Available via license: CC BY-NC-ND
Content may be subject to copyright.
55
©Copyright 2019 by the Turkish-German Gynecological Education and Research Foundation - Available online at www.jtgga.org
Journal of the Turkish-German Gynecological Association published by Galenos Publishing House.
Review
Introduction
Fibroids are common in women in their reproductive years
and are frequently detected in women who are about to
undergo treatment with assisted reproductive technologies
(ART). Although many fibroids are completely harmless and
have no clinical significance, 10-15% of white women and
30-40% of black women between the ages of 35 to 39 years
have been found to have clinically relevant fibroids (uteri nine
weeks gestation size or larger, at least one submucosal fibroid
or at least one fibroid of ≥4 cm) (1). As a result, questions are
inevitably raised by physicians and couples about the possible
detrimental impact of fibroids on the planned ART or whether
removal of fibroids would be expected to be beneficial in
improving the ART outcome. The published literature on the
impact of fibroids on fertility/fertility treatment outcome and
potential benefit of fibroid removal is marred by a number
of problems. The majority of studies are observational and
are prone to selection bias. It is quite likely that women with
larger and more ‘significant’ fibroids undergo surgery and
are excluded from these studies. In addition, there are a
large number of confounding parameters that are difficult to
control in fibroid-related studies; fibroids come in all different
numbers, sizes, and locations. Studies set out to diligently study
the impact of intramural fibroids to ensure that uterine cavity
distortion is excluded with a high quality or reliable test. This
has resulted in exclusion of a large subgroup of women who
have intramural fibroids with cavity distortion and the published
systematic reviews do not provide a clear outcome analysis for
this group. As a result, recommendations from professional
Abstract
Fibroids are relatively common in women undergoing in vitro fertilization (IVF) treatment due to their high prevalence in women. It is generally
accepted that submucosal fibroids are deleterious to IVF outcomes and their removal is beneficial. Evidence from relatively low quality studies on
the impact of intramural fibroids on IVF outcome is also suggestive of a detrimental impact. The majority of published studies included women
with relatively small intramural fibroids and women with cavity-distorting fibroids were usually excluded, hence it is quite likely that the detected
impact in the systematic reviews is an underestimation. Evidence of benefit is scarce for the removal of noncavity-distorting intramural fibroids.
It is quite likely that numbers needed to treat for this purpose would be very high for small fibroids but lower for larger fibroids. This would need
to be taken into account when decisions are made on myomectomy and potential benefits should be weighed against the associated morbidity,
cost, and delay in fertility treatment. Whilst there is a need to perform prospective randomised studies in this field, a pragmatic approach that
takes prognostic factors into account to estimate the magnitude of the possible impact of the fibroid(s) and potential benefit of removal is likely
to lead to better reproductive outcomes. (J Turk Ger Gynecol Assoc 2019; 20: 55-9)
Keywords: Fibroids, leiomyoma, in vitro fertilization, assisted reproductive technology
Received: 13 November, 2018 Accepted: 15 November, 2018
DOI: 10.4274/jtgga.galenos.2018.2018.0148
Address for Correspondence: Erdinç Sarıdoğan
Phone: +90 535 824 59 00 e.mail: erdinc_saridogan@hotmail.com ORCID ID: orcid.org/0000-0003-2183-7689
1Clinic of Obstetrics and Gynecology, University of Health Sciences, Ankara Zekai Tahir Burak Women’s Health Training and
Research Hospital, Ankara, Turkey
2Department of Obstetrics and Gynecology, University College London Hospitals, London, United Kingdom
Erdinç Sarıdoğan1, Ertan Sarıdoğan2
Management of fibroids prior to in vitro fertilization/
intracytoplasmic sperm injection: A pragmatic
approach
56 J Turk Ger Gynecol Assoc 2019; 20: 55-9
organisations end up representing the opinion of the people
who write them, sometimes with conflicting views even in the
same document.
A number of meta-analyses since 2007 reported different
conclusions despite mostly including the same studies (2-7).
This is likely to be the result of differences in the methodology
of reviews and inclusion/exclusion criteria that were used.
In this article, the evidence from the published literature
will be critically analysed in an attempt to provide guidance
to physicians as to how fibroids can be managed in women
undergoing in vitro fertilization (IVF)/intracytoplasmic sperm
injection (ICSI) treatment.
Evidence from Meta-Analyses
We will look at six major reviews that analysed the impact of
fibroids on reproductive outcomes (2-7). Three of these reviews
included studies that investigated the impact of all-type fibroids
on both spontaneous pregnancies and IVF treatment outcomes
(2-4), and the other three specifically addressed studies that
assessed the impact of intramural fibroids that did not distort
the uterine cavity on the outcome of IVF treatment (5-7).
