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UTERINE FIBROIDS (N NARVEKAR, SECTION EDITOR)
Fibroids and Infertility
P. Purohit
1
&K. Vigneswaran
1
Published online: 25 April 2016
#The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract The precise impact of fibroids, which are the most
common benign gynaecological tumours in women, on repro-
ductive function and infertility is unknown. The need to treat
submucosal fibroids is widely accepted, but fibroids in other
locations and sizes continue to present a clinical conundrum.
This article examines the mechanisms by which fibroids affect
implantation and fertility, and stratifies their impact on basis of
size, location and nature. It also explores the evidence base of
the available treatment modalities in specific relation to im-
proving fertility outcomes. Traditionally, a myomectomy has
been advocated to treat fibroids for the reproductive popula-
tion; however, as well as evaluating the benefits of surgery
including endoscopic, this article explores alternative thera-
pies including medical and radiological interventions.
Keywords Infertility .Fibroids .Myomectomy .
Implantation .Miscarriage .Laparoscopy
Introduction
Fibroids are the most common uterine tumour in the repro-
ductive age group affecting 20–50 % of these women, and
hence, their relation with infertility although controversial
is always a great concern to the clinician as well as the
patient [1,2••].
Mechanisms of Infertility
Fibroids vary to a great extent in terms of their size, location
and number and so does the mechanism by which they may
cause infertility.
Physical Factors
Given their size and location, it is unsurprising that simple
physical impedance to the transport of sperm, egg or embryo
has been proffered as a mechanism to explain the anti-fertility
effects of fibroids. However, the microscopic size of the gam-
etes and both the bilateralism and the resilience of the repro-
ductive system suggest that this by itself is unlikely to be sole
mechanism in the vast majority of cases.
Alteration of Uterine Contractions
Uterine contractions increase in frequency in the early follic-
ular phase from the fundus to cervix whereas in peri-ovulatory
and luteal phase, their direction is reversed from the cervix to
fundus [3]. Fibroids are also known to influence the contrac-
tility of the myometrium and induce a chronic inflammatory
reaction, both of which may hinder implantation [4–7,8•].
Some studies have reported increase in myometrial peristalsis
in patients with intramural and submucosal fibroids when
compared with healthy controls during the mid-luteal cycle
phase, although there was a decrease in the peri-ovulatory
phase [4–6].
Yoshino et al. using Cine mode, MRI demonstrated accel-
erated mid-luteal uterine peristalsis (defined as ≥2peristaltic
movements in 3 min) in the presence of intramural fibroids
and achieved 40 % pregnancy rate in this population over
1 year following restoration of normal peristalsis by myomec-
tomy [7]. Yoshino also reported another prospective study
This article is part of the Topical Collection on Uterine Fibroids
*P. Purohit
prashant.purohit@nhs.net
1
Kings College Hospital, London, UK
Curr Obstet Gynecol Rep (2016) 5:81–88
DOI 10.1007/s13669-016-0162-2
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
(n= 95) where they looked at the impact of uterine peristaltic
movements due to fibroids on outcome of non-IVF fertility
treatment. Thirty-four per cent women in the low-frequency
group achieved pregnancy, compared with none (0 %) in the
high-frequency group (P<0.005) [8•].
Many underlying mechanisms have been suggested for in-
crease in myometrial contractility like excess of cytokines,
growth factors, neurotensin, neuropeptides, enkephalin and
oxytocin modulators in the fibroid capsule [9].
Cytokine Factors
Certain early pregnancy intrauterine cytokines are thought to
be responsible for implantation and early embryonic develop-
ment. Ben-Nagi et al. reported significant reduction in levels
of certain cytokines mainly IL10 and glycodelin in the mid-
luteal uterine washings of women with submucosal fibroids
[10••]. Glycodelin is a progesterone-regulated glycoprotein
secreted into uterine luminal cavity by secretory/
decidualized endometrial glands and has properties like pro-
moting angiogenesis and suppressing natural killer (NK) cells.
