Accepted Manuscript

“Infertility and Uterine Fibroids”

Leonidas I. Zepiridis, Grigoris F. Grimbizis, Basil C. Tarlatzis, Professor

PII: S1521-6934(15)00235-7
DOI: 10.1016/j.bpobgyn.2015.12.001
Reference: YBEOG 1584

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 27 November 2015

Accepted Date: 15 December 2015

Please cite this article as: Zepiridis LI, Grimbizis GF, Tarlatzis BC, “Infertility and Uterine Fibroids”, Best
Practice & Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/j.bpobgyn.2015.12.001.

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 ACCEPTED MANUSCRIPT
“Infertility and Uterine Fibroids”

Leonidas I. Zepiridis, Grigoris F. Grimbizis, Basil C. Tarlatzis,

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1st Department of Obstetrics and Gynaecology, ‘Papageorgiou’ University Hospital
Aristotle University of Thessaloniki, Greece

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Corresponding author: Professor Basil C. Tarlatzis 1st Dept of OB/GYN,
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“Papageorgiou” Hospital, Medical School of Aristotle University of Thessaloniki;
Email: basil.tarlatzis@gmail.com
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Abstract
Uterine fibroids are the most common tumours in women and their

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prevalence is higher in patients with infertility. At present, they are classified
according to their anatomical location, since there is no classification system to
include additional parameters, like their size or number.

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There is a general agreement that submucosal fibroids negatively affect
fertility, compared to women without fibroids. Intramural fibroids above a

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certain size (>4cm), even without cavity distortion, may also negatively influence
fertility. On the other hand, the presence of subserosal myomas has little or no
effect on fertility. Many possible theories have been proposed to explain how

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fibroids impair fertility: mechanisms involving alteration of local anatomical
location, others involving functional changes of the myometrium and
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endometrium, and finally endocrine and paracrine molecular mechanisms. After
all, the reduced reproductive potential can be the consequence of any of the
above, that may lead to impaired gamete transport, reduced ability for embryo
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implantation and the creation of a hostile environment.

The published experience defines the best practice strategy, as there are
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not a big number of large, well-designed and powerful studies available.

Myomectomy appears to have an effect in improving fertility in certain cases.
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Excision of submucosal myomas seems to restore fertility with pregnancy rates

after surgery similar to normal controls. Removal of intramural myomas
affecting pregnancy outcome seems to be associated with higher pregnancy rates
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than in non-operated controls, although evidence is not still sufficient. Treatment

of subserosal myomas of reasonable size is not necessary for fertility reasons.
The results of endoscopic and open myomectomy are similar; thus, endoscopic
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treatment is the recommended approach due to its advantages in patient’s post-

operative course.
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keywords
uterine fibroid, myoma, infertility, fertility
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General issues
Uterine fibroids are the most common tumours in women and they are
almost always benign (1). Moreover, they have high dependency on the ovarian
steroids. Although their cellular origin remains unknown, they are considered to
be monoclonal tumours, arising from the mutation of a single myometrial
somatic stem cell after multiple cycles of growth followed by involution under
hormonal influence (1).

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According to recently published data, about 7 to 8 out of 10 women will
have a fibroid during their lifetime (1). Pathology examination of hysterectomy

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specimens revealed also a prevalence of more than 75%(2). Nevertheless, their
overall rate does not seem to exceed 8-10% in the decade of 30 to 40 (1).
It is also important, that their prevalence is higher in patients with

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infertility (3). Thus, among women undergoing in-vitro fertilization (IVF) or
intracytoplasmic sperm injection (ICSI), more than one out of four do have
fibroid(s), although it is estimated that, if all other causes of infertility are

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excluded, fibroids might be responsible for only 2–3% of the cases (1). Therefore,
it is the most common benign uterine condition, whereas their location and size
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determine their clinical presentation, if any.

Classification
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Fibroids represent a heterogeneous disease, varying from a single small

lesion to multiple extra large lesions that may fill the whole peritoneal cavity (1,4)
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having different location characteristics. Similarly, the reproductive prognosis

and clinical presentation of women with fibroids are variable, from totally
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asymptomatic to symptomatic needing treatment.