Somigliana et al. (2) conducted a number of meta-analyses on
the published literature related to fibroids and reproduction. In
one of these, they assessed 16 articles on IVF outcomes and
fibroids. Two studies, which included submucosal fibroids,
showed that the presence of these fibroids significantly reduced
pregnancy [odds ratio (OR): 0.3, 95% confidence interval (CI):
0.1-0.7] and delivery rates (OR: 0.3, 95% CI: 0.1-0.8). Intramural
fibroids (seven studies) caused a small but significant
detrimental impact of intramural fibroids on conception (OR:
0.8, 95% CI: 0.6-0.9) and delivery (OR: 0.7, 95% CI: 0.5-0.8) rates
following IVF/ICSI treatment. Studies showed that subserosal
or intramural/subserosal fibroids did not significantly reduce
IVF/ICSI outcomes. They noted that the average diameter of
fibroids in the included studies was rarely above 3 cm and that
the detrimental impact emerging from the published articles
may have been an underestimation of the real impact. They
based this opinion on the finding that the negative impact was
seen in women with fibroids >4 cm (8). Somigliana et al. (2)
highlighted a nonrandomised comparative study by Bulletti et
al. (9) who found higher cumulative clinical pregnancy (33% vs
15%) and delivery (25% vs 12%) rates after one to three cycles
of IVF treatment in women who underwent myomectomy for
intramural fibroids >5 cm compared with those who decided
against myomectomy.
Klatsky et al. (3) included three studies on submucosal fibroids
and IVF outcomes. This showed a significant reduction in
implantation (OR: 0.39, 95% CI: 0.24-0.65) and clinical pregnancy
rates (OR: 0.44, 95% CI: 0.28-0.70) and increase in miscarriage
rates (OR: 3.89, 95% CI: 1.12-13.27). Nineteen studies compared
IVF outcomes in women with intramural fibroids of 1-8 cm with
those of controls without fibroids. Most studies included women
with relatively small fibroids of 2-3 cm. The meta-analysis by
Klatsky et al. (3) showed a significant decrease in implantation
(OR: 0.79, 95% CI: 0.71-0.88) and clinical pregnancy rates (OR:
0.84, 95% CI: 0.74-0.95) and increase in miscarriage rates (OR:
1.82, 95% CI: 1.43-2.30). Klatsky et al. (3) did not analyse the
impact of subserosal fibroids on IVF outcomes.
Pritts et al. (4) analysed 23 studies, which mostly gave IVF/
ICSI related outcomes. Four of these studies on submucosal
fibroids showed significantly reduced clinical pregnancy (OR:
0.36, 95% CI: 0.18-0.74), implantation (OR: 0.283, 95% CI: 0.12-
0.65), and ongoing pregnancy/live birth rates (OR: 0.32, 95%
CI: 0.12-0.85) and increased miscarriage rates (OR: 1.678, 95%
CI: 1.37-2.05). Twelve studies that included outcomes related
to intramural fibroids showed lower clinical pregnancy rate
(OR: 0.81, 95% CI: 0.70-0.94), ongoing pregnancy/live birth (OR:
0.70, 95% CI: 0.58-0.85), and implantation rates (OR: 0.68, 95%
CI: 0.59-0.80), and higher miscarriage rates (OR: 1.75, 95% CI:
1.23-2.49) compared with control women without fibroids.
When only prospective studies or studies that assessed uterine
cavity distortion with hysteroscopy or sonohysterography were
included, the implantation rates remained significantly lower
in women with intramural fibroids, but clinical pregnancy
rates were no longer significantly different. Two studies that
assessed the clinical pregnancy rates and one that gave the
ongoing/live pregnancy rates showed that myomectomy for
intramural fibroids did not improve the outcomes compared
with controls with in situ fibroids. This review did not show a
significant impact of subserosal fibroids.
Sunkara et al. (5) published an analysis of 19 studies on the
impact of non-cavity distorting intramural fibroids on IVF
outcomes. They found significant reductions in live birth rates
(OR: 0.79, 95% CI: 0.70-0.88) and clinical pregnancy rates (OR:
0.85, 95% CI: 0.77-0.94) in women with fibroids compared with
women without fibroids. Implantation and miscarriage rates
were not statistically different. The studies included in this
article had data from women with fibroids of 0.4-8.0 cm, the
majority being less than 5 cm.
