FERTILITY AND STERILITYt
VOL. 70, NO. 4, OCTOBER 1998
Copyright ©0 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
Printed on acid-free paper in U.S.A.
Received February 23,
1998; revised and
accepted May 26, 1998.
Presented in part at the
XVI Annual Meeting of The
Fertility Society of
Australia, Adelaide, South
Australia, Australia,
December 2– 4, 1997.
Reprint requests: Talia
Eldar-Geva, M.D., Ph.D.,
Monash IVF Epworth
Program, Level 4 Epworth
Hospital, 89 Bridge Road,
Richmond, Victoria,
Australia 3121 (FAX: 61-3-
94271973; E-mail: teldar
@monashivf.edu.au).
* Monash In Vitro
Fertilization.
†
Department of Obstetrics
and Gynecology, Monash
University.
‡
Monash Ultrasound for
Women.
0015-0282/21900/$19.00
PII S0015-0282(98)00265-9
Effect of intramural, subserosal, and
submucosal uterine fibroids on the
outcome of assisted reproductive
technology treatment
Talia Eldar-Geva, M.D., Ph.D.,*† Simon Meagher, M.D.,‡ David L. Healy, Ph.D.,*†
Vivien MacLachlan, B.Sc.,* Sue Breheny, B.Sc.,* and Carl Wood, M.B., B.S.*†
Monash In Vitro Fertilization; Monash University; and Monash Ultrasound for Women, Melbourne, Victoria,
Australia
Objective: To investigate the effect of subserosal, intramural, and submucosal fibroids on the outcome of assisted
reproductive technology (ART) treatment.
Design: A retrospective comparative study.
Setting: A tertiary referral center for infertility.
Patient(s): Treatment outcome of 106 ART cycles in 88 patients with uterine fibroids (33 subserosal, 46 intramural without
cavity distortion, and 9 submucosal) was compared with that of 318 ART cycles in age-matched patients without fibroids.
Intervention(s): Controlled ovarian hyperstimulation and ART.
Main Outcome Measure(s): Findings on transvaginal uterine ultrasonography performed before the initiation of treatment
and pregnancy and implantation rates.
Result(s): The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids,
intramural fibroids, submucosal 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 intramural fibroids than in those with subserosal
fibroids or no fibroids.
Conclusion(s): 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 and implantation rates were not
influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients
who have intramural and/or submucosal fibroids before resorting to ART treatment. (Fertil Sterilt 1998;70:687–91. ©1998
by American Society for Reproductive Medicine.)
Key Words: Uterine fibroid, leiomyoma, infertility, assisted reproductive technology, implantation rate
Uterine fibroids (leiomyomata) are the most However, the effect of their presence on fertil-
common tumors found in women. Their occur- ity is still subject to controversy (5). These
rence increases with age; they occur in 20%– tumors occur in both apparently normally fer-
50% of women over the age of 30 years (1, 2). tile and infertile women. However, a signifi-
The clinical features of these benign tumors are cant number (43%) of pregnant women with
variable, and most are asymptomatic. The fibroids have a history of infertility before
symptomatology and severity usually depend pregnancy (6). Impaired gamete transport, dis-
on the size, position, and number of fibroids tortion of the endometrial cavity, impairment
present (1). of blood supply to the endometrium, and atro-
The influence of uterine fibroids on repro- phy and ulceration might be responsible for
duction is expressed in several ways. Uterine reduced implantation in patients carrying these
tumors (3–5, 7–11).
fibroids, especially the submucosal type, are
associated with increased risks of spontaneous The role of uterine fibroids in infertility was
abortion, preterm delivery, abnormal presenta- evaluated indirectly by fertility performance
tion in labor, pelvic outlet obstruction, postpar- after myomectomy. In a review by Buttram and
tum hemorrhage, and puerperal sepsis (3, 4). Reiter (3) published in 1981, they described 76
687
patients who underwent abdominal myomectomy with no
other apparent cause for their infertility, of whom 54%
conceived postoperatively. In a review of later studies
(1983–1991), Verkauf (2) described 79 similar patients, of
whom 59.5% conceived postoperatively. Recently, Sudic et
