Key words
pregnancy - radiotherapy - sterility - ultrasound - uterus - uterine tumor
Schlüsselwörter
Schwangerschaft - Radiotherapie - Sterilität - Ultraschall - Uterus
Introduction
Uterine fibroids are benign, hormone-sensitive tumours of the smooth muscles; the
incidence in women of
child-bearing age has reported to be as high as 40 %, depending on age [1], [2]. Fibroids are considered the most common benign uterine
tumours in women of reproductive age. Associated symptoms include dysmenorrhoea, spotting,
hypermenorrhoea leading to anaemia, lower abdominal pain, pressure on adjacent organs
and disorders of
micturition and defecation [3]. The presence of uterine fibroids has a
particularly important impact on women who may desire to become pregnant, as fibroids
can negatively
affect fertility. Sterility and a higher risk of complications in pregnancy have both
been associated
with uterine fibroids [4]. Submucosal and intramural fibroids which distort
the endometrial cavity are considered to impair fertility [5]. Intramural
fibroids which distort the uterine cavity have also been found to reduce implantation
and pregnancy
rates [6], while surgical excision of submucosal fibroids resulted in higher
rates for implantation and pregnancies carried to term [7]. Thus, despite the
lack of prospective randomised studies comparing outcomes with those of untreated
controls, [8] surgical enucleation is considered the gold standard for patients with
symptomatic fibroids wanting to have children [9], [10]. The choice of approach (hysteroscopy, laparoscopy or open abdominal surgery) depends
on
the location and size of the fibroid. Conservative medical approaches such as GnRH-analogues
or
ulipristal acetate administration, hormone-releasing intrauterine devices, progesterone-based
oral
contraceptives, etc. can improve individual fibroid-related symptoms, but they can
significantly delay
pregnancy, often have only a temporary effect, or have not been approved for this
application [3]. Although interventional radiology has been shown to be clinically effective
in the treatment of uterine fibroids, the data show that complication rates in subsequent
pregnancies
are higher, indicating that uterine artery embolization (UAE) is unsuitable as a routine
treatment for
patients wanting to have children [11], [12], [13]. Similarly, a consensus meeting by a German panel of
experts came to the conclusion that UAE should only be considered as a last resort
in women requiring
treatment to have children [14].
Treatment of fibroids using high-intensity focused ultrasound (HIFU; synonym: MRgFUS
= magnetic
resonance-guided focused ultrasound) is an organ-sparing, non-invasive, thermoablative
procedure applied
transcutaneously. In this procedure, the fibroid is gradually heated under continuous
MRI monitoring in
small, focussed stages, until temperatures > 55 °C are reached to achieve complete
denaturation of
the localised tumour. The high energy concentration in a very small, ellipsoid focus
to create discrete
areas of tissue necrosis preserves both adjacent tissue and the structures between
the energy source and
the target tissue [15]. The effectiveness of HIFU/MRgFUS treatment can be
increased even further using feedback regulation during volumetric ablation [16]. HIFU/MRgFUS procedures can be done on an outpatient basis without anaesthesia.
HIFU/MRgFUS is much less invasive compared to surgical procedures. In clinical practice,
HIFU treatment
is offered as a potential therapeutic option to women of childbearing age with symptomatic
fibroids who
may wish to have children. It is therefore important to discuss HIFU/MRgFUS as a potential
treatment
option.
The use of MRgFUS to treat fibroids was approved in the USA in 2004. The method was
accorded a European
CE (conformité européenne) mark in 2002 [15]. The procedure is generally
considered to be effective and safe [17], [18], [19], [20], [21], [22]; to date, around 10 000 HIFU/MRGFUS procedures have been
performed worldwide to treat women presenting with symptomatic uterine fibroids [23].
There is still some uncertainty in clinical practice requiring further interdisciplinary
discussion about
the use of HIFU/MRgFUS as a treatment option for women who have not yet completed
their families. It is
possible for women to become pregnant after undergoing HIFU/MRgFUS treatment [24]. However, the German consensus recommendations explicitly state that there is
insufficient data to make any recommendation for or against the use of planned HIFU/MRgFUS
treatment in
women who wish to have children [25].