Metwally et al. (6) conducted a further analysis of the effect
of intramural fibroids on ART treatment using published
studies that included an aged-match control group, analysed
intramural fibroids separately (not grouping them together
with subserosal fibroids), and excluded submucosal fibroids
by assessing the endometrial cavity using an objective method
(hysteroscopy or sonohysterography). With this approach, no
differences in live births, clinical pregnancy or miscarriage
rates were found between women with and without fibroids.
However, inclusion of studies with less strict criteria suggested
lower clinical pregnancy rates (OR: 0.60, 95% CI: 0.42-0.87),
Sarıdoğan and Sarıdoğan.
Fibroids prior to assisted reproductive technologies
57
J Turk Ger Gynecol Assoc 2019; 20: 55-9
whilst live birth and miscarriage rates were still similar.
Importantly, four studies that gave the size of fibroids included
women with fibroids sized of 5 cm or less.
Wang et al. (7) recently performed an updated meta-analysis
of the impact of noncavity-distorting fibroids on the outcomes
of IVF. The authors included 28 studies comprising 9189 IVF
cycles, including the 19 studies included in the meta-analysis
by Sunkara et al. (5). Seven of these were prospective trials
and 23 studies controlled for compounding factors such
as the woman’s age. This meta-analysis demonstrated
significantly reduced clinical pregnancy [risk ratio (RR): 0.86,
95% CI: 0.80-0.93], live birth (RR: 0.81, 95% CI: 0.73-0.91) and
implantation rates (RR: 0.90, 95% CI: 0.81-1.00) and increased
miscarriage rates (RR: 1.27, 95% CI: 1.08-1.50). Separate
analysis of prospective studies only and outcome of first cycle
IVF confirmed the detrimental impact of noncavity-distorting
fibroids on clinical pregnancy and live birth rates.
It appears that, despite some degree of differences in the
conclusions of these systematic reviews, the common finding
is that the presence of fibroids has a detrimental impact on
the outcome of IVF. It is generally accepted that submucosal
fibroids do have a detrimental impact on fertility outcome.
However, the quality of evidence to support this is weak and
the significance of benefit of submucosal fibroid removal was
brought into question in a Cochrane review (10).
Importance of Fibroid Size
A common feature in the majority of studies is that they
included only women with relatively small intramural fibroids,
probably because women with larger fibroids were excluded
and underwent a myomectomy. Hence, the published literature
is very likely underestimating the impact of intramural fibroids,
particularly larger fibroids.
Only a few studies attempted to assess the impact of fibroid
size. Oliveira et al. (8) found that a detrimental impact was
seen in the presence of relatively larger fibroids. The clinical
pregnancy rates were lower after IVF/ICSI in women with
intramural or subserosal fibroids of 4.1-6.9 cm compared with
women with no fibroids or fibroids ≤4 cm. There was no
difference in pregnancy rates between the control group and
women with fibroids ≤4 cm. Women with fibroids of ≥7 cm
were excluded.
Another retrospective study of impact of fibroids that did not
distort the cavity found that delivery rates were lower in the
presence of fibroids >2.85 cm, whilst there was no detrimental
impact in the presence of smaller fibroids (11).
A more recent retrospective matched cohort study showed that
fibroids ≥30 mm had a deleterious effect on live birth rates,
whereas this effect was not seen in the presence of fibroids
<30 mm (12).
Impact of Fibroid Removal
Evidence on the potential benefit of removal of fibroids prior
to IVF/ICSI for women with fibroids is relatively scarce. A
retrospective case controlled study of women with submucosal
fibroids undergoing IVF using own or donated eggs showed
that hysteroscopic or abdominal myomectomy for submucosal
fibroids normalised the cycle outcomes. In this group of
women, implantation and ongoing pregnancy rates were
similar to the controls who had no fibroids, suggesting that the
detrimental impact of submucosal fibroids is eliminated by
fibroid removal (13).
A comparative non-randomised study assessed the potential
benefit of myomectomy for intramural fibroids prior to IVF
(10). One hundred sixty-eight women with at least one fibroid
>5 cm were allowed to choose between myomectomy and
expectant management prior to IVF. Submucosal fibroids were
excluded. In the 84 women who had a myomectomy, clinical
pregnancy (33% vs 15%, p<0.05) and delivery (25% vs 12%,
p<0.05) rates were significantly better compared with the
other 84 women who did not have surgery after one to three
cycles of IVF treatment.
Hysteroscopic myomectomy is a relatively safe procedure with
minimal surgical morbidity. However, it can cause intrauterine
adhesions, which could lead to a reduction in fertility and
chances of success with fertility treatment. Special attention
should be paid to treatment of multiple and large submucosal
fibroids. Hysteroscopic removal of large fibroids is more
challenging and multiple fibroid removal is more likely to cause
intrauterine adhesions.