Genetic
Endometrial HOXA10, HOXA11 and BTEB1 gene expres-
sion has been shown to modulate endometrial receptivity. The
reduction or absence of HOXA10 in the uterine endometrium
leads to infertility due to the inability of the embryo to implant
[11•]. Rackow et al. demonstrated a significant reduction in
concentration of these genes during follicular phase in infertile
women with submucosal fibroids (FIGO L0 to L2).
Interestingly, the reduction was present throughout the uterine
cavity and not just in the endometrium overlying the fibroid.
There was no significant decrease for intramural (IM) fibroids,
although a trend to lower levels was noted [5]. On the other
hand, Matsusaki et al. was able to demonstrate a significant
decrease in HOXA10 concentrations during luteal phase in
infertile women with intramural fibroids compared to healthy
patient controls [12].
The downregulation of endometrial HOXA 1 gene expres-
sion results in defective decidualization possibly mediated via
secretion of transforming growth factor beta3 (TGF-β3) [13].
Alizadeh reported increase in endometrial HOXA1 gene ex-
pression following myomectomy [14].
Alterations in the Endo-myometrial Junctional (EMJ)
Zone
The EMJ which represents the inner 1/3rd of the myometrium
abutting the endometrium contributes macrophages and uter-
ine natural killer (uNK) cells which are essential for the pro-
cess of endometrial decidualization in the mid-luteal window
of implantation. In women with uterine fibroids, Kitaya et al.
found significant reduction in concentrations of both macro-
phages and uNK cells in the EMJ, thus, negatively affecting
implantation [15]. Also, it is possible that the presence of
intramural or submucosal fibroids physically disrupts the
EMJ and alters the steroid receptors, leading to implantation
failure [16].
Infertility and Reproductive Outcomes
The evidence base in relation to fibroids and infertility is com-
plex, with an overrepresentation of observational data and a
lack of well-designed controlled trials. Moreover, the hetero-
geneity in patient populations and fibroid disease and multi-
factorial aetiology of infertility mean that it is often difficult to
plan and successfully execute large scale multi-centre
randomised controlled trials.
So far, we have explored biological plausibility by which
fibroids may cause infertility. In this section, we will explore
the evidence base for harm and treatment benefit.
Evidence of Harm: Does Presence of Uterine Fibroids
Reduce Implantation Rates?
It is generally accepted that submucous fibroids have a nega-
tive impact on fertility and early pregnancy by the virtue of
their involvement in the endometrial cavity. A systematic re-
view by Pritts et al. concluded that submucosal fibroids (FIGO
L0 to L2) which cause distortion of the uterine cavity resulted
in the decreased rates of clinical pregnancy, implantation and
ongoing pregnancy/live birth, as well as an increased rate of
spontaneous miscarriage [17••].
In contrast to this, there is a considerable controversy re-
garding fibroids that do not cause distortion of the uterine
cavity. The review by Pritts et al. found that women with
fibroids with no submucosal involvement, i.e. pure intramural
fibroids (FIGO L3 to L4), had decreased rates of implantation
and ongoing pregnancy/live birth, and an increased rate of
spontaneous miscarriage when compared with controls with-
out fibroids. One weakness of Pritts’review is that most of the
studies included did not use a formal means such as hysteros-
copy or saline sonography to exclude the involvement of the
uterine cavity, i.e. there may be an ascertainment bias and
overestimation of effect size in that some of the cases deemed
as intramural and may have an undiagnosed submucosal com-
ponent [17••]. What is clear from the review is that there was
no evidence to suggest that subserosal (FIGO L5 to L7) fi-
broids decreased any measure of fertility.
A synthesis of available evidence shows a 21 % reduction
in live birth rates following in vitro fertilization (IVF) in wom-
en with non-cavity distorting intramural fibroids, when com-
pared with non-fibroid controls [18••]. The group whilst ac-
knowledging the inherent weakness ofthe review owing tothe
82 Curr Obstet Gynecol Rep (2016) 5:81–88
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heterogeneity of patient populations highlighted the relatively
lower chance of achieving a live birth, when compared with
clinical pregnancy rate, and attributed this to increased rates of
miscarriage and premature birth [18••].