There is no widely accepted classification system to categorize fibroids.
They are usually classified, according to their anatomical relationship to the
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myometrium and endometrium. Thus, at present, the location is the basic and
only characteristic for their classification, while additional parameters, e.g the
size or the number, are not taken into account, although they could have a
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prognostic role for their clinical significance. Thus, any correlation effort makes
the assessment and any comparisons difficult (2).
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Usually, they are divided in 3 topographic categories: the submucosal, the

intramural and the subserosal fibroids. According to the needs of hysteroscopic
treatment, the submucosal category is further divided in type 0 (the fibroid is
inside the endometrial cavity), type I (more than 50% of the fibroid is protruding
in the endometrial cavity), and type II myomas (less than 50% of the fibroid
protruding in the endometrial cavity) (Table 1).
Aiming to a more universal and detailed classification, FIGO proposed the
allocation of fibroids into seven types, from type 0, where the subserosal part is
totally inside the uterine cavity, to type 7, where the pedunculated fibroid is
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inside the pelvis (Table 1) (5). This new classification represents an extension of
the submucosal sub-classification, including sub-categories for the intramural
and subserosal fibroids, also depending on the extent of their occupancy of the
muscle and serosa layer of the uterus (5). However, the prognostic role as well as
the usefulness of this classification new system needs further investigation.

Do fibroids affect reproductive potential?

An important question is what is the level of evidence and the significance

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of the available data, to determine the impact of fibroids on fertility.
In 2007, Somigliana et al (6) performed a meta-analysis, which was the

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first serious attempt to this direction, studying the effect of fibroids on the
reproductive outcome of the women. They observed that child-bearing was
associated with decreased likelihood of fibroid existence (6). However, it was not

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clear which was the explanation of this observation: fibroids negatively affect
fertility or pregnancy “per se” protects against the development of fibroids.
Therefore, meta-analyzing 13 studies that included assisted reproduction

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patients, they showed a statistically significant negative effect on clinical
pregnancy rates mainly of submucosal (common OR = 0.3; 95% CI: 0.1 – 0.7) and
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to a lesser extent of intramural fibroids (common OR = 0.8; 95% CI: 0.6 – 0.9). A
similar effect of those two types of fibroids was also observed on delivery rates.
On the other hand, the impact of subserosal myomas was not significant
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(common OR = 1, 95% CI: 0.7 – 1.5), and, consequently, these lesions did not
seem to play an important role in this aspect (6).
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Nevertheless, in the same study, the authors concluded that the design of
a clear strategy and formulation of guidelines for the management of subfertile
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women with fibroids, seems to be very difficult because of the lack of large
randomized controlled trials. Moreover, they suggested that physicians should
explain to the patients the possible complications of fibroids or myomectomy
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during pregnancy, taking into account their age, as well as the number, the size
and the location of fibroids. It is notable that after 2006, the practice committee
of ASRM has already adopted this suggestion.
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Two years later, in 2009, Pritts et al (7) tried to answer the same questions
through their meta-analysis. Based on data from 18 studies, they found that the
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presence of fibroids in general, regardless of localization, led to a statistically

significant decrease in fertility, regarding clinical pregnancy (RR=0.85; 95% CI:
0.73-0.98) and birth rates (RR=0.69; 95% CI: 0.59-0.82) and, at the same time an
increase in miscarriage rates (RR=1.68; 95%CI: 1.37-2.05) (7). They also showed,
that the greatest negative statistical correlation was observed with the
submucosal fibroids, reducing the clinical pregnancy rates up to 70% (RR=0.36;
95% CI: 0.18-0.74) (7). Interestingly, even fibroids not interfering with the
intrauterine cavity architecture, resulted to significantly lower birth rates
(RR=0.78; 95% CI: 0.69-0.88) and higher miscarriage rates (RR=1.89; 95% CI:
1.47-2.43) (7).
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When all studies were included in the meta-analysis, they further
observed that the intramural fibroids had the same effects on clinical pregnancy,
(RR=0.81; 95%CI: 0.70-0.94), live birth (RR=0.70; 95% CI: 0.58-0.85) and
miscarriage rates (RR=1.75; 95% CI: 1.23-2.49). Narrowing the analysis to only
prospective studies, although they failed to find a significant decrease in clinical
pregnancy rates, they still observed impaired implantation (RR=0.55; 95% CI:
0.39-0.78) and live birth rates (RR=0.46; 95% CI: 0.29-0.74) as well as higher
abortion rates (RR=2.38; 95% CI: 1.11-5.12). (7)

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Based on these findings, the authors concluded that both patients with
fibroids affecting the endometrial cavity and with fibroids located in the
muscular layer, even not affecting the endometrial cavity architecture have

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poorer reproductive outcomes than patients without fibroids. On the other hand,
subserosal fibroids do not seem to generate any obvious fertility issue (7).