Abdominal myomectomy is a major operation that can cause
significant morbidity, especially in the presence of multiple and
large fibroids. Potential long-term harm of postoperative pelvic
adhesions on spontaneous conception is well recognised but
the impact of myometrial trauma or intrauterine adhesions after
abdominal myomectomy on IVF is less well recognised. At the
same time, questions still remain on its effect on fertility and
outcome of ART due to the absence of convincing evidence.
When an abdominal myomectomy is indicated, the
potential benefits of the laparoscopic approach against open
myomectomy have been well established (14). In comparison
with traditional open myomectomy, the laparoscopic approach
is associated with less postoperative pain and fever, and
shorter hospital stay at the expense of longer operating times
in a number of randomized clinical trials (15). Other potential
advantages of the laparoscopic approach include a shorter
recovery time with a quicker return to activities of daily living
(16).
There will be a need to delay pregnancy after myomectomy
to allow the uterine wall to heal. This is relatively short after
hysteroscopic myomectomy because it does not involve a
Sarıdoğan and Sarıdoğan.
Fibroids prior to assisted reproductive technologies
58 J Turk Ger Gynecol Assoc 2019; 20: 55-9
Sarıdoğan and Sarıdoğan.
Fibroids prior to assisted reproductive technologies
myometrial incision, but needs to be long enough for the
fibroid bed to ‘recover’ and be covered with endometrium.
However, women are usually advised to avoid pregnancy for at
least three months after abdominal myomectomies, resulting
in delays in the planned IVF treatment. This may potentially be
an issue for older women, particularly for those with reduced
ovarian reserve. This delay may, however, be overcome by
performing IVF before myomectomy and freezing the embryos
for transfer after the recovery period. One potential problem
with this approach is difficulties with access to the ovaries due
to fibroids.
Conclusions and a Pragmatic Approach to Management of
Fibroids Prior to IVF/ICSI
There is overall consensus that submucosal fibroids have
a detrimental impact on the chances of success with IVF/
ICSI. Furthermore, there is some evidence of the benefit
of myomectomy for submucosal fibroids to improve ART
outcomes. For this reason, we make every effort to remove
all submucosal fibroids in our practice. It is usually possible
to remove all type 0 and I fibroids hysteroscopically (17). We
administer gonadotropin releasing hormone treatment for 2-3
months when the fibroid is ≥4 cm to reduce the likelihood
of two-stage procedures. We also aim to remove single type
II submucosal fibroids <4 cm hysteroscopically; some 3-4
cm type II fibroids require a two- stage approach. For type II
fibroids of ≥4 cm, we give serious consideration to abdominal
myomectomy (laparoscopic when possible, open in the
presence of numerous fibroids). We pay special attention to
reducing the risk of intrauterine adhesions in the presence of
multiple submucosal fibroids, including removal of fibroids on
opposing walls in different sessions.
Subserosal fibroids are unlikely to have an impact on ART
outcomes, except when they cause difficulties with ovarian
access for egg collection. For this reason, the majority of
subserosal fibroids are left alone during IVF cycles.
The management of noncavity-distorting intramural fibroids
prior to IVF/ICSI is less straightforward. Current evidence
suggests a detrimental impact of the presence of these fibroids;
however, this is based on relatively low quality studies that
show significant variability in selection criteria and outcome
measures. This is not unexpected considering that fibroids
come in different numbers, sizes, locations, and consistencies.
There is a clear need to perform prospective randomised
studies on this subject, but this is likely to be difficult due to a
high number of confounding factors that would be difficult to
stratify.
A major problem with the published studies that were analysed
in the meta-analyses is that they included women with relatively
small intramural fibroids, probably because women with larger
fibroids and those with fibroids that distort the cavity undergo
myomectomy. Therefore, the real impact of these fibroids on
IVF outcomes is likely to be larger. An additional problem is that
there is a shortage of evidence regarding benefit of removing
noncavity-distorting intramural fibroids. However, abdominal
myomectomy (laparoscopic or open) is relatively frequently
performed for these fibroids. It is likely that the numbers
needed to treat (NNT) for this purpose would be lower for
larger fibroids but very high for small fibroids. This point would
need to be weighed against the associated morbidity, cost, and
delay in treatment when decisions are made on myomectomy.