A major confounding factor in infertility success is access
to health care. There is a strong residual effect in that women
who receive treatment early are most likely to have successful
outcomes, whereas those who suffer long duration of infertil-
ity are the residuals whose prognosis is worse irrespective of
treatment.
There is plethora of evidence that, Afro-Caribbean women,
in whom fibroids are more common and more severe, have
poor access to health care compared to Caucasian women, and
therefore under-represented in ART databases [19]. Feinberg
et al. examined the disparity in outcomes of the first non-
donor IVF cycles between African-American patients and
Caucasian patients, in the Department of Defence population,
which is an equal access to care setting [20]. Fibroids were
approximately three times as common in African-American as
opposed to Caucasian women (30.8 versus 10.7 %). Women
were offered routine saline sonography prior to IVF, and those
with fibroids larger than 3 cm or submucosal component of-
fered surgery. Although, the study could neither ascertain the
staging of fibroids at baseline scan nor the proportion of pa-
tients who underwent surgery, African-American women
were found to have statistically significant higher rates of mis-
carriage, when compared to Caucasian patients and fibroids
were thought to be a contributing factor for this variation [20].
The reproductive outcomes between the two groups were sim-
ilar when adjusted for fibroids. In both groups of women, the
presence of fibroids at baseline scan reduced IVF implantation
and live birth rates by 18 % (95 % CI 2–31 %) and 27 % (95 %
CI 4–44 %), respectively [20].
Evidence of Treatment Benefit: Does Treatment of Uterine
Fibroids (For Example Myomectomy) Improve Fertility
Rates and Outcomes?
There are many case series reporting the benefits of myomec-
tomy. For example, Babaknia et al. in 1978 reported 38 %
term pregnancy rate following myomectomy in 34 women
with otherwise unexplained infertility [21•].
Casini et al. reported the only RCT published to date, in the
group of women with fibroids but otherwise unexplained in-
fertility [22••]. All women except for those whose fibroids
were purely subserous, i.e. no intramural component
(n= 11), were included and randomised (total randomised
n= 170) to undergo myomectomy or not and spontaneous
conception rates observed over 12 months following surgery.
All women undergoing myomectomy, which was carried out
either hysteroscopically or by laparotomy, reported increased
pregnancy rates irrespective of baseline fibroid staging [22••].
Statistically, significant increase was, however, only observed
in women with submucosal fibroid [pregnancy rates myomec-
tomy versus no myomectomy; submucosal group = 43.3 ver-
sus 27.2 %; intramural with submucosal component = 40 ver-
sus 15 %; all submucosal = 21/52 (40.4) versus 9/42
(21.4 %)]. The pregnancy rates of the 11 women excluded
on basis of pure subserous staging was 63.6 % [22••].
Whilst there are many non-randomised controlled trials in
published literature, their common fallacy is the choice of
inappropriate controls, i.e. to give a valid answer, both the
treatment and control arm should suffer disease in question
of uterine fibroids. It is not correct to compare women who
undergo myomectomy with infertile controls who do not have
fibroids at all. In absence of appropriate controls, evidence
from studies where patients serve as their own internal con-
trols, i.e. a before and after effect, is acceptable, although not
without its own methodological problems.
A review of literature reveals only one such adequately
controlled trial, albeit non-randomised, which investigated
the treatment effect of myomectomy prior to IVF [23]. All
the patients selected had between one and five fibroids, with
one measuring at least 5 cm and all without a submucosal
component. The study established the beneficial effects of
pre-IVF myomectomy, as shown by the 25 % delivery rate
in the myomectomy group, when compared to the 12 % de-
livery rate in the no surgery group.
A Cochrane review of three RCT’s[22••,24,25]conclud-
ed that there is insufficient evidence to recommend a myo-
mectomy for the purpose of improving fertility outcomes in
thecaseofintramuralorsubserosalfibroids[26••].
