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also at high risk of developing OHSS, underwent normally timed follicular
aspiration of both ovaries. No cases of severe OHSS occurred in the aspiration
group compared to 16 cases in the control group (p < 0.0005).


LUTEAL PHASE SUPPORT
Luteal Phase Support with Progesterone
GnRH agonist long protocols became the standard of care for IVF protocols
in the 1980s. It became apparent that the prolonged pituitary recovery from
downregulation during the luteal phase resulted in luteal phase de¬ciency
(Smitz et al., 1992; Donderwinkel et al., 1993; Stoufer, 1990). Corpus luteum
could be rescued by the administration of hCG which became the standard of
care for luteal support during the late 1980s (Fauser and Macklon, 2004). A
meta-analysis by Soliman et al. (1994) combining results from 18 randomized
trials demonstrated an increase in IVF pregnancy rates with supplementation.
While the outcome was better than compared with progesterone, OHSS
developed in 5% of patients receiving hCG supplementation. Because of the
association between hCG and OHSS, luteal phase progesterone supplementa-
tion replaced hCG support in patients at high risk of developing OHSS
(Rizk and Smitz, 1992), and over the years, for all patients undergoing IVF
(Penzias, 2002). A recent meta-analysis (Pritts and Atwood, 2002) concluded
that intramuscular hCG or intramuscular progesterone are equally ef¬cacious
in improving IVF outcome compared with no treatment. Furthermore,
intramuscular progesterone was slightly more effective than oral or vaginal
administration, and implantation rates were slightly improved with the
addition of oral estrogens to progesterone (Pritts and Atwood, 2002; Fauser
and Macklon, 2004).


Luteal Phase Progesterone and Estradiol vs. hCG
In a prospective, randomized trial including 945 IVF cycles, the ef¬ciency of
high-dose progesterone and estradiol administration during the luteal phase
180 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




was evaluated for the prevention of OHSS (Schwarzler et al., 2003). After
ovulation induction, patients were allocated by a series of computer-generated
random numbers to receive either 5000 IU of hCG, four and eight days after
embryo transfer (n ¼ 534), or 500 mg hydroxyprogesterone caproate and 10 mg
estradiol valerate on days 2, 6, 10 and 14 after embryo transfer (n ¼ 411) by
intramuscular injection. A total of 163 women (30.5%) in the hCG group and
22 women (5.4%) in the estradiol“progesterone group developed signs of
OHSS (p < 0.0001). The authors suggested that steroidal ovarian suppression
during the luteal phase is a promising tool to reduce the incidence and severity
of OHSS in patients at high risk of developing this syndrome, without
compromising the pregnancy rate.


CRYOPRESERVATION OF EMBRYOS AND SUBSEQUENT
REPLACEMENT

The availability of cryopreservation has made it possible not to lose the cycle
and to achieve pregnancy by replacement of the frozen-thawed embryos
at a later cycle (Table VII.18). In one of the ¬rst reports, Amso et al. (1990)
presented four cases in which cryopreservation and later replacements resulted
in pregnancies and avoided hyperstimulation. Salat-Baroux et al. (1990)
electively deferred fresh embryo transfer in 33 high-risk patients monitored
for the development of OHSS. Embryo transfer was performed in 87% of the
cycles and there was only one severe case of OHSS.
Wada et al. (1991; 1992a, b; 1993a, b) performed a series of studies to
address the relevance of cryopreservation as a secondary prevention method. In
the ¬rst study, the authors collected all IVF cycles with (n ¼ 203) and without
(n ¼ 38) embryo transfer. The groups were classi¬ed according to their estradiol
level and whether or not pregnancy occurred. No cases of OHSS occurred in the
non-embryo transfer group when estradiol levels were below 3500 pg/ml.
However, in the cycles when embryo transfer occurred, OHSS was observed
in 12% of pregnant patients and 2.3% of non-pregnant patients with estradiol
levels <3500 pg/ml. When estradiol levels were 43500 pg/ml, OHSS occurred
in 60% (8%, severe) in the non-transfer group but was 11% and 57% (28%,
severe) in non-pregnant and pregnant women with embryo transfer. Wada
et al. (1992a) suggested that withholding transfer does not reduce the incidence
of OHSS in women with estradiol levels 43500 pg/ml. The same investigators
(Wada et al., 1992a) reported a series of 78 cases of elective cryopreservation
for estradiol levels 43500 pg/ml on the day of hCG. OHSS occurred in 27%,
of which severe OHSS was detected in 8%. Frozen-thawed embryo replacement
was performed subsequently with 71.8% of embryos surviving, a pregnancy
rate of 26% and an implantation rate of 11.7%. This pregnancy rate was
comparable to the pregnancy rate of IVF patients in Manchester during that
period of time.
In the third study, the authors compared two periods (Wada et al.,
1993a). During the ¬rst period no cryopreservation of embryos was done and,
181
CRYOPRESERVATION OF EMBRYOS AND SUBSEQUENT REPLACEMENT