al. (12) reported a pregnancy rate (PR) of 58.2% after
myomectomy in 67 patients with no other recognizable in-
fertility factor other than fibroids. Finally, fertility has been
shown to increase after either laparoscopic myomectomy
(13, 14) or hysteroscopic resection of submucosal fibroids
(15–17), with clinical outcomes similar to those seen after
myomectomy at laparotomy.
A few studies have evaluated the impact of uterine fi-
broids on the results of assisted reproductive technology
(ART) treatment. Farhi et al. (18) showed that the PR after
IVF-ET treatment was impaired only when the fibroids
caused deformation of the uterine cavity. Stovall et al. (19)
showed that even after excluding patients with submucosal
fibroids, the presence of fibroids reduced the efficacy of ART
treatment. However, both studies analyzed the results in
patients with subserosal fibroids, intramural fibroids, or both
as a homogeneous group. Our aim was to determine, in a
large group of patients, whether the presence of subserosal,
intramural, or submucosal fibroids has an influence on PRs
and live birth rates after IVF-ET treatment.
MATERIALS AND METHODS
Between January 1995 and May 1997, a diagnosis of
uterine fibroids was made by vaginal ultrasonography (US)
(Acuson XP/10 ultrasound system) in 88 patients undergoing
ART treatment who had 106 treatment cycles. Of these 88
patients, 33 had only subserosal fibroids (SS group), 46 had
intramural or mixed intramural and subserosal fibroids (IM
group), and 9 had submucosal or mixed submucosal and
other fibroids, all with cavity distortion (SM group). The
patients in the IM group had neither submucosal fibroids nor
distortion of the uterine cavity.
The number of fibroids ranged between 1 and 7 per
patient. Their size ranged between 6 mm and 51 mm in
average diameter. Seven patients in the IM group also had
seedling fibroids throughout extensive areas of the myome-
trium. 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 described previously (20). Briefly,
688 Eldar-Geva et al. Uterine fibroids and ART outcome
patients were down-regulated using the GnRH agonist na-
farelin acetate at a dosage of 0.5 mg/d (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 FSH (Metrodin; Serono, Melbourne, Victoria, Aus-
tralia). The ovarian response was monitored with serum E2
levels and transvaginal US.
Patients were given 5,000 IU of hCG IM (Profasi; Se-
rono) when at least three follicles of .17 mm were present
and the serum E2 level was rising appropriately. Oocytes
were retrieved transvaginally 36 hours later under general
anesthesia. In gamete intrafallopian transfer cycles, 1– 4
oocytes were transferred laparoscopically to one tube to-
gether with 150,000 motile spermatozoa purified on a Percoll
density gradient.
Routine IVF or intracytoplasmic sperm injection and em-
bryo culture were used as indicated and 1– 4 embryos were
transferred 48 –72 hours after egg retrieval. Clinical preg-
nancies were confirmed with serial serum b-hCG measure-
ments starting 16 days after oocyte pick-up and the detection
of at least one gestational sac on vaginal US at 6 weeks’
gestation.
Statistical analysis was performed with the use of the x2
test and the Mann-Whitney U test where appropriate. The
results are expressed as means 6 95% confidence intervals
unless stated otherwise. P,0.05 was considered statistically
significant.
RESULTS
There were 98 clinical pregnancies in the control group
(PR per transfer 5 30.1%), 14 clinical pregnancies in the SS
group (PR per transfer 5 34.1%), 9 clinical pregnancies in
the IM group (PR per transfer 5 16.4%), and 1 clinical
pregnancy in the SM group (PR per transfer 5 10%) (Fig. 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 PR (P,0.05, x2 test)
and highly significant for the implantation rate (P,0.005,
IM versus controls; P,0.02, IM versus SS). Altogether,
patients with fibroids had a PR of 22.6% (no statistically
significant difference from the control group) and an implan-
tation rate of 9.7% (P,0.02 versus the control group).
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 PR
was 32.6% (31/95) in the controls, 38.9% (7/18) in the SS
Vol. 70, No. 4, October 1998
 FIGURE 1