In summary, the published literature make clear divisions be-
tween the location of fibroids and the benefit of myomectomy on
reproductive outcomes, both in terms of spontaneous pregnan-
cies as well as IVF outcomes. The consensus based on clinical
experience would appear to imply very little causation linking
subserosal fibroids and infertility. Therefore, unless there were
other indications, a myomectomy to remove subserosal fibroids
for infertility is not evidence based. Submucosal fibroids, on the
other hand, are shown to lower fertility rates and studies have
demonstrated by removing such fibroids; there is an improve-
ment in both conception and live birth rates.
With regard to intramural fibroids, both the evidence and
consensus for myomectomy, purely for infertility, is weak.
Given the risk of significant morbidity of surgery including
that of postoperative adhesion formation, particularly those
performed through posterior uterine incisions, [27] further re-
search is outstanding and cases have to be managed on an
individual basis.
A Pragmatic Approach to Management
Attribution is the exercise of determining a causal association
between a finding and a symptom, i.e. the exercise of
Curr Obstet Gynecol Rep (2016) 5:81–88 83
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establishing causation. In vast majority of cases, it is difficult
or even impossible to ascertain causation with absolute cer-
tainty, and therefore, the attribution exercise should also in-
clude a means of determining the strength/likelihood of the
causal association, so a treatment effect can be estimated.
Accurate fibroid mapping, i.e. description of size, location
and nature of fibroids, using ultrasound scan is a critical step
in such an assessment. Saline infusion sonography (SIS) can
be used to rule out submucosal involvement, and MRI re-
served for complex cases or to differentiate from
adenomyosis.
All patients should complete preliminary investigations to
ascertain causation of infertility; the important domains in-
clude assessment of ovarian reserve and ovulation, as well
as seminal fluid analysis. Tubal patency tests are invasive,
and in the presence of fibroids are inaccurate [28].
Accordingly, patency should be assessed opportunistically at
time of myomectomy, or if indicated, by HSG or HyCoSy as
appropriate. An overview of the investigations and treatment
of infertility is outlined in Fig. 1(adapted with permission
from WILEY-TOG article) [28].
The two critical factors which help assess the need for
treatment are (a) the absence or presence of other causal aeti-
ologies and (b) the overall chance of conception, whether
natural or otherwise. For example, if fibroids are a part of a
multi-factorial aetiology, it is difficult to determine which
aetiology is most causative in infertility. On the other hand,
if the aetiology is otherwise unexplained, then it is appropriate
to consider treatment either surgical or medical for the fi-
broids. The overall chance of conception is also an important
factor in decision making. For example, the removal of
submucous or large intramural fibroids is likely to be success-
ful in a woman age <40 with otherwise unexplained infertility,
as opposed to a woman age 40 or more with low/poor ovarian
reserve, where myomectomy irrespective of size and location
of fibroids is unlikely to be of major benefit.
Surgical Treatments
Hysteroscopic Myomectomy
If the fibroids are predominately located within the cavity
(FIGO L0, L1), hysteroscopic myomectomy would appear
to help restore cavity dimensions and subsequently improve
fertility outcomes. The risk of endometrial damage and intra-
uterine adhesions, and its subsequent effect on conception and
pregnancy outcomes, has to be discussed with patient during
pre-operative counselling.
Intrauterine adhesions have been reported to occur in up to
7.5 % of hysteroscopic myomectomies [29]. Valle et al.
showed that increasing severity of intrauterine adhesions cor-
related with corresponding decrease in reproductive
outcomes. This ranged from a term pregnancy rate of
81.3 % in patients with mild disease to 31.9 % in patients with
severe disease [29].
FIGO L2 fibroids, whereby less than 50 % of the fibroid is
located with the cavity, are more difficult to resect and may
require a two-stage procedure, especially if larger than 3 cm.
Camanni et al. demonstrated that hysteroscopic approach is
suitable for fibroids measuring up to 5 cm in diameter [30].