In our practice, we take the number and size of fibroids, the
overall size of the uterus, history of previous surgery, and
ovarian accessibility into account when we counsel patients
who have intramural fibroids that do not distort the cavity prior
to IVF treatment. We try to avoid surgery in the presence of
fibroids <5 cm when the uterine cavity is regular. We tend to
offer surgery first to women with intramural fibroids ≥7 cm, but
proceed with IVF treatment without surgery in the presence
of fibroids of 5-6 cm in the first IVF attempt. We usually offer
surgery for fibroids of 5-6 cm if the woman had one or two
failed IVF attempts. This approach aims to keep the NNT as low
as possible per additional pregnancy achieved.
If there are difficulties with ovarian accessibility due to fibroids,
we prefer surgery before IVF. We usually wait for three months
before proceeding with IVF postoperatively, but in older women
with reduced ovarian reserve, we proceed with IVF earlier and
freeze embryos for delayed transfer.
Peer-review: Externally peer-reviewed.
Conflict of Interest: No conflict of interest is declared by the
authors.
Financial Disclosure: The authors declared that this study
received no financial support.
References
1. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High
cumulative incidence of uterine leiomyoma in black and white
women: ultrasound evidence. Am J Obstet Gynecol 2003; 188: 100-
7.
2. Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O,
Crosignani PG. Fibroids and female reproduction: a critical analysis
of the evidence. Hum Reprod Update 2007; 13: 465-76.
3. Klatsky PC, Tran ND, Caughey AB, Fujimoto VY. Fibroids and
reproductive outcomes: a systematic literature review from
conception to delivery. Am J Obstet Gynecol 2008; 198: 357-66.
4. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated
systematic review of the evidence. Fertil Steril 2009; 91: 1215-23.
5. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The
effect of intramural fibroids without uterine cavity involvement
59
J Turk Ger Gynecol Assoc 2019; 20: 55-9
Sarıdoğan and Sarıdoğan.
Fibroids prior to assisted reproductive technologies
on the outcome of IVF treatment: a systematic review and meta-
analysis. Hum Reprod 2010; 25: 418-29.
6. Metwally M, Farquhar CM, Li TC. Is another meta-analysis on the
effects of intramural fibroids on reproductive outcomes needed?
Reprod Biomed Online 2011; 23: 2-14.
7. Wang X, Chen L, Wang H, Li Q, Liu X, Qi H. The impact of noncavity-
distorting intramural fibroids on the efficacy of in vitro fertilization-
embryo transfer: an updated meta-analysis. Biomed Res Int 2018;
2018: 8924703.
8. Oliveira FG, Abdelmassih VG, Diamond MP, Dozortsev D, Melo
NR, Abdelmassih R. Impact of subserosal and intramural uterine
fibroids that do not distort the endometrial cavity on outcome of in
vitro fertilization-intracytoplasmic sperm injection. Fertil Steril 2004;
81: 582-7.
9. Bulletti C, DE Ziegler D, Levi Setti P, Cicinelli E, Polli V, Stefanetti
M. Myomas, pregnancy outcome, and in vitro fertilization. Ann N Y
Acad Sci 2004; 1034: 84-92.
10. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BW, D'Hooghe
TM. Hysteroscopy for treating subfertility associated with suspected
major uterine cavity abnormalities. Cochrane Database Sys Rev
2015: CD009461.
11. Yan L, Ding L, Li C, Wang Y, Tang R, Chen ZJ. Effect of fibroids
not distorting the endometrial cavity on the outcome of in vitro
fertilization treatment: a retrospective cohort study. Fertil Steril
2014; 101: 716-21.
12. Christopoulos G, Vlismas A, Salim R, Islam R, Trew G, Lavery S.
Fibroids that do not distort the uterine cavity and IVF success rates:
an observational study using extensive matching criteria. BJOG
2017; 124: 615-21.
13. Surrey ES, Minjarez DA, Stevens JM, Schoolcraft WB. Effect
of myomectomy on the outcomes of assisted reproductive
technologies. Fertil Steril 2005; 83: 1473-9.
14. Bean EM, Cutner A, Holland T, Vashisht A, Jurkovic D, Saridogan E.
Laparoscopic Myomectomy: A Single-center Retrospective Review
of 514 Patients. J Minim Invasive Gynecol 2017; 24: 485-93.
15. Bhave Chittawar P, Franik S, Pouwer AW, Farquhar C. Minimally
invasive surgical techniques versus open myomectomy for uterine
fibroids. Cochrane Database Syst Rev 2014: CD004638.
16. Tulandi T, Youseff H. Laparoscopy-assisted myomectomy of large
uterine myomas. Gynaecol Endosc 1997; 6: 105-8.
17. Saridogan E. Surgical treatment of fibroids in heavy menstrual
bleeding. Womens Health (Lond) 2016; 12: 53-62.
