperal sepsis (3,4).
However, the effect of their presence on fertility is still subject to controversy (5). These tumors occur in both apparently normally fertile and infertile women. However, a significant number of pregnant women with fibroids (43%) have a history of infertility before pregnancy (6). Impaired gamete transport, distortion of the endometrial cavity, impairment of blood supply to the endometrium, and atrophy and ulceration might be responsible for reduced implantation in patients carrying these tumors (3-5,7-11).
The role of uterine fibroids in infertility was evaluated indirectly by fertility performance after myomectomy. In a review by Buttram and Reiter published in 1981 (3), they described 76 patients who underwent abdominal myomectomy with no other apparent cause for their infertility, of whom 54% conceived postoperatively. In a review of later studies (1993-1991), Verkauf (2) described 79 similar patients, of whom 59.5% conceived postoperatively. Recently, Sudic et al. (12) reported a pregnancy rate of 58.2% after myomectomy in 67 patients with no other recognizable infertility factor other than fibroids. Finally, fertility has been demonstrated after either laparoscopic myomectomy (13) or hysteroscopic resection of submucosal fibroids (14-16), with clinical outcomes similar to those seen after myomectomy at laparotomy.
A few studies have evaluated the impact of uterine fibroids on the results of assisted reproductive technology (ART) treatment. Farhi and colleagues (17) showed that the pregnancy rate after in-vitro fertilization-embryo transfer (IVF-ET) treatment was impaired only when the fibroids caused deformation of the uterine cavity. Stovall and co-workers (18) showed that even after excluding patients with SM fibroids, the presence of fibroids reduced the efficacy of ART treatment. However, both studies analyzed the results in patients with subserosal (SS) fibroids, intramural (IM) fibroids, or both as a homogeneous group. Our aim was to determine, in a large group of patients, whether the presence of SS, IM, or SM fibroids has an influence on pregnancy rates and live birth rates after IVF-ET treatment.
Between January 1995 and May 1997, a diagnosis of uterine fibroids was made by vaginal ultrasonography (US) (Acuson XP/10 ultrasound system; Acuson Corp., Mountain View, CA, USA) in 88 patients undergoing ART treatment who had 106 treatment cycles. Of these 88 patients, 33 had only SS fibroids (SS group), 46 had IM or mixed IM and SS fibroids (IM group), and 9 had SM or mixed SM and other fibroids, all with cavity distortion (SM group). The patients in the IM group had neither (SM) fibroids nor distortion of the uterine cavity. It is recognized that the uterine cavity is a potential but not real space. It was judged normal ultrasonically if there were smooth endometrial echoes in an uninterrupted shallow Y contour. It is recognized that sonohysterography or hysteroscopy may be more sensitive techniques to assess the endometrial cavity, but these methods are invasive.
The number of fibroids ranged between one and seven per patient. Their size ranged between 6 and 51 mm in average diameter. Seven patients in the IM group also had seedling fibroids throughout extensive areas of the myometrium. There were 41 treatment cycles in the SS group, 55 in the IM group, and 10 in the SM group. The mean patient age was 35.4 years (range, 25-42 years).
Each cycle was matched according to patient age, with three cycles in patients without fibroids who were treated at the same time (control group: 249 patients undergoing 318 cycles). Patients with other uterine anomalies (e.g., septae or polyps) or previous myomectomy were excluded from the study. Institutional Review Board approval was not required because we retrospectively analyzed ART results.
The controlled ovarian hyperstimulation protocols used at our institute have been previously described (19). Briefly, patients were downregulated using the gonadotropin hormone releasing hormone agonist nafarelin acetate at a dosage of 0.5 mg/day (Synarel; Searle, Sydney, New South Wales, Australia), starting in the luteal phase (long protocol) or on day 2 of the follicular phase (flare or boost protocol). Multiple follicular development was initiated using individually adjusted doses of purified urinary follicle-stimulating hormone (Metrodin; Serono, Melbourne, Victoria, Australia). The ovarian response was monitored with serum estradiol (E2 ) levels and transvaginal US.