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In 2010, Sunkara et al (8), published another meta-analysis on this topic,
trying to focus only on the “gray” zone fibroids. It was almost unanimously
accepted that the submucosal fibroids are mostly detrimental to fertility, while

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the subserosal ones do not harm or interfere with fertility, when of reasonable
sizes. But what happens with the intramurals?
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They meta-analyzed 19 trials including 6089 patients, of which 5 were
prospective with 1127 patients, who had intramural fibroids, ranging, between
0.7 and 5 cm in size and not having the slightest interference with the
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intrauterine cavity. The authors tried to investigate if the existence of fibroid

affected the outcomes of IVF. (8) When all studies were taken into account, they
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found that in women undergoing IVF, the presence of fibroids not reaching the
endometrium and not disrupting the endometrial cavity at all, are associated
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with significantly lower clinical pregnancy (RR=0.85; 95% CI: 0.77-0.94) and live
birth rates (RR=0.79; 95% CI: 0.70-0.88) (8). However, when they included the
five prospective studies, then a significant decrease in live birth rates was only
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observed (RR=0.6; 95% CI: 0.41-0.87) (8). Thus, they concluded that the presence
of non-cavity-distorting intramural fibroids was associated with adverse
pregnancy outcomes by reducing expected live birth rates, although they
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acknowledged that well designed randomized controlled trials were necessary to

address this question (8).
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Although intramural location of fibroids seems to interfere with fertility

potential, additional parameters related to them, like the size and number could
also play a critical role. Somigliana et al (9), compared patients with
asymptomatic intramural or subserosal fibroids <5 cm with controls and found
similar live birth rates in both groups, concluding that the presence of
asymptomatic small fibroids did not affect ART outcomes (9). On the other hand,
Oliveira et al (10), found that patients with intramural fibroids >4cm had
statistically lower pregnancy rates than patients with intramural fibroids <4cm
(10). Furthermore, in a recent study, Yan et al (11) reported that patients with

intramural fibroids with the largest diameter >2.85 cm, had a significantly lower
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delivery rates when compared with matched controls without fibroids (adjusted
OR=0.86; 95% CI: 0.74–0.99) (11). It seems, therefore, that size is probably a
critical independent variable for the intramural fibroids not affecting the
architecture of endometrial cavity. Apparently, they could play a significant role
in the fertility potential of the woman only if they are larger than 3 to 4 cm (11).

Mechanisms of action
As shown above, fibroids have adverse effects on reproduction, being

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associated with infertility and early pregnancy complications but, also, with
adverse obstetric outcomes (2). Several possible theories have been proposed in

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order to explain how fibroids may impair fertility:
a) Mechanisms involving alteration of local anatomy, which is the case with
the anatomic distortion of the endometrial cavity, or the obstruction of the

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fallopian tubes. Histologically, there are observations e.g elongation and
distortion of the glands, cystic glandular hyperplasia, polyposis and endometrial
venule ectasia, that may play a significant role (6).

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b) Mechanisms involving functional changes e.g increased uterine
contractility, impairment of the endometrial blood supply, and chronic
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endometrial inflammation. One of the most frequently seen histological changes
attributed to fibroids, is glandular atrophy and ulceration, affecting the proximal
and, even the distal part of the endometrium(6).
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c) Endocrine mechanisms, supported by the theory of an abnormal local

hormonal milieu (1,3,7,2,4)
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d) Finally, fibroids may induce paracrine molecular affects on the adjacent

endometrium e.g the secretion of vasoactive amines, local inflammatory
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substances, to the extent, that they are capable to impair fertility (12).
It is also possible that more than one of these mechanisms may be present
at the same time, contributing in varying degree, to fertility impairment. After all,
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any of the above, may lead to impaired gamete transport and reduced ability for
embryo implantation (2), possibly through the creation of a hostile environment
for gametes or the zygote, leading to reduced reproductive potential. It is also
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important to keep in mind that the location of fibroids is the main parameter
affecting fertility outcome.
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Does myomectomy restore reproductive potential?

