How to deal with fluid in the endometrial cavity

during assisted reproductive techniques

Rong-Huan Hea and Xiao-Ming Zhu
Purpose of review
Patients with endometrial cavity fluid (ECF) in assisted reproductive techniques (ARTs) are
poor in prognosis. This review presents the research development of ECF during ARTs,
particularly in treatment.
Recent findings
ECF patients with or without tubal infertility may represent a different clinical entity. ECF
impairs the ART outcome in tubal factor, but not polycystic ovarian syndrome, patients.
Actually, it was tubal infertility, not only hydrosalpinx, that was related to the development of
ECF. Both appearance time and accumulation amount of ECF are critical in the impact of ECF
on the ART outcome. Since excessive ECF (equal to or higher than
3.5mm in the anteriorposterior diameter) usually had a negative impact on the ART
outcome, postponing embryo transfer should be considered. A nonexcessive ECF
usually disappeared by the time of embryo transfer. The routine embryo transfer in these
ECF patients could yield the same ART outcome as in patients without ECF. If a
nonexcessive ECF persisted until the day of embryo transfer, particularly in patients with
nontube infertility, transvaginal sonographic aspiration could be an alternative of
treatment.
Summary
The treatment of ECF during ARTs should be individual according to the causes,
appearance time and accumulation amount of ECF.
Keywords
assisted reproductive techniques, endometrial cavity fluid, polycystic ovarian
syndrome, treatment, tube infertility

Introduction
Endometrial cavity fluid (ECF) is a fluid accumulation
within the endometrial cavity. It is not a common complication
during assisted reproductive techniques
(ARTs), but it, especially the excessive one, is detrimental
to embryo implantation and thus negatively impacts
the ART outcome [1__,210]. The relevant factors of
ECF during ARTs remain unclear, much less the
relevant treatments [1__,210]. In this short review,
the recent developments of ECF during ARTs are highlighted
and discussed, with particular emphasis on the
development of ECF treatment.

The relevant factors of ECF development

during assisted reproductive techniques

The relevant factors of ECF during ARTs have been

documented a lot. Tubal infertility (including hydrosalpinx)
[1__,35,7,9], polycystic ovarian syndrome (PCOS) [3,7], poor ovarian response [6],
physiological generation
by the genital tract [2], and so on were all included in
this respect.
As to tubal infertility, a recent retrospective investigation
based on the clinical data of 1557 infertility patients
enrolled for the IVF program showed again that it was
tubal infertility, not only hydrosalpinx, that was related to
the development of ECF during ARTs [1__]. In that
clinic investigation, over half (28/46 cases, 60.87%) of
ECF patients had tubal infertility and only 12 cases
(12/46 cases, 26.09%) had visible hydrosalpinx on ultrasonography
before ovarian stimulation. In those patients
with tubal infertility, subclinical uterine infections or the
subsequent drainage imperfection of uterine or fallopian
tube fluid might be associated with the development of

ECF [5,8].
As to PCOS as a relevant factor of ECF during ARTs,
over-reactive fluid generation and secretion of the genital tract or the peritoneal
membrane during ARTs in PCOS
patients might contribute to the development of ECF
[2,3,11]. Here, higher levels of serum estrogens or gonadotrophins
and the relevant changes of aquaporins in
expression and fluid transport might be a mechanism for
ECF development [2,3,11,12].
Key points
_ Both tubal infertility and polycystic ovarian syndrome
are the two main factors related to the
development of endometrial cavity fluid (ECF).
_ It was excessive ECF (equal to or higher than
3.5mm in the anteriorposterior diameter) that
would have a negative impact on the assisted reproductive
technique outcome, especially in those
patients with tubal infertility and with the ECF
persisted until the implantation period.
_ In ECF patients with nontube infertility, embryo
transfer can be performed safely if the ECF has
disappeared and not returned by the day of embryo
transfer.
_ Removing ECF with an embryo transfer catheter
immediately before embryo transfer may be a successful
method of treatment to those nonexcessive
ECF patients with nontube infertility.
_ In patients with excessive ECF, particularly those
with tubal infertility, postponing embryo transfer
with medical or surgical intervention should, however,
be considered.

The relevant impact of ECF on the assisted

reproductive technique outcome

The ART cycles with ECF were considered by most

researchers to have low implantation and pregnancy rates
as well as a high incidence of cycle cancellation [1 __,39].
A recent retrospective controlled investigation in this
aspect demonstrated that no significant difference was
found in clinical pregnancy rate between the patients
with their ECF below 3.5mm in the anteriorposterior
diameter of ECF and the control group (35.48 vs. 30.47%,
P>0.05). No clinical pregnancy was found among those
patients with their ECF equal to or higher than 3.5mm in
the anteriorposterior diameter [1__]. This investigation
indicates that it was excessive ECF (equal to or higher
than 3.5mm in the anteriorposterior diameter), not the
nonexcessive ECF (<3.5mm in the anteriorposterior
diameter), that would have a negative impact on the ART
outcome. The presence of a relatively small amount of
ECF at the day of oocyte retrieval did not appear to
negatively impact the ART outcome. This was similar to
those in this respect described previously in some
relevant studies [2,3]. The researchers of those studies
held that ECF observed in patients with PCOS or without
tubal infertility may represent a different clinical
entity from that in patients with tubal diseases. If the
ECF was generated physiologically or reactively by the
genital tract during ARTs, the clinical pregnancy rate of
the involved ECF patient was not worse than that of

