Prevention of ovarian hyperstimulation syndrome

Prevention of Ovarian
Hyperstimulation Syndrome
(OHSS)
Yasser Saad El Kassar
A. professor Obest./Gyn.
Alex. University

Definition
It is an iatrogenic complication of controlled ovarian
stimulation (COS).
COS is needed for production of multiple ovarian follicles
during assisted conception cycles to increase the number of
oocytes available for collection.
OHSS, however, is characterized by an exaggerated response
to this process.

Incidence
The incidence of moderate to severe OHSS is between
3.1 and 8% of in vitro fertilization (IVF) cycles but can be
as high as 20% in high risk women.
OHSS has been documented to arise spontaneously
either in conjunction with clomiphene or with
gonadotrophins use.

Navot et al. classification for OHSS
Mild OHSS
Abdominal bloating
Mild abdominal pain
Ovarian size usually < 8 cm

Moderate OHSS
Moderate abdominal pain
Nausea ± vomiting
Ultrasound evidence of ascites
Ovarian size usually 8 to 12 cm

Severe OHSS
Clinical ascites (occasionally
pleural effusion)
Oliguria
Haemoconcentration:
hematocrit (> 45%)
Hypoproteinemia
Ovarian size usually > 12 cm

Critical OHSS
Tense ascites or large pleural effusion
Hematocrit (> 55%)
White cell count > 25 000
Oligouria/anuria
Thromboembolism
Acute respiratory distress syndrome

ASCITES
Fluid
extravasation
Angiogenic
activity
???
Vascular
Permeability
ANASARCAHYDROTHORAX
Pathophysiology:
hCG
VEGF-A
RAS

Dahl Lyons, 1994; Mathur, 2000
EARLY
OHSS
LATE
OHSS
hCG 3-9 days 10-17 days
Ovarian
response
Pregnancy
Classification:
hCG

Prevention is better than cure
Being aware of the risk factors for OHSS will allow
clinicians to predict its occurrence and so reduces its
incidence during ovulation induction wit gonadotrophins.
We have primary and secondary risk factors.

Primary Risk Factors
1. PCOS
2. Young age
3. Low body weight
4. Previous OHSS
5. AMH ( Anti-mullerian hormone)
6. AFC ( antral follicle count)

Secondary Risk Factors
1. Rapidly rising E2 level
2. large number of developing follicles on the day of hCG
administration
3. large number of oocytes retrieved
None of the above predictors are independently
predictive of OHSS.

Before stimulation After stimulation

Cutoff points for OHSS risk
1. AMH > 3.4 ng/ml.
2. AFC > 25.
3. development of > 25 follicles.
4. E2 > 3.500 pg/ml.
5. Oocytes retrieved > 25.
All are grade B evidence.

Primary Prevention of OHSS
1. Unifollicular Ovulation.
2. Individualizing COS Regimens ( i COS)
3. Alternatives for Triggering Ovulation
4. Avoiding hCG for Luteal Phase Support (LPS)

Unifollicular Ovulation
A. Reducing the Gonadotrophin Dose
B. GnRH Antagonist (GnRHan) protocol
C. Adjuvant MetforminTherapy
D. Aromatase Inhibitors (AIs)

Reducing the Gonadotrophin Dose
The minimum gonadotrophin dose should be used for OI
given its lower risk of OHSS. This favors a “step-up”
regimen over a “step-down” regimen.
In the “step-up” regimen, ovarian stimulation is initiated
with a low dose of FSH (i.e., 75 IU) and increases
every7days (i.e., 37.5 IU) until an ovarian response is
noted (follicle >10 mm).
This dose is then continued until the criteria for an
ovulatory trigger are met.

GnRH Antagonist (GnRHan) protocol
This allows less gonadotropin use than agonist protocol
and also less days of stimulation.
This allows avoiding hCG for ovulation triggering.
This protocol has a lower risk of OHSS and multiple
pregnancies and is cost effective
level 1b evidence

Adjuvant Metformin Therapy
Metformin exerts its influence in preventing OHSS by
inhibiting the secretion of vasoactive molecules, such as
VEGF, during OI, so modulates vascular permeability.
In the recent Cochrane Review by Tso et al, it was noted
that there was a lower risk of OHSS with metformin use.

Metformin reduced the risk of OHSS by 63% and
increased the clinical pregnancy rate without an effect
on live birth rates.
A daily dose between 1000 and 2000mg at least 2
months prior to COS is recommended for the purpose of
preventing OHSS.

Aromatase Inhibitors (AIs)
A recent Cochrane Review by Franik et al, failed to show
any difference in OHSS rates through utilization of AIs in
contrast to other methods of OI.
As such, AIs are not routinely recommended for
prevention of OHSS.
Letrozole can be used in luteal phase, in freeze-all cases,
to decrease the incidence of OHSS, but little evidence
available.