It is quite reasonable to assume that, if all these reported results are true,
excising the causa causans (the fibroids in this case), the infertility issue would
be resolved, restoring fertility of the patient after the intervention. However,
surgical excision of myomas is always associated with myometrial trauma,
repaired by suturing and scar healing, with potential functional consequences
due to defective myometrium and adhesion formation. Even after treatment of
submucosal myomas with hysteroscopic myomectomy, there is always a trauma
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of the endometrial cavity, with the same potential implications. Thus, the issue of
the surgical treatment of myomas is not that simple involving a highly
demanding clinical dilemma for gynecologists and fertility specialists: will
fertility return to the patient after fibroid excision?
Somigliana et al (6), in their comprehensive review, examined the success
rate after abdominal myomectomy. The post-surgical pregnancy rate in the
prospective studies was 57% (95% CI: 48 – 65) (6). When focusing on women
with otherwise unexplained infertility, this rate was 61% (95% CI: 51 – 70) (6). In

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a review of prospective and retrospective studies, Donnez and Jadoul (13) found a
pooled pregnancy rate of 45% (95%: CI 40 – 50) in patients who underwent
hysteroscopic and 49% (95% CI 46 – 52) in those with laparoscopic/abdominal

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myomectomy (13). These post-myomectomy pregnancy rates were further
confirmed by more recent large studies (4). However, the lack of randomized

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control trials represents a serious limitation to the assessment of the effect of
myomectomy on woman’s fertility (6).
Despite the large number of series reporting the pregnancy rates after

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myomectomy, comparative studies are scarce and randomized control trials
extremely rare. Bulletti et al (14) investigated the role of myomectomy in a study
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of 106 patients with fibroids who underwent laparoscopic removal compared to
106 patients who did not and 106 patients with unexplained infertility without
myomas. Patients were followed for 9 months after allocation. Delivery rates
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were significantly higher in the group of laparoscopically treated patients (42%)

than in the groups of non-treated patients with fibroids (11%, p<0.001) and
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patients without myomas (25%, p<0.001) (14). The same authors (15), five years
later, compared myomectomy results to expectant management prior to IVF.
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Patients with at least one intramural-subserosal fibroid >5cm, were informed

about the pros and cons of myomectomy and were then divided into two groups
with similar characteristics (myomectomy and expectant management), upon
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their own decision (15). The cumulative delivery rate in women who did and did
not undergo surgery was 25 and 12%, respectively (p <0.01) (15). Despite the fact
that those two studies were not randomized (6), they provide evidence for the
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beneficial role of myomectomy on the fertility potential of the women. Casini et

al (16) performed a prospective randomized control trial examining the
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pregnancy rates in women with fibroids who underwent laparoscopic and/or

hysteroscopic myomectomy, compared to those who did not. They found
significantly higher pregnancy rates in women with submucous myomas who
were treated surgically than those who did not (43.3% vs 27.2% respectively,
p<0.05) and the ones with submucosal/intramural myomas (36.4% vs 15%,
respectively, p<0.05) (16). Despite the criticism on the strength of this study (17), it
is obvious that it provides good quality evidence on the benefits of surgical
treatment of myomas.
The impact of myomectomy, in patients with submucous myomas, on IVF
outcome as compared to controls without myomas, was examined in three other
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studies (18,19,20). The observed delivery rates were similar in both groups. This
finding indicates that submucous myomas have a negative impact on the
achievement of pregnancy, which is alleviated by myomectomy. Overall, even if
the available evidence is still not sufficient, previous myomectomy does not
appear, also, to negatively affect the chances of pregnancy in IVF cycles.
Two systematic reviews tried to examine the effect of myomectomy on
the fertility potential of woman. In 2009, Pritts et al (7), meta-analyzing all the
available studies, failed to demonstrate a beneficial effect of excision of

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intramural fibroids, since pregnancy and birth rates prior and after surgical
excision, had no statistically significant differences. However, this is due to the
scarcity of studies. On the other hand, with submucosal fibroids, included in 2

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out of 13 trials, they found a significant improvement of clinical pregnancy rates
(7).