One has to exercise extreme caution in assessing what is fea-
sible technically and what is best for the management of pa-
tient’s symptoms. Whilst it is perfectly reasonable to perform
resection of large L2 fibroids, albeit in multiple procedures,
for the management of severe menstrual symptoms, the risk of
endometrial damage and adhesions may negate any fertility
benefits. As such, for infertility, it may be prudent to remove
such fibroids by laparoscopy, although it does increase the
risks associated with a full thickness myometrial incision such
as uterine rupture in the future pregnancy and labour.
Laparoscopic Versus Laparotomy
All fibroids FIGO L3 and above (and large L2 as outlined
above) are best removed by laparoscopy or laparotomy. The
improvement in reproductive outcomes appears to be similar
by both the approaches. Combined data of 267 women from
two RCTs comparing laparoscopic myomectomy and abdom-
inal myomectomy demonstrated similar reproductive out-
comes in both groups [24].
In the first study of 131 patients undergoing myomectomy
for infertility and at least 1 fibroid > 5 cm, pregnancy rates were
similar in the laparoscopy and laparotomy groups (53.6 versus
55.9 %).Febrile morbidity was reduced in the laparoscopy
group (26.2 versus 12.1 %), when compared with laparotomy
as well as a smaller mean drop in haemoglobin and a shorter
inpatient stay [24]. In the second study involving 132 women
with fibroids, whilst cumulative outcomes within the first
12 months following surgery were similar (cumulative preg-
nancy rate 52.9 versus 38.2 %), the per cycle outcomes such as
pregnancy rate per cycle (6.5 versus 3.9 %) and time to the first
pregnancy (WMD = 1 month) were significantly higher in the
laparoscopic compared to the laparotomy group [25].
Medical Treatments
Medical treatments such as combined oral contraceptive pill
(COCPs), progesterone only-pill (POP) and levonorgestrel in-
trauterine system (LNG-IUS), whilst useful in managing men-
strual and pain symptoms, are contraceptive and therefore not
applicable to the infertile women. Other medical treatments
such as mefenamic and tranexamic acid can be safely pre-
scribed [31].
Ulipristal acetate (UPA), a selective progesterone receptor
modulator is now approved and licensed for the medical
84 Curr Obstet Gynecol Rep (2016) 5:81–88
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
treatment of uterine fibroids in many countries. UPA has been
shown to improve menstrual symptoms and lead to regression
in fibroid size [32]. The regressive effects are maintained for
6 months, primarily because the compound increases apopto-
sis of leiomyoma cells [33•]. This phenomenon has allowed
for intermittent dosing, and UPA is now licensed accordingly
[34]. The maximum duration of therapy is 3 months, and the
recommended interval between therapies has to be a minimum
of two washout-menstrual cycles, which also allows for any
endometrial changes, the so-called PAEC to revert to normal.
UPA is marketed in strengths of up to 100 mg for emergen-
cy contraception [35]; however, contraceptive effects of a dai-
ly 5 mg dose are unknown, and therefore, patients should be
advised to use alternate contraception such as condoms during
therapy in order to avoid any teratogenicity. Any conception
benefits of UPA, resulting from fibroid regression, have to be
evaluated following end of therapy or in the washout cycles if
prescribed intermittent dosing.
Luyckx et al. reported the first series of 18 such pregnan-
cies in 52 women participating from a single centre in Pearl II
and Pearl III studies. Thirty-seven women were treated with
one-off 3-month UPA therapy (Pearl II, Pearl III) and 15 with
intermittent therapy lasting a total of 6 to 12 months (Pearl III
extension). Of the 21 women who wished to conceive after
completion of UPA therapy, 19 underwent myomectomy, and
2 were not. Seventy-one per cent (15/71) women conceived
for a total of 18 times, 12 of which were spontaneous and a
further 6 achieved with IVF [36]. There were a total of 13 live
births (1 twin) and 6 miscarriages. The two women, who did
not undergo myomectomy, had a total of three pregnancies
between them, but only one live birth [36].
Whilst the data shows feasibility and safety of conception
after UPA therapy, it also highlights the high miscarriage rate
in the presence of fibroids despite reduction in size (2/3 versus
4/15 conceptions in women who did not undergo myomecto-
my versus those who did) and therefore the superiority of
myomectomy over reductive therapies.