furthermore, hCG was given for luteal phase supplementation (Wada et al.,
1993a). During the second period cryopreservation was employed. OHSS
occurred in 9.5% in the ¬rst period and 8.8% in the second period. More
importantly, OHSS in its severe form occurred in 6% when cryopreservation
was performed compared with 60% when pregnancy occurred in women with
estradiol levels 43500 pg/ml. Wada et al. (1993a) concluded that cryopreserva-
tion of all embryos from women with high estradiol levels would reduce
the severity of OHSS but not its incidence.
Pattinson et al. (1994) in a retrospective study of 69 patients at risk of
OHSS cryopreserved all embryos and delayed embryo transfer, resulting in
a low incidence of severe OHSS (1.8%). The subsequently replaced embryos
resulted in a 25% pregnancy rate.
Queenan et al. (1997) reported that cryopreservation of all prezygotes in
patients at risk of severe hyperstimulation did not eliminate the syndrome,
but the chances of pregnancy were excellent with subsequent frozen-thawed
transfers. In their series of 15 patients, two patients (13%) developed severe
OHSS and two others developed moderate OHSS. Subsequent transfer of the
cryopreserved embryos resulted in a 58% pregnancy rate.
Ferraretti et al. (1999) performed a prospective randomized study on
125 patients at risk of OHSS. All the patients had serum estradiol ¸1500 pg/ml
on the day of hCG, and 15 or more oocytes were retrieved. One group of
patients had all their embryos cryopreserved at pronucleate stage (n ¼ 58) and
the control group had fresh embryo transfers (n ¼ 67). No cases of OHSS
occurred in the group with cryopreservation, while four patients developed the
syndrome in the group that had fresh embryo transfers. The implantation rate
was slightly but not signi¬cantly lower in the cryopreserved group. Ferraretti
et al. (1999) suggested that elective cryopreservation of all zygotes might
prevent the risk of OHSS.


Is Continuation of GnRH Agonist Necessary to Prevent OHSS?
Studies addressing the issue of continuation of GnRH agonist have given
con¬‚icting results. Wada et al. (1992b) studied 28 women undergoing IVF
using hMG and buserelin for stimulation. Group I consisted of 17 women given
hCG (10 000 IU) to trigger ovulation, and the resulting embryos were
cryopreserved because of the high risk of OHSS since their serum estradiol was
43500 pg/ml. Six women continued buserelin therapy in the luteal phase and
11 did not. In the second group, consisting of 11 patients, the hMG injections
were discontinued because of their exaggerated ovarian response and the hCG
was cancelled. Six of these 11 women continued the buserelin until the onset
of menses and ¬ve did not. In both groups, the ovarian response to the
induction of ovulation, as judged by the number of follicles and the serum
estradiol concentration, was similar for those who did or did not continue
buserelin therapy. There was no difference in the rate of ovarian quiescence,
as judged by the fall in the serum estradiol concentration following the
stimulation, between those women who did or did not continue the buserelin
Table VII.18 Cryopreservation as a prevention of OHSS




182
Reproduced with permission from Delvigne and Rozenberg (2002). Hum Reprod Update 8:559“77

OHSS with
Pregnancy with cryo-preservation
Study Design Control group (n) Risk factors (n) thawed embryos (vs. control) Comments

Amso et al. (1990) observational “ 25 to 45 follicles, 100%/trsf * 10% moderate “
abdominal
Salat-Baroux et al. (1990) observational “ 27%/trsf 3% severe “
E2 4722 + 1190 pg/ml
the day
Wada et al. (1991) retrospective pregnant (49) and NA (38) “ 18% all grades, 0% if E2 <3500 pg/ml;
observational non-pregnant (154) 1 with cryopreservation
only if E243500 pg/ml
(18 and 4%)
Wada et al. (1992b) retrospective “ 26%/trsf 27% all grades “
E243500 pg/ml (78)
observational (8% severe)
Wada et al. (1993a) retrospective historical group 21%/trsf 8.8%, only 6% severe, 7.8% survival embryos
E243500 pg/ml (136)
observational without (9.5%, 60% severe)
prevention (105)
Pattinson et al. (1994) retrospective general IVF 25.2%/trsf 1.4% (1.8% severe) 84% survival embryos;
E2 ¸ 4086 pg/ml and
without risk 450 follicles (69) 40%/patient 14% canceling
Tiitinen et al. (1995) prospective general IVF 32.6%/trsf 4.3% moderate 22.7% implantation rate
E242724 pg/ml
without risk and/or420 65.2%/patient (vs. 0.5%)
oocytes (33)
Awonuga et al. (1996) retrospective 17%/trsf 3% severe; signi¬cantly higher PR in
E242724 pg/ml E242724 pg/ml
controlled and/or415 and/or415 3% moderate; controls (35%; p < 0.05)
oocytes (52) oocytes (65) (3.8% severe and
moderate) NS**
Queenan et al. (1997) prospective, “ 58%/trsf, 67% 13% severe, “
E244500 pg/ml
noncontrolled and415 oocytes (15) delivery/patient 13% moderate
Benavida et al. (1997) retrospective coasting 25.6%/trsf 7.6% (4.5%) NS “
E243000 pg/ml (26)
controlled group (22)
Ferraretti et al. (1999) prospective 35.4%/trsf, 0% (versus 6%) “
E241500 pg/ml E241500 pg/ml
randomized and415 and415 oocytes (58) 48.3% per patient
oocytes (67)