In analogy to a previous article published in this journal on fertility-related aspects
of fibroid
embolization, [11], this review aims to examine to what extent HIFU/MRgFUS
treatment affects fertility and pregnancy. The review discusses potential, fertility-limiting
injuries
to the ovaries and uterus associated with the procedure as well as the possible impact
on pregnancy and
births based on the literature since the first publication of a pregnancy after MRgFUS
treatment [26] and concludes with recommendations based on this discussion.
Material and Methods
A systematic PubMed analysis was done to assess the impact of HIFU/MRgFUS treatment
on fertility in women
with uterine fibroids. The search was done using the term “fibroid” combined with
the keywords “HIFU”,
“MRgFUS”, “ultrasound ablation” and “pregnancy”, “miscarriage” and “fertility” (date
of retrieval August
1st, 2013). Out of the initial total of 47 articles, publications referring to non-human
settings
(n = 4) were excluded as were publications on HIFU use to abort pregnancy (n = 1)
and the use of HIFU to
treat men (n = 2). The remaining publications (n = 40) were then analysed further.
There were no
restrictions with regard to publication dates.
Implementation, Therapeutic Success and Side-effects of HIFU Treatment
Implementation, Therapeutic Success and Side-effects of HIFU Treatment
The indications for HIFU/MRgFUS treatment are basically the same as for surgical removal
of fibroids –
only patients suffering from fibroid-related symptoms should receive treatment. It
is important to note
that clinical or technical exclusion criteria mean that fewer than half of all patients
with fibroids
are considered eligible for HIFU/MRgFUS treatment [27]. Whether HIFU/MRgFUS
treatment can be a treatment option for women with subfertility caused by uterine
fibroids is discussed
below. Two companies currently offer therapy units for such procedures; the units
have been available
for varying lengths of time (MRgFUS – GE/Insightec since 2004; HIFU – Philips since
2010).
A preparatory MRI with contrast medium (CM) must be done, preferably with the patient
in a ventral
position, prior to carrying out the HIFU/MRgFUS procedure to determine the exact position
of adjacent
organs, the perfusion of the targeted fibroid and a suitable ultrasound window for
the approach. A
special patient table mounted with an ultrasound transducer is required for HIFU/MRgFUS
procedures. For
treatment, the abdomen above the uterus is shaved and the patient is placed face downward
on the table
of the HIFU/MRgFUS therapy unit. After controlling that the uterus is positioned centrally
to the
ultrasound transducer above the Plexiglas window ([Fig. 1]), a gel pad is
applied between the Plexiglas window and the abdomen for acoustic coupling to the
ultrasound transducer.
The patient table is then moved into the scanner. MRI monitoring is done repeatedly
to ensure that the
uterus remains in the correct position above the transducer and to ensure that there
are no interposed
intestinal loops. Fibroid sonication results in denaturation with subsequent diminution
of fibroid
tissue, although this contraction process can take several months. Contrast medium
is administered post
procedure to measure results; the non-perfused volume (NPV) of the fibroid serves
as measure of success.
International studies report a median NPV of between 36 % (6 months post procedure)
and 39 % (12 months
post procedure) [28], which can rise to as high as 54 % (12 months post
procedure) [29]. According to some of the older publications, this is
associated with a mean decrease in fibroid volume of 10–15 % after 6–12 months [18], [20], [22], while a more recent
publication reported a decrease of around 32 % after 3 years [30]. None of
these studies was done as a prospective randomised trial.
Fig. 1 HIFU treatment unit: patient table with integrated ultrasound transducer in front
with
the MRI scanner in the background.