Pregnancy and implantation rates in the groups of patients without fibroids (controls) and with subserosal fibroids (SS),
intramural fibroids (IM), and submucosal (SM) fibroids. *P ,0.05 for IM versus controls or SS. **P ,0.005 for IM versus controls.

group, 5.3% (1/19) in the IM group, and 0% (0/6) in the SM
group (P,0.02 for IM versus 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, per-
centage of 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 down-regulation
protocol were distributed equally.
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 preg-
nancy 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

TABLE 1

Clinical data and ART outcome in the groups of patients without fibroids (controls) and with subserosal fibroids, intramural
fibroids, and submucosal fibroids.

Fibroid

Controls Subserosal Intramural Submucosal

Variable (n 5 318)* (n 5 41)* (n 5 55)* (n 5 10)*

Age (y) 35.5 6 0.4 35.2 6 1.1 35.3 6 1.2 36.0 6 2.0
Treatment cycle no. 3.0 6 0.2 2.9 6 0.9 3.4 6 0.8 2.3 6 0.7
Percentage undergoing GIFT 17.1 24.4 23.6 20.0
Maximum serum E2 level (pmol/L) 6,022 6 340 6,475 6 964 5,514 6 805 5,078 6 1,384
No. of eggs 8.8 6 0.6 9.7 6 2.0 8.3 6 1.1 9.0 6 3.3
No. of embryos transferred per egg 2.4 6 0.1 2.4 6 0.3 2.5 6 0.2 2.3 6 0.5
No. of fibroids — 1.29 6 0.15 1.82 6 0.35 2.67 6 1.23
Total fibroid diameter (mm)† — 24.0 6 4.9 23.7 6 7.1 44.78 6 26.2
Note: All values are means 6 95% confidence intervals unless otherwise indicated.
* No. of cycles.
† Mean of the sum of all fibroids’ diameters in each patient.