* Trsf ¼ embryo transfer
** NS ¼ non signi¬cant
183
SELECTIVE OOCYTE RETRIEVAL IN SPONTANEOUS CONCEPTION CYCLES




therapy in either group. The serum LH concentrations remained low in all
women in both groups. The authors concluded that the omission of buserelin
after the discontinuation of hMG in women at risk of developing OHSS does
not affect subsequent ovarian quiescence.
Endo et al. (2002) designed an open-controlled clinical trial at three
infertility centers in Sapporo, Japan to determine the impact of continuation of
GnRH agonist for one week after hCG injection on the prevention of OHSS
following cryopreservation of all pronuclear embryos. A total of 138 patients at
risk of OHSS during IVF were assigned either to Group I with elective
cryopreservation of all pronuclear embryos (n ¼ 68), or to Group II with
continuation of GnRH agonist administration for one week after hCG injection
following elective cryopreservation (n ¼ 70). The embryos were transferred in
subsequent hormone replacement cycles. A total of 10% of patients developed
severe OHSS, requiring hospitalization because of the remarkable increase
of ascites in the upper abdomen and hemoconcentration in the elective-
cryopreservation-alone group. At the same time, no patients developed severe
OHSS in the GnRH agonist continuation group. Endo et al. (2002) concluded
that GnRH agonist continued one week after hCG injection prevented severe
early OHSS following elective cryopreservation of all embryos. In addition,
they concluded that this treatment is safe and cost-bene¬cial, and also
recommended that this treatment should be performed in patients at risk of
developing OHSS.
In a Cochrane review, D™Angelo and Amso (2002b) identi¬ed studies, two
of which met the inclusion criteria. In one of the two studies (Shaker et al.,
1996), cryopreservation was compared with intravenous albumin, and in the
other study, cryopreservation of all embryos was compared with fresh embryo
transfer and intravenous albumin was administered to all the patients which
may have in¬‚uenced the severity of OHSS. When elective cryopreservation
was compared with fresh embryo transfer, no difference was found between
the two groups. This Cochrane review suggests that there is insuf¬cient
evidence at present to support routine cryopreservation, and also insuf¬cient
evidence to be able to determine the relative merits of intravenous albumin
and cryopreservation.


Cryopreservation: Conclusion
Cryopreservation would signi¬cantly decrease late-onset OHSS and the overall
incidence of severe cases. However, OHSS will not be completely prevented
if cryopreservation is the only tool applied in patients at high risk.


SELECTIVE OOCYTE RETRIEVAL IN SPONTANEOUS
CONCEPTION CYCLES

Selective oocyte retrieval was used for prevention of OHSS and multiple
pregnancies in spontaneous conception, by puncturing most of the ovarian
184 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




follicles 35 h after hCG administration, as in IVF programs. The remaining
intact follicles may still result in singleton or twin pregnancy (Belaish-Allart
et al., 1988).


COMBINED APPROACH FOR THE PREVENTION
OF SEVERE OHSS

Clinicians faced with an over-responsive patient should be prepared to employ
more than one method at the same time for prevention. It would be advisable
to decrease the dose of gonadotrophin followed by coasting. A lower dose of
hCG to trigger ovulation and progesterone for luteal phase support should
be employed in sequence to avert the serious consequences of severe cases.
Isik and Vicdan (2001) compared the results of a combined approach in
87 patients considered at high risk to those in 274 low-risk patients. Their
combined approach consisted of step-down administration of gonadotrophins,
a lower dose of hCG, intravenous albumin at the time of oocyte retrieval and
progesterone usage for luteal phase support. There was only one moderate
and no severe cases of OHSS in the high-risk group, while ¬ve moderate and
one severe case of OHSS developed in the control group of low-risk patients.
The authors concluded that the combined approach is an effective approach
for the prevention of OHSS in high-risk patients. I cannot overemphasize this
message, as the ¬nal objective is complete prevention of severe cases, and not
testing the ef¬ciency of one or another method of prevention.


VEGF RECEPTOR BLOCKADE

Rizk and Nawar (2004) critically evaluated the place of VEGF receptor blockade
in the management and prevention of OHSS. Since VEGF is a mediator of the
OHSS cascade, receptor blockade could prove to be a wise step in the preven-
tion of this syndrome. In an ASRM prize-winning presentation, Gomez et al.
(2001) investigated the release and production of VEGF by human granulosa
cells and luteal cells in experimental animals who developed OHSS. In a second
series of experiments, the authors investigated whether VEGF receptor 2
blockade would prevent OHSS. They concluded that the ovary is the major
source of VEGF in hyperstimulated animals. VEGF-121 and 164 isoforms
were differentially expressed. The increased vascular permeability through the
VEGF receptor 2 and its speci¬c inhibition prevents increased vascular
permeability.


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