Sonication close to the fibroid edge appears to play an important role in determining
the extent of
fibroid volume shrinkage [31]. But it should be noted that there is no linear
relationship between the change in fibroid diameter and its volume, as fibroid volume
is calculated
using the formula 4/3 π r3 based on the assumption that the fibroid has a spherical shape. A
decrease in fibroid diameter from 5 to 4 cm thus corresponds to an almost 50 % decrease
in volume. If it
is assumed that the fibroid has an ellipsoid shape, then the volume of the fibroid
would be calculated
using the formula 1/6 × d1 × d2 × d3 × π with “d” representing the respective orthogonal
diameters of
the fibroid [32]. Controlling symptoms is more important than merely reducing
fibroid volumes: HIFU/MRgFUS treatment resulted in higher levels of patient satisfaction
[33]. In a retrospective study of 130 women, the rates for relief of symptoms
(bleeding disorders, feeling of pressure, etc.) were 86 %, 93 % and 88 % at 3, 6 and
12 months post
procedure, respectively [34]. A prospective study with a follow-up of 3 years
demonstrated the long-lasting impact of HIFU/MRgFUS treatment using a standardised
questionnaire to
measure quality of life [30]. According to the data of a German study group,
the technical success rate for HIFU/MRgFUS treatments of uterine fibroids is more
than 90 %, while
around 11 % required additional treatment (hysterectomy, UAE) within a period of one
year post procedure
[35]. It should be noted that this cohort did not explicitly consist only
of women who wished to have children, and it is therefore not possible to make any
statement about the
therapeutic effectiveness of HIFU/MRgFUS treatment for women who wish to have children.
Not all fibroids are suitable for HIFU/MRgFUS treatment. One study found that hyperintense
fibroids on
T2-weighted magnetic resonance imaging had lower long-term success rates after ultrasound
ablation due
to their higher perfusion (the heat is “dissipated” more quickly) [36];
success rates are similarly poor for septated, subserous or strongly dorsal fibroids
close to the sacral
nerves (shorter sonication times because of pain).
Potential side-effects or complications after HIFU/MRgFUS treatment as described below
are actually quite
rare (modified based on [25]):
-
peri-interventional pain (usually low and of short duration), can usually be managed
well with
analgesia
-
(slight) skin burns
-
slight inflammation of subcutaneous fat tissue and of the abdominal muscles
-
paraesthesia of the legs due to irritation of, or damage to, the nerves
-
deep vein thrombosis of the legs (very rare)
-
intestinal lesions or intestinal perforation (extremely rare)
-
discharge of vaginal tissue
-
increased and/or irregular bleeding for around 3 months post procedure
Possible Negative Impact of HIFU Treatment on Fertility
Possible Negative Impact of HIFU Treatment on Fertility
Exposure to radiation
In contrast to fibroid embolization, the ovaries are not exposed to ionising radiation
during
HIFU/MRgFUS treatment. The procedure involves no risk of mutagenity.
Adverse effect on ovarian and fallopian tube function
The development of permanent amenorrhoea due to premature menopause would constitute
a serious
complication of any interventional treatment of fibroids using HIFU/MRgFUS. This could
be caused by
inadvertent direct sonication of the ovaries or if the uterine fibroid treated by
sonication is too
close to the ovaries. In fact, it is possible to induce a permanent loss of ovarian
function by
focussing HIFU/MRgFUS treatment directly on the ovaries [37]. However,
these results obtained by a Chinese study group were done as part of study of targeted,
non-surgical
ovarian ablation in women with hormone receptor-positive breast cancer and cannot
be considered as a
complication of uterine focussed ultrasound treatment. Another group carried out a
preliminary study
into the serial use of HIFU/MRgFUS therapy to treat tubal pregnancy (n = 40): 64 %
of the treated
tubes were found to be patent at 6 months post treatment, and the tubal patency rate
was 82 % at 12
months after treatment [38]. This figures are comparable with the results
after surgery or methotrexate administration [39]. There are no studies
on changes in endocrine parameters or case reports of inadvertent iatrogenic ovarian
failure or
tubal occlusion after HIFU/MRgFUS treatment of uterine fibroids. In particular, no
studies have been
published to date on changes to anti-Müllerian hormone levels, an established marker
of ovarian
reserve. For technical reasons, HIFU/MRgFUS treatment always involves continuous MRI
monitoring of
the treated area and this alone precludes the inadvertent sonication of the ovaries.