those patients without ECF and no impact of this kind of

ECF on embryo implantation was found.
As mentioned above, the amount of ECF is critical in the
impact of ECF on the ART outcome. Excessive ECF
would have a negative impact on the ART outcome.
Among the previous relevant studies, only two were
conducted on the effects of ECF amount on the ART
outcome [1__,4]. The earlier one reported that the ECF
greater than 3mm in the largest diameter of the endometrial
cavity was a large amount of ECF and that the
large amount of ECF was usually detrimental to embryo
implantation [4]. In the later study, the large amount of
ECF was defined as the ECF equal to or higher than
3.5mm in the anteriorposterior diameter [1__]. The
small amount of ECF (<3.5mm in the anteriorposterior
diameter) usually disappeared by the time of embryo
transfer; whereas the large amount of ECF usually persisted
and even enlarged until during implantation
period. The presence of a small amount of ECF did not appear to negatively impact
the ART outcome, when
compared with that of the control patients without ECF,
whereas the large amount of ECF would do [1__].
The time of ECF development is also important in the
impact of ECF on the ART outcome. Many studies
demonstrated that the ECF detected during ovarian
stimulation usually had a negative impact on the ART
outcome [3,6,7,9]. If ECF transiently developed after
receiving a human chorionic gonadotropin (HCG) injection
and disappeared by the day of embryo transfer, the
ECF did not impact the clinical pregnancy rate [1__,3,6].

The relevant treatment of ECF during assisted

reproductive techniques
There is a mostly accepted opinion by clinicians that
ECF during ARTs could be observed in patients with
both tubal and nontubal factors [1__,3,4]. ECF observed
in patients with or without tubal infertility may represent
a different clinical entity [2,3]. Both appearance time and
accumulation amount of ECF are critical in the impact of
ECF on the ART outcome [3,6,7,9]. Therefore, the
treatment of ECF during ARTs should be individual
according to the causes, the appearance time and the
accumulation amount of ECF. Any methods beneficial to
eliminate causes, to prevent fluid from over generation or
from entering the uterine cavity, to promote the drainage
of ECF, could be utilized to deal with ECF. The relevant
treatment options include expectant treatment, postponing
embryo transfer, transvaginal sonographic ECF
aspiration, and other subsidiary modifications and optimizations
in ARTs. Expectant treatment and postponing embryo transfer are two main kinds of
treatment options
that have proved effective in improving ART outcome in
patients with ECF. Transvaginal sonographic aspiration
may also be considered as a suitable alternative of treatment
if ECF persisted and was not excessive, but this
option has only been evaluated in a small sample and is
thus of less validity. New treatments and modifications
in ARTs may improve the ART outcome of patients
with ECF.

Expectant treatment

Expectant treatment is mainly used in patients with a

transient ECF during ARTs. Lots of ECFs during ARTs
were transient, particularly those generated physiologically
or reactively by the genital tract during ARTs in
patients without tube infertility [2,3,7]. A retrospective
investigation showed that the ratio of transient ECF in
patients with PCOS was 88.9% (24/27) [3]. Those transient
ECFs usually appeared after HCG administration
during ARTs or earlier during undergoing the ovarian
stimulation. Most of them were nonexcessive in volume
and disappeared before the day of embryo transfer
[1__,2,3,10]. The same embryo implantation rate and
clinical pregnancy rate were also observed after the
scheduled embryo transfer between those nontube-infertility
patients with and without ECF [2,3]. It was concluded
that, for those possibly transient ECFs, expectant
treatment could be used and the scheduled embryo transfer
could be conducted on time[1__,2,3].During expectant
treatment, continuous monitoring of the sequelae of ECF
is mandatory [8]. If the ECF persisted and even enlarged
until the scheduled day for embryo transfer, the subsequent
strengthened treatments, such as postponing
embryo transfer, transvaginal sonographic ECF aspiration,
and so on, should be considered [1__,310].