FERTILITY & STERILITYt 689

 TABLE 2
Pregnancy outcome in the groups of patients without fibroids (controls) and with subserosal fibroids and intramural
fibroids.
Controls
Pregnancy outcome (n 5 98)
Liveborn singletons 48 (49.0)
Liveborn twins 27 (27.6)
Liveborn triplets 3 (3.1)
Early abortion 15 (15.3)
Late abortion 1 (1.0)
Ectopic pregnancy 4 (4.1)
Birth weight of singletons (g)* 3,275 6 150
Note: Values are absolute numbers with percentages in parentheses unless otherwise indicated.
* Values are means 6 95% confidence intervals.
pregnancies in the IM and SM groups was more than one
embryo implanted.
DISCUSSION
Our aim was to determine whether the presence of sub-
serosal, intramural, or submucosal fibroids has an influence
on the PR after ART treatment. We found that the clinical
PR per transfer was considerably lower in the group of
patients with intramural and/or submucosal fibroids, even
when there was no deformation of the uterine cavity (Fig. 1).
The PR was not influenced by the presence of subserosal
fibroids.
Our results are in agreement with those of Seoud et al.
(21), who found in a small group of patients that the presence
of subserosal fibroids did not worsen the PR after IVF
treatment. Farhi et al. (18) also investigated the influence of
various types of fibroids on IVF-ET treatment. They com-
pared 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 abnor-
malities. Both PRs 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
(PRs 5 9%, 29.1%, and 25.1%, respectively; implantation
rates 5 2.7%, 8.9%, and 9.7%, respectively).
These investigators concluded that implantation is im-
paired in women with uterine fibroids only when there is
associated deformation of the uterine cavity. Unfortunately,
patients with subserosal fibroids and those with intramural
fibroids were analyzed together, which might have biased the
analysis of their results and their resultant conclusions.
Stovall et al. (19) compared the results of 91 ART cycles
performed in women with uterine fibroids to 91 ART cycles
690 Eldar-Geva et al. Uterine fibroids and ART outcome
Fibroid
Subserosal Intramural
(n 5 14) (n 5 9)
9 (64.3) 6 (66.7)
2 (14.2) —
— —
2 (14.3) 3 (33.3)
— —
1 (7.1) —
3,062 6 183 3,065 6 210
performed in matched controls. The clinical PR per transfer
in the patients with fibroids was significantly lower com-
pared with the controls (37% and 53%, respectively). How-
ever, although they excluded from their study, patients with
submucosal fibroids, they analyzed the results in patients
with intramural fibroids and those with subserosal fibroids as
one homogeneous group.
Indirect support for our conclusion can be found in a
recent study by Daraı̈ et al. (14), who analyzed the results of
myomectomy by either laparoscopy or conversion to lapa-
rotomy in 143 patients. The largest fibroid was intramural in
61% of their patients and subserosal in 39%. Of the 41
patients who underwent laparoscopic myomectomy for in-
fertility, the largest fibroid was intramural in 93% and sub-
serosal in only 7%. These partial data (no data on the
conversion to laparotomy group could be found in the arti-
cle) support an important role for intramural fibroids in
infertility, which is in agreement with the results of our study.
Fibroids have been associated with a higher rate of mis-
carriage, particularly when implantation occurs in relation to
a submucosal 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 than that in either the control group (16.3%) or the SS
group (14.3%); however, this difference was not statistically
significant.
Assisted reproduction provides a unique setting for ex-
amining 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 subserosal fibroids.
Vol. 70, No. 4, October 1998
However, it was significantly decreased in the groups of
patients with intramural and submucosal fibroids. The dif-
ference 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 impor-
tant than the size or number of the tumors (Table 1).
Our results support a role for intramural and submucosal
fibroids in infertility caused by impaired implantation, even
when there is no deformation of the uterine cavity. In con-
trast, our results suggest that subserosal fibroids do not
interfere with implantation. We speculate that the presence
of intramural or submucosal fibroids can cause endometrial
changes and/or changes in vascularization through the secre-
tion of growth or angiogenic factors, through impairment of
the normal secretion of these factors, through changes in the
surrounding myometrial contractility, or simply through me-
chanical pressure.
We found support for this hypothesis in a recent study by
El-Badawy et al. (22), who performed ultrasonic assessment
of endometrial thickness and morphology in 25 premeno-
pausal 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 ultra-
sonic morphology from hyperechogenic to normal in 11 of
11 patients.
Patients with uterine fibroids could have improved fertil-
ity after removal of these tumors (2, 3, 12–17). 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 intramural and/or
submucosal fibroids. This recommendation is especially im-
portant for those patients who do not conceive after IVF treat-
ment and who have no other obvious cause for this failure.
The conclusions taken from our results are most impor-
tant for patients with unexplained infertility. The PR after
ART treatment in this group of patients was reasonable for
patients with either subserosal fibroids (38.9%) or no fibroids
(32.6%). However, it was significantly lower for patients
with intramural fibroids (5.3%). Thus, ART treatment could
be considered as an option in patients with unexplained
infertility and subserosal fibroids, but not in patients with
intramural or submucosal fibroids.
The cumulative PR after myomectomy in infertile pa-
tients with no other apparent cause for their previous infer-
tility is 54%– 60% (2, 3, 12–17). These patients should be
considered for medical or surgical treatment of their fibroids
before resorting to ART treatment. A controlled trial of
women with intramural and/or submucosal 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 subserosal fi-
FERTILITY & STERILITYt
broids but was considerably impaired in patients with either
intramural or submucosal fibroids, even when there was no
deformation of the uterine cavity. Surgical or medical treat-
ment should be considered for these patients.
Acknowledgments: The authors thank all the clinical, nursing, embryology,
and administration staff of Monash IVF and Monash Ultrasound for Women
for their invaluable help. They also thank G. Simmons (Department of
Mathematics, Monash University) for statistical analysis of the data.
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