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Cochrane database has also published a review on this topic. In 2012,
Metwally et al (21) collected any prospective randomized controlled trial that
existed at that time, aiming to examine the consequences of myomectomy on

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fertility and to compare different surgical approaches. Thus, they included only
prospective randomized clinical trials, comparing myomectomy to no
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intervention at all. Unfortunately, there were not plenty of suitable papers
available. Three studies fulfilled the criteria including 474 patients (21). They
concluded that, at present, the existing RCTs, assessing the effect of
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myomectomy in improving fertility, did not provide sufficient evidence.

Moreover, there was no indication of significant effectiveness of hysteroscopic
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myomectomy in fertility. However, they stated that these figures should be

interpreted with caution, due to the very low number of available and included
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studies (21). Regarding the surgical approach, the two available RCTs asserted
that there was no difference in fertility restoration, but the use of laparoscopy
appeared to be more advantageous for post-operative recovery and morbidity
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(21,22).

Based on the available evidence from all types of studies, it seems that:
(1) previous myomectomy does not negatively affect pregnancy rates,
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supporting the notion that surgery per se is not detrimental, (2) hysteroscopic
excision of submucosal myomas seems to restore fertility potential of patients
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and pregnancy rates after surgery are similar to normal controls, (3) removal of
intramural myomas larger than 5cm seems to be associated with higher
pregnancy rates than in non-operated controls, although evidence is not still
sufficient, (4) both the abdominal and laparoscopic approach are equally
effective in fertility restoration but laparoscopy is associated with better post-
operative course and less morbidity. Treatment of subserosal myomas of
reasonable size is not necessary for fertility reasons.

Current practice
Based on the currently available evidence, what would be the
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recommended management of fibroids in patients wishing pregnancy either
spontaneously or after IVF?
Gynecologists should establish an integrated personalized approach,
taking into account the age, the number, the size and the location of the fibroids.
In the final decision for the surgical treatment of a myoma, the following
parameters should be assessed: (1) what is the expected impact of the lesion on
patient’s fertility, (2) how effective surgical intervention is, and (3) are there
additional clinical indications related to the presence of the myoma.

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The existing data, concerning the influence of subserosal fibroids on
fertility, support the hypothesis that they do not have any effect. Furthermore, no
benefit was observed on fertility, when myomectomy was performed (3,4,6,7).

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Thus, surgical removal of subserosal fibroids is not recommended for fertility
reasons. However, a decision over surgical treatment of a subserosal myoma

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could be justified if: (1) it is associated with symptoms due to its size or location,
(2) it could create complications during pregnancy, taking into account its
volume increase, and (3) there is another type of co-existing myoma.

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On the contrary, there is a general agreement that submucosal fibroids
negatively affect fertility, compared to women without fibroids. Women with
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submucosal myomas have reduced chances for conception, significantly higher
miscarriage rates and reduced live birth rates, irrespective of the way of
conception (1,3,4,6,7). Hysteroscopic removal improves fertility potential and IVF
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outcome (4,7). Thus, it is reasonable to recommend surgical treatment in women

wishing pregnancy. Apart from that, submucosal myomas are associated with
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abnormal uterine bleeding, which is a usual independent indication for their

removal.
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Intramural fibroids have always been the grey zone and there is an
ongoing, debate regarding their role in fertility and reproductive outcomes. The
recent literature asserts that intramural fibroids above a certain size (>4cm),
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even without cavity distortion, may also negatively influence fertility (4,6,7,8,10,11).
Furthermore, myomectomy is associated with an improvement in post-surgical
conception rates, reaching that of women without fibroids, although evidence is
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still not still sufficient (14,15,16). Additionally, even if the available evidence is
scanty, previous myomectomy does not appear to negatively affect the chances
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of pregnancy. Therefore, myomectomy should be considered for these fibroids in

patients with infertility. It is noteworthy that intramural myomas are also
associated with severe pregnancy complications (23), which is an additional
independent indication for their removal in patients wishing pregnancy.
Very recently, in 2015, Galliano et al (4), in their review also conclude that
the submucosal and intramural fibroids disrupting the endometrial cavity, may
lead to poor results after IVF attempts, a fact that might be altered by their
surgical removal. Myomectomy is recommended as the practice of choice for
those ranked in FIGO stages between 3 and 6, are easily accessible and are 4 cm
or more in diameter. Smaller fibroids may be removed only after multiple IVF
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failures and if complications are not expected (4). Finally, although minimally
invasive surgery is preferred, there is not a statistically significant superiority
compared to the open method, regarding the achievement of a successful term
pregnancy (4).