Adverse effect on uterine function
Intramural fibroids can lead to disturbances in uterine contractility, and this has
been proposed as
a risk factor for sterility [40]. There are no data on the possible
adverse impact on uterine function of HIFU/MRgFUS treatment. The change in position
occurring during
degeneration of the fibroid could also result in endometrial changes and changes in
uterine
contractility and thus lead to a loss of uterine functionality. There are no data
on systematic
hysteroscopic monitoring to exclude the presence of intracavitary adhesions after
vaginal expulsion
(post treatment) of fibroid tissue. In this case, due to the lack of studies the possibility
cannot
be excluded that HIFU/MRgFUS treatment could create a new risk factor for uterine
sterility, similar
to that demonstrated in a UAE cohort [41]. The possibility that
sonication of adjacent tissue could have an adverse impact on the endometrium must
also be
considered: it is well known that one of the significant effects of sonication is
based on intended
injury to small blood vessels [42]. But, to date, there are not
sufficient data which clearly demonstrate the impact of sonication, in particular
of submucosal
fibroids, on adjacent endometrial tissue and any impairment of implantation. This
is important
because (planned) sonication of the endometrium has been associated with clear morphological
abnormalities [43].
Pregnancy after HIFU/MRgFUS treatment
[Table 1] provides an overview of all pregnancies occurring after
HIFU/MRgFUS treatment published to date.
Table 1 Published reports of pregnancies after HIFU/MRgFUS treatment
(modified, based on [23]; (n. s.: not specified; * absolute
numbers have only limited significance because of possible double publication of data,
# incomplete publication of some of the data).
Reference
|
Treated patients
|
Women wishing to have children
|
Pregnancies
|
Rate of miscarriages
|
Pregnancies carried to term
|
Age (years) of pregnant women
|
Rate of preterm births
|
Rate of Caesarean sections
|
Characteristics
|
Gavrilova-Jordan et al. [55]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
40
|
0 % (0/1)
|
0 % (0/1)
|
case report
|
Hanstede et al. [44]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
40
|
0 % (0/1)
|
0 % (0/1)
|
case report
|
Morita et al. [56]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
n. s.
|
0 % (0/1)
|
n. s.
|
case report
|
Funaki et al. [28]
|
80
|
n. s.
|
4
|
50 % (2/4)
|
2 (50 %)
|
n. s.
|
0 % (0/2)
|
n. s.
|
case series
|
Rabinovici et al. [24]
|
n. s.
|
n. s.
|
54 (in 51 women)
|
25.9 % (14/54)
|
22 (41 %)
|
28–49 (at the time of HIFU treatment)
|
7 % (4/54)
|
36 % (8/22)
|
11 ongoing pregnancies > 20 GW 7 elective abortions 0
SGA/IUGR
|
Zaher et al. [57]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
39
|
0 % (0/1)
|
0 % (0/1)
|
case report
|
Yoon et al. [58]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
31
|
0 % (0/1)
|
0 % (0/1)
|
case report
|
Bouwsma et al. [59]
|
1
|
1
|
1
|
0 % (0/1)
|
1 (100 %)
|
37
|
0 % (0/1)
|
0 % (0/1)
|
case report s/p several successful inseminations prior to HIFU
|
Millan Cantero et al. [60]
|
3
|
3
|
4 (in 3 women)
|
0 % (0/4)
|
4 (100 %)
|
36–41
|
0 % (0/4)
|
25 % (emergency C-section) (1/4)
|
|
Zaher et al. [61]
|
1
|
1
|
1 (1st IVF cycle after HIFU)
|
0 % (0/1)
|
1 (100 %)
|
45
|
0 % (0/1)
|
100 % (emergency C-section) (1/1)
|
case report s/p 4 unsuccessful IVF attempts prior to HIFU
|
Qin et al. [48]
|
435
|
8
|
24 (16 women with unplanned pregnancies)
|
8.3 % (2/24)
|
7
|
n. s.