Patients were given 5,000 IU of human chorionic gonadotropin (hCG) intramuscularly (Profasi; Serono, Geneva, Switzerland) when at least three follicles of > 17 mm were present and the serum E2 level was appropriately rising. Oocytes were retrieved transvaginally 36 hr later under general anesthesia. In gamete intrafallopian transfer cycles, one to four oocytes were transferred laparoscopically to one uterine tube, together with 150,000 motile spermatozoa purified on a Percoll density gradient.
Routine IVF or intracytoplasmic sperm injection and embryo culture were used as indicated and one to four embryos were transferred 48-72 hr after egg retrieval. Clinical pregnancies were confirmed with serial serum ß-hCG measurements starting 16 days after oocyte pickup and the detection of at least one gestational sac on vaginal US at 6 weeks of gestation.
Statistical analysis was performed with the use of the 
2 test and the Mann-Whitney U test where appropriate. The results are expressed as means ± 95% confidence interval (CI) unless stated otherwise. p < 0.05 was considered statistically significant.
There were 98 clinical pregnancies in the control group (pregnancy rate per transfer = 30.1%), 14 clinical pregnancies in the SS group (pregnancy rate per transfer = 34.1%), 9 clinical pregnancies in the IM group (pregnancy rate per transfer = 16.4%), and 1 clinical pregnancy in the SM group (pregnancy rate per transfer = 10%) (Figure 1). The implantation rates were 15.8, 15.7, 6.4, and 4.3% in the control, SS, IM, and SM groups, respectively. The differences between the IM group and either the controls or the SS group were significant for the pregnancy rate (
p < 0.02, IM vs SS). Altogether, patients with fibroids had a pregnancy rate of 22.6% (no statistically significant difference from the control group) and an implantation rate of 9.7% (
p < 0.05 vs the control group).
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Figure 1. Pregnancy and implantation rates in the groups of patients without fibroids (controls) and with SS fibroids, IM fibroids, and SM fibroids. The IM group had significantly lower rates of pregnancy (p < 0.02) and implantation (p < 0.05) than the SS or control groups (Mann-Whitney U test).
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There was no statistically significant difference between the study and control groups with respect to the main causes of infertility. These were unexplained infertility in 29 and 30%, respectively; male factor infertility in 37 and 36%, respectively; tubal factor infertility/endometriosis in 28 and 30%, respectively, and miscellaneous in 6 and 4%, respectively. In patients with unexplained infertility, the pregnancy rate was 32.6% (31/95) in the controls, 38.9% (7/18) in the SS group, 5.3% (1/19) in the IM group, and 0% (0/6) in the SM group (p < 0.02 for IM vs controls or SS).
There were no statistically significant differences between the groups with respect to age, treatment cycle number, maximum serum E2 levels, number of eggs retrieved, percentage of gamete intrafallopian transfer (GIFT) cycles, or number of embryos transferred per egg (Table 1). In all groups, the proportions of patients who underwent the flare versus the long downregulation protocol were equally distributed.
There was no statistically significant difference between the groups with respect to pregnancy outcome and the birth weight of singleton infants (Table 2). The multiple pregnancy rates were 30.7% in the controls (27.6% twins, 3.1% triplets) and 14.3% in the SS group. In none of the 10 pregnancies in the IM and SM groups was more than one embryo implanted.
Our aim was to determine whether the presence of SS, IM, or SM fibroids has an influence on the pregnancy rate after ART treatment. We found that the clinical pregnancy rate per transfer was considerably lower in the group of patients with IM and/or SM fibroids, even when there was no deformation of the uterine cavity (Figure 1). The pregnancy rate was not influenced by the presence of SS fibroids.
Our results are in agreement with those of Seoud and colleagues (20), who found in a small group of patients that the presence of SS fibroids did not worsen the pregnancy rate after IVF treatment. Farhi and associates. (17) also investigated the influence of various types of fibroids on IVF-ET treatment. They compared the results of 55 IVF cycles in 18 patients with fibroids, causing distortion of the uterine cavity, to those of 86 cycles in 28 patients with fibroids not causing cavity distortion, and a control group of 127 cycles in 50 age-matched patients with tubal infertility and no uterine abnormalities. Both pregnancy rate and implantation rates were significantly lower in the group with cavity distortion than in the controls and in the group with fibroids and a normal uterine cavity (pregnancy rate = 9, 29.1, and 25.1%, respectively; implantation rates = 2.7, 8.9, and 9.7%, respectively).