Conclusions
The actual effect of fibroids on fertility and ART is not completely known nor
understood. The published experience defines our best practice strategy, as long

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as there are not a big number of large, well-designed and properly powered
studies. The available evidence suggests that the submucosal of any size and

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intramural uterine fibroids of > 4cm, significantly impairs fertility and IVF
results. The presence of subserosal myomas has little or no effect on fertility.
Myomectomy appears to have an effect in improving fertility in certain cases.

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The results of endoscopic and open myomectomy are similar; thus, endoscopic
treatment is the recommended approach, due to its advantages in patient’s post-
operative course.

Practice points
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• Submucosal fibroids negatively affect fertility, compared to women
without fibroids
• Hysteroscopic excision of submucosal fibroids improves fertility potential
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and IVF outcome and it is recommended for their treatment

• Intramural fibroids above 4cm, even without cavity distortion, might
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negatively impair reproductive outcome

• Myomectomy seems to be associated with an improvement in post-
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surgical conception rates and it should be considered for intramural

fibroids >4cm in patients with infertility
• Subserosal fibroids have no impact on fertility and their treatment is not
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recommended for fertility reasons

• Endoscopic treatment is the recommended approach, although it has
similar results with open myomectomy, due to its advantages in patient’s
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post-operative course
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Research agenda
• effect of intramural fibroid’s size and number on reproductive potential of
the woman
• effect of the intramural fibroid’s location in relation to the inner (FIGO
type 4) and outer endometrium (FIGO type 5) on fertility and pregnancy
outcome
• effectiveness of a myomectomy in restoring reproductive potential of the
patients
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• Non-reproductive indications for the treatment of fibroids in fertility
patients
• Mechanisms of fibroid’s action on the achievement and evolution of
pregnancy

Conflicts of Interest: None

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Gynecol. 2008; 198: 357-366
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Table 1. Fibroid classifications systems

Fibroid Classification
Classical FIGO (2011)
Submucosal - type 0 100% intracavity 0
Submucosal – type I >50% intracavity 1

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Submucosal – type II <50% intracavity 2
Intramural In contact with endometrium 3
Intramural 100% intramural 4

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Intramural Intramural but <50% subserosal 5
Subserosal Subserosal but <50% intramural 6

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Subserosal Pedunculated 7

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Table 2. Current recommended practice for the treatment of myomas

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Indication for surgical treatment

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Current
Type
Impact on Effectiveness of recommendations

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Additional indications
reproductive potential surgical intervention

Significant Significant Abnormal Uterine

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Submucosal Excision - Hysteroscopic
impairment improvement Bleeding

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Potential pregnancy
Significant Improvement (need Excision -

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Intramural >4cm complications
impairment further evidence) Preferably laparoscopic
Symptoms

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Intramural <4cm Unclear Unclear Unclear Expectant management *

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Potential
Subserosal Non Significant Non Significant Expectant management **
complications
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* surgery indicated only in cases of multiple IVF failures or poor obstetrical outcome
** surgery indicated only in the presence of associated symptoms or poor obstetrical outcome
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The actual effect of fibroids on fertility and ART is not completely known nor
understood. The published experience defines our best practice strategy, as long
as there are not a big number of large, well-designed and properly powered

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studies. The available evidence suggests that the submucosal of any size and
intramural uterine fibroids of > 4cm, significantly impairs fertility and IVF
results. The presence of subserosal myomas has little or no effect on fertility.

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Myomectomy appears to have an effect in improving fertility in certain cases.
The results of endoscopic and open myomectomy are similar; thus, endoscopic

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treatment is the recommended approach, due to its advantages in patient’s post-
operative course.

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