Uterine Artery Embolization
Uterine artery embolization was first described in 1995 by
Ravina as an alternative radiological treatment option for
women with large fibroids no longer desiring their fertility
IVF
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Fig. 1 Overview of investigations and treatment of infertility (adapted with permission from Yalandu and Narvekar, Wiley publishing) [28]
Curr Obstet Gynecol Rep (2016) 5:81–88 85
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
[37]. MRI imaging shows a transient ischemia within the body
of the uterus and the endometrium typically lasting for up to
72 after the uterine artery embolization (UAE) procedure. This
ischemic change is intended to be irreversible within fibroid
tissue only, and temporary within healthy uterine muscle and
endometrium, but nevertheless, raises concerns regarding its
effect on whole uterine and endometrial function. Also, the
uterine and ovarian artery has been shown to anastomose on
angiography, in at least one side in approximately 46 % of
women. Therefore, inadvertent embolization of ovarian tissue
may result in premature ovarian insufficiency and failure es-
pecially in older women or those with low baseline ovarian
reserve. Reassuringly, the reported incidence of amenorrhea in
the under 40 age group is less than 1 %.
Mara et al. conducted an RCT evaluating UAE versus ab-
dominal myomectomy in an infertile population [38]. The
pregnancy rates were 50 and 78 % in the UAE and myomec-
tomy arms, respectively. They recruited young patients below
age 35 [mean age 32 (SD ±4.1) years] which may explain the
high conception rates overall. Also, the latency period, i.e.
time to conception was longer for UAE (mean = 18 months)
compared with myomectomy (mean = 13 months). The re-
intervention rates were higher (19 out of 58) in the UAE
arm, as has been observed in other studies [39].
Following a systematic review of the published literature,
Homer et al. reported a 35.2 % rate of miscarriage in UAE
conceptions as compared to 16.5 %in fibroid-containing preg-
nancies (odds ratio [OR] 2.8; 95 % confidence interval [CI]
2.0–3.8) matched for age and fibroid location [40]. There was
a higher incidence of caesarean section and PPH in the UAE
pregnancies, whereas rates for preterm delivery and
malpresentation were similar in the two groups.
Given the current evidence base, UAE is not a treatment of
first choice for women with infertility or those desirous of
future fertility. Instead, it is to be reserved for poor surgical
candidates.
Magnetic Resonance-Guided Focused Ultrasound
Surgery
Another alternative treatment modality which has demonstrat-
ed encouraging preliminary results is the use of magnetic
resonance-guided focused ultrasound surgery (MRgFUS).
This treatment involves the application of MRI-directed
beams of ultrasound capable of heating an area of fibroid
tissuetoupto70°Candcausing destruction through
coagulative necrosis.
Rabinovici et al. reviewed all pregnancies reported to the
FDA MAUDE (manufacturer and user facility device experi-
ence) database following MRgFUS. In total, 54 pregnancies
were reported in 51 women with a mean age at MRgFUS of
37.2 years and mean time to conception of 8 months [41,42].
The miscarriage rate was 28 %. The preliminary experience is
encouraging, with a high rate of delivered and ongoing
pregnancies.
Conclusion
The evidence regarding effect of fibroids on infertility and
reproductive outcomes is weak and mostly inconclusive. In
infertile women, appropriate evaluation and classification of
fibroids, particularly those involving or suspected to be in-
volving the endometrial cavity is essential. Submucosal fi-
broids (FIGO L0-L2) should be treated hysteroscopically (or
laparoscopic for large L2) to improve conception rates. The
management of intramural fibroids should be individualised
on a case to case basis, whereas subserosal fibroid are unlikely
to have any major impact on fertility. Conservative treatment
measures (Medical, UAE and MrgRUS) should not be rou-
tinely offered to women who wish to maintain or improve
their fertility due to lack of data on their safety and
effectiveness.
Compliance with Ethical Standards
Conflict of Interest P. Purohit and K. Vigneswaran declare that they
have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
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