|
n. s.
|
n. s.
|
15 elective abortions (Chinese study group)
|
Kamp et al. [35]
|
54
|
n. s.
|
8
|
0 % (0/8)
|
7
|
n. s.
|
n. s.
|
43 % (3/7)
|
1 lost to follow-up
|
Total, insofar as figures can be calculated
|
> 579#
|
> 18#
|
≤ 101*
|
17.8 % (18/101)*
|
≤ 49*
|
28–49#
|
~ 5.9 % (4/67)*, #
|
33.3 % (13/39)*, #
|
11 ongoing pregnancies 22 abortions 1 lost to follow-up
|
Several aspects must be given additional consideration in this context. It must be
assumed that all
pregnancies published before 2010 occurred in women who were treated using a treatment
unit from the
company GE/Insightec. As the review by Rabinovici et al. [24] published
in 2010 is based on a registry held by this company, it is not possible to exclude
the possibility
that individual pregnancies were listed twice (e.g., as a case history and as part
of the review),
and at least in one case [44], this is highly probable (E. Stewart, pers.
communication). Since then, the same authors have presented updated evaluations of
the registry at
various conferences with case numbers > 100 [45], [46], but these have not yet been published in full. The outcomes described
in the presentations do not differ in any essentials from the study published in 2010.
The inclusion
of the results obtained with units from a second manufacturer in a common registry
should make a
systematic evaluation of higher numbers of pregnancies possible [47].
The work of a Chinese study group [48] which reported pregnancy outcomes
after ultrasound ablation of uterine fibroids was also included in [Table
1]. It should be noted that in this study target volumes were monitored sonographically
and not using MRI; moreover the authors reported a high rate of elective abortions
in subsequent
pregnancies. The article does not indicate to what extent country-specific population
policies could
be partly responsible for the rate of elective abortions.
The literature on fertility after HIFU/MRgFUS treatment remains limited, but the existing
literature
appears to show that fertility may be preserved after HIFU/MRgFUS treatment [24]. Two important aspects which are strikingly different to uterine artery embolization
done prior to pregnancy will be discussed in more detail below.
Risk of miscarriage after HIFU
In all statements on the rate of miscarriages in a post HIFU/MRgFUS cohort, both the
age of the
mother and the “basic risk” of a miscarriage when fibroids are present in the uterus
must also be
taken into consideration, as both of these factors can independently have a negative
impact on the
rate of miscarriages. Hypothetically, changes in position during fibroid degeneration
could even
increase the risk of miscarriage, similar to results reported for UAE [49]. In contrast to the data available for UAE procedures [12], there are currently no comparative prospective data on women with fibroids who
have not
had HIFU treatment. But the largest published collection of case histories [24] included in [Table 1] shows that the risk of miscarriage
after HIFU/MRgFUS does not appear to be significantly higher compared to an age-matched
control
group of patients wanting to have children in the literature: the rate of miscarriages
after
IVF/ICSI reported for women wanting to have children is also around 20 % ([Table 2]) [50].
Table 2 Comparison of abortion rates in this publication with a historical
cohort (from [12] and cohort of women who had therapy to
conceive [50]; (Table analogous to [11]).
|
Evaluable pregnancies after HIFU treatment (n = 101)
|
Patients with untreated fibroids (n = 1 121)
|
German IVF registry (n = 13 841)
|
Number of miscarriages
|
18
|
185
|
2 564 (excluding extrauterine pregnancies)
|
Rate of miscarriages
|
17.8 %
|
16.5 %
|
18.52 %
|
Obstetrical outcome after HIFU
To answer the question whether pregnancies are at particular risk if the mother has
previously had
HIFU/MRgFUS treatment, we will need to look at the results of prospective randomised
clinical
trials. But no such trials comparing outcomes for women who did not have treatment
and women who had
uterine fibroid enucleation with outcomes for women treated with HIFU/MRgFUS have
been done to date.