These investigators concluded that implantation is impaired in women with uterine fibroids only when there is associated deformation of the uterine cavity. Unfortunately, patients with SS fibroids and those with IM fibroids were analyzed together, which might have biased the analysis of their results and their resultant conclusions.
Stovall and co-workers (18) compared the results of 91 ART cycles performed in women with uterine fibroids to 91 ART cycles performed in matched controls. The clinical pregnancy rate per transfer in the patients with fibroids was significantly lower compared with the controls (37 and 53%, respectively). However, although they excluded patients with SM fibroids from their study, they analyzed the results in patients with IM fibroids and those with SS fibroids as one homogeneous group.
Fibroids have been associated with a higher rate of miscarriage, particularly when implantation occurs in relation to an SM fibroid. In their review of myomectomies, Buttram and Reiter (3) reported a 41% miscarriage rate preoperatively and a 19% rate postoperatively. In our study (Table 2), the abortion rate in the IM group (33.3%) was double that in either the control group (16.3%) or the SS group (14.3%). However, the difference was not statistically significant, and the number of patients was small.
Assisted reproduction provides a unique setting for examining the effects of fibroids on implantation. It allows us to exclude factors such as obstruction of both uterine tubes or the cervix by fibroids, greater distance for gametes to travel, displacement of the cervical os compromising exposure to the ejaculate, or menometrorrhagia. Advanced patient age also can be excluded because our control group was matched for age.
The implantation rate per embryo/egg transferred was not influenced by the presence of SS fibroids. However, it was significantly decreased in the groups of patients with IM and SM fibroids. The difference was highly significant between the IM group and the controls. Comparing ART outcome for the IM and SS groups, the location of the uterine fibroids was more important than the size or number of the tumors (Table 1).
Our results support a role for IM and SM fibroids in infertility caused by impaired implantation, even when there is no deformation of the uterine cavity. In contrast, our results suggest that SS fibroids do not interfere with implantation. We speculate that the presence of IM or SM fibroids can cause endometrial changes and/or changes in vascularization through the secretion, or the impairment of secretion, of growth or angiogenic factors.
We found support for this hypothesis in a recent study by El-Badawy and colleagues (21), who performed ultrasonic assessment of endometrial thickness and morphology in 25 premenopausal women before and after myomectomy. They found that myomectomy was followed by a significant decrease in mean endometrial thickness in the early follicular phase in these patients and by an improvement in endometrial ultrasonic morphology from hyperechogenic to normal in 11 of 11 patients.
Patients with uterine fibroids could have improved fertility after removal of these tumors (2,3,12-16). A practical application of our study is a recommendation to consider the option of surgical removal or medical shrinkage of fibroids in patients undergoing ART who have IM and/or SM fibroids. This recommendation is especially important for those patients who do not conceive after IVF treatment and who have no other obvious cause for this failure.
The conclusions taken from our results are most important for patients with unexplained infertility. The pregnancy rate after ART treatment in this group of patients was reasonable for patients with either SS fibroids (38.9%) or no fibroids (32.6%). However, it was significantly lower for patients with IM fibroids (5.3%). Thus, ART treatment could be considered an option in patients with unexplained infertility and SS fibroids but not in patients with IM or SM fibroids.
The cumulative pregnancy rate after myomectomy in infertile patients with no other apparent cause for their previous infertility is 54-60% (2,3,12-16). These patients should be considered for medical or surgical treatment of their fibroids before resorting to ART treatment. A controlled trial of women with IM and/or SM fibroids as the main suspected cause of infertility or IVF failure, comparing IVF or fibroid therapy, may be worthwhile.
In summary, we found that the treatment outcome after ART was not influenced by the presence of SS fibroids but was considerably impaired in patients with either IM or SM fibroids, even when there was no deformation of the uterine cavity.
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Last Updated: October 4, 2000