Postponing embryo transfer

Postponing embryo transfer is a mainstream treatment of
ECF during ARTs. It consists of embryo cryopreservation
and the subsequent optional frozen embryo transfer,
accordingly and medical and surgical interventions
[1__,310]. The treatment was originally designed for
the treatment of tube-infertility patients with ECF,
particularly those with excessive ECF during ARTs
[1__,4,7]. Here, the defining value of excessive ECF
was the anteriorposterior diameter of ECF equal to
or higher than 3.03.5mm [1__,4]. The excessive ECF
state during ARTs usually persisted and even enlarged
until during implantation period. In this situation, the
ART outcome of embryo transfer usually was poor [1__,4].
That is why many researchers recommend postponing
embryo transfer as the main treatment of this kind of
ECF [1__,4,7]. Through postponing embryo transfer and
medical and surgical interventions, a physiological state of uterine cavity and
endometrium for embryo implantation
and development, and therefore a better ART
outcome, could be expected.
As to the patients with nontube infertility and with
excessive ECF, such as the patients with PCOS, postponing
embryo transfer and some medical interventions
during the subsequent frozen embryo transfer program
are recommended [10,13,14]. Here, the supplemented
medical intervention, including a mild ovarian stimulation
or a modified natural cycle [15_,16_], is intended
to avoid ovarian hyperstimulation and thus to obtain a
better milieu of uterine cavity and endometrium for the
subsequent frozen embryo implantation and development.
The use of the natural cycle in this respect has
been described in one retrospective study [13]. Patients
with hydrosalpinges undergoing IVF in a natural cycle
(n72) demonstrated significantly higher pregnancy
rates compared with patients who received controlled

ovarian hyperstimulation (n49; 18 vs. 7%, P<0.05)

[13,14].
In the patients with tube infertility and, particularly,
with a detectable hydrosalpinx [14,17], surgical intervention
should be supplemented as a part of the treatment
of postponing embryo transfer. Before the optional
frozen embryo transfer, the underlying pathology in
patients with tube infertility, particularly in those
with a detectable hydrosalpinx, should be corrected
[3,5,8,14,17,18__]. Performing the supplemented surgical
intervention is thought to improve the likelihood of
successfulARToutcome in patients with hydrosalpinges
[3,5,8,18__].
Surgical interventions for hydrosalpinx include salpingectomy,
proximal tubal occlusion, aspiration of the
hydrosalpinx fluid, or salpingostomy [14,18__]. A recent
Cochrane database systematic review showed that both
salpingectomy and proximal tubal occlusion are alternatives
of treatments in improving ART outcome in
patients with hydrosalpinges [18__]. Further research is
required in this respect to assess the value of aspiration of
hydrosalpinges prior to or during ARTs and the value of
tubal restorative surgery [18__]. Throughout the different
comparisons, no significant differences were seen in
adverse effects of these kinds of surgical treatments for
hydrosalpinx [18__].
If the ECF persisted until the embryo transfer period,
transvaginal sonographic ECF aspiration could be used as
an alternative treatment of ECF [4].

Transvaginal sonographic ECF aspiration

Transvaginal sonographic ECF aspiration was originally

designed for the treatment of patients with ECF who did not wish to postpone the
embryo transfer during their
ARTs [5,8,19]. A successful pregnancy could be conceived
in a patient with tube infertility after up to 7ml
volume of ECF was aspirated at the time of embryo
transfer [5]. Now, this kind of treatment has been developed
to a suitable alternative of treatment only for
patients with their ECF persisted until at the day of
embryo transfer and not excessive in volume, especially
those with nontube infertility, for example, the ECF
in patients with PCOS [3,19,20]. The nonexcessive
ECF developed in PCOS patients is usually reactive,
self-limited and, thus, seldom recurrent, unlike the high
risk of ECF recurrence after the transvaginal fluid aspiration
in patients with hydrosalpinges [8,19,20]. The
observation of the same ART outcome in nontubeinfertility
patients with transient ECF as that without
ECF also provided a support to the treatment of
transvaginal ECF aspiration without a delay of embryo
transfer [2,3].
Removing ECF with a transvaginal embryo-transfer
catheter was usually conducted immediately before
embryo transfer [5]. The on-time embryo transfer could
be conducted in either transvaginal intrauterine
embryo transfer or laparoscopic tubal embryo transfer
[2,5]. The administration of prophylactic antibiotics
was recommended as a subsidiary medical treatment
to the transvaginal aspiration [5,8,14]. Because of no
delay in embryo transfer, this kind of treatment of

ECF could avoid some disadvantages in biology and

psychology when compared with the treatment of postponing
embryo transfer, such as avoiding a possibly
decreased implantation rate from frozen embryo transfer,
and avoiding frustration and disappointment for
the infertile couple [5].
As to the impact of the removal operation of ECF on
embryo implantation, a prospective matched controlled
study was performed [21]. In that study, no reduction of
embryo implantation was found after the ECF aspiration
prior to embryo transfer. Both biochemical and ongoing
pregnancy rates per embryo transfer were compared with
those in matched control patients (respectively, 36 vs.
33%, P0.84; 33 vs. 30%, P0.85). So it is concluded
that ECF aspiration prior to embryo transfer is a well
tolerated operation and, possibly, to improve the ART
outcome by facilitating the process of implantation,
namely adhesion of the embryo to the endometrial surface
[21].

Conclusion

Both tubal infertility and PCOS are related to the development

of ECF. ECF patients with or without tubal
infertility may represent a different clinical entity. Apart
from causes, the appearance time and accumulation amount of ECF are critical in
the impact of ECF on
the ART outcome. The treatment of ECF should be
individual according to the causes, the appearance time
and the accumulation amount of ECF. New treatments
and modifications in ARTs may improve the ART outcome
of patients with ECF [15_,16_].