However, comparisons of current data with outcomes reported for historical cohorts
[11] show that there are no indications of complication rates being higher
intrapartum after HIFU/MRgFUS. It is also important to note that there are no reported
cases of
peripartal haemorrhage after HIFU/MRgFUS, in contrast to UAE where peripartal haemorrhage
occurred
after UAE due to significantly higher rates of placentation disorders [51]. It is also important to highlight the low rate of preterm births (< 10 % in all
reports) and to mention the high rate of Caesarean sections, which are common clinical
practice in
industrialised countries ([Table 3]). The rates of elective C-sections
among women with fibroids treated with HIFU/MRgFUS could be due to a wish expressed
by the patient
herself, to an increased need for safety or due to uncertainty on the part of the
physician.
Table 3 Comparison of C-section and preterm birth rates in this paper with a
historical control cohort of fibroid patients (from [12] and
from a normal population giving birth in a hospital [53];
Table analogous to [11]).
|
Evaluable pregnancies after HIFU treatment
|
Patients with untreated fibroids
|
Normal population (n = 34 711)
|
Caesarean section rate
|
33.3 % (13/39)
|
48.5 % (2 098/4 322)
|
25.9 %
|
Preterm birth rate
|
5.9 % (4/67)
|
16 % (183/1 145)
|
9.1 %
|
It is still unclear to what extent scarred areas in the uterus after HIFU/MRgFUS treatment
will
remain stable during labour. Given that rates of uterus rupture in a “normal cohort”
of untreated
women without uterine scarring are very low, further studies in larger cohorts are
necessary.
Conclusion
For patients who may potentially want to have children, the role of HIFU/MRgFUS as
a treatment option for
uterine fibroids has not yet been sufficiently clarified.
At present there are only a few retrospective studies and the results of these studies
do not provide
sufficient evidence for any statement to be made about the impact of HIFU/MRgFUS treatment
on fertility
rates and pregnancy outcomes. There are still no prospective comparative studies (fibroid
enucleation
vs. HIFU/MRgFUS), although the need for such studies was emphasised some time ago
[52].
For people searching for information/women with fibroids who wish to have children,
a statement whether
HIFU/MRgFUS treatment is associated with additional reproductive risks or, instead,
could potentially
improve fertility is important.
While data from reviews and case histories of preoperative uterine artery embolization
are available
[53], similar information on the use of targeted preoperative HIFU/MRgFUS
treatment to reduce fibroid size and bleeding tendency is currently still lacking.
Based on the publications to date, the following preliminary conclusions can be drawn:
-
The currently existing but limited evidence does not suggest that HIFU/MRgFUS treatment
should
replace surgical fibroid removal as the method of choice for women who require treatment
of
their fibroids to improve fertility. This was confirmed again by the existing consensus
recommendation.
-
For patients with symptomatic fibroids who may wish to have children in the future
but do not
immediately wish to have children, the data on the long-term impact of HIFU/MRgFUS
treatment on
fertility are still insufficient, but to date there is no evidence of any relevant
impairment of
fertility after HIFU/MRgFUS treatment.
-
The existing case series of small patient cohorts offer no indications of an increased
risk for
miscarriage or increased rates of bleeding postpartum after prior HIFU/MRgFUS treatment.
-
Further studies of larger cohorts must focus particularly on the issue of whether
scarred uterine
tissue after HIFU/MRgFUS treatment remains stable during labour.
-
Currently, HIFU/MRgFUS treatment for fibroids can only be recommended to women with
fibroid-associated subfertility who strictly reject surgical treatment or who have
a very great
or inacceptably high surgical risk. It should also be discussed whether pregnancies
with their
associated risks are justifiable in these women.
-
The data are still insufficient to answer the question whether a “latency period”
before becoming
pregnant to allow the fibroid to shrink or change its size should be recommended to
patients
treated in exceptional cases with HIFU/MRgFUS. Individual published cases have reported
very
short periods of just a few months [24] between HIFU/MRgFUS treatment
and the start of a pregnancy successfully carried to term.
Acknowledgement
We would like to thank Mr Oliver Kuty for his excellent photography.