Individualised COS (iCOS)
One example of this can be seen through the study by La
Marca et al., where an algorithm was formulated based
on age, AFC, and FSH to calculate the FSH starting dose.
This algorithm was able to accurately predict ovarian
sensitivity and account for 30% of the variability of
ovaries to FSH.
Further research is required to prove cost- effectiveness
of this method.

Alternatives for Triggering Ovulation
The agent of choice for triggering ovulation should be
picked based on the risk of the woman for developing
OHSS.
No agent, however, completely eliminates the risk of
OHSS.
Exogenous hCG is the agent used for this purpose as it
mimics the ovulatory LH surge.

Exogenous hCG
Its long half-life (2.32 days) however causes prolonged
luteotrophic effects, multiple corpora lutea development,
and higher luteal phase P4 and E2 concentrations
There is a higher risk of OHSS and to solve this problem:
1. The lowest possible dose (i.e., 5000 IU) is used.
2. Avoid hCG in high risk women.

GnRH agonists (GnRHa) to trigger ovulation
It produces a more tempered and shorter midcycle
gonadotrophin surge (24–36 hours) in contrast to hCG by
stimulating pituitary LH secretion.
Theoretically, this LH surge should be sufficient to induce
ovulation without being prolonged enough to induce
hyperstimulation.

OHSS is virtually eliminated with GnRHa utilization
BUT in conjunction with a “freeze all” approach
which should be considered in high risk woman.
This is called OHSS – Free Clinic

There is good evidence that live birth rate (LBR) is lower
in fresh cycles after GnRHa trigger.
The mechanism for this:
1. Rapid and dramatic drop in hormonal LH support as
compared to hCG ( luteal phase insufficiency).
2. Poor final oocyte maturation.

Improve LBR with GnRHa
1. Freeze all embryos.
2. Co-trigger with 1500 IU hCG either:
A. Single dose--------------- reduced risk of OHSS.
B. 2 doses ( 2nd dose on day of OR or subsequent day),
increases risk of OHSS (3.4%).
3. Low dose of hCG for luteal support ( 1000, 500 or 250
IU every third day).
4. Estradiol supplementation in luteal phase.

Recombinant LH (rhLH)
It has a half-life of 10 hours, and a shorter and/or lower
LH peak, so this means:
it is expected to have a minimal risk of causing OHSS.
A Cochrane Review by Youssef et al. however, did not
show any difference in the risk for severe OHSS between
rhLH and urinary hCG.
It is associated with a lower pregnancy rate and a poor
cost benefit ratio.
Its routine use cannot be recommended for prevention of OHSS.

Avoiding hCG for Luteal Phase Support (LPS)
hCG, which is similar to LH in its physiological actions,
has been used effectively in LPS to improve LBR.
A Cochrane Review (M. van der Linden et al, 2011 ),
noted that it potentiated the risk of OHSS and also
showed no effect on live birth rate (LBR) and clinical
pregnancy rate (CPR).
In contrast, the use of progesterone (P) halves the OHSS
risk while significantly improving the LBR and CPR.
The routine use of progesterone over hCG is recommended for LPS.

Secondary Prevention of OHSS
It is directed to women who have undergone COS and
had an exaggerated response. The aim of interventions
in these cases is to prevent progression to OHSS.
This can be done by:
(A) Coasting.
(B) Cryopreservation of Embryos.
(C) Cycle Cancellation.

Coasting
Coasting is a preventative strategy by which
gonadotrophins are withdrawn when a certain E2
concentration and/or a critical number of follicles are
reached.
hCG trigger is subsequently delayed until E2 levels
significantly decrease or plateau.
Once the E2 reaches a “safe” level, hCG is administered
followed by oocyte retrieval and embryo transfer or
freezing depending on the E2 concentration.

It is generally employed for a period less than 3-4 days.
Coasting is a commonly used as a first line secondary
prevention strategy by clinicians.
Question marks remain however about the evidence
behind the procedure.

Coasting diminishes the granulosa cell cohort
Intheabsenceofgonadotropinstimulation,dominantfollicleswillcontinuetheir
growth,whileintermediateandsmalloneswillundergoatresia.
E2

• The granulosa cells aspirated from coasted
patients showed a ratio in favor of apoptosis,
especially in smaller follicles.
• VEGF protein secretion and gene expression in
granulosa cells especially in small and medium
follicles were reduced in coasting.

What happens when you start coasting?
Follicular growth will continue with the same rate.
E2 will continue to rise then will platform and then
decline.
When to stop gonadotropins?
When the leading follicles reach 14-16mm.
What is the safe E2 level?
< 3000 pg/ml.

Problems with coasting
1. Occasionally E2 drops markedly to very low levels and cycle
is canceled.
2. Difficulty in identification of oocytes in aspirated follicular
fluid after prolonged coasting.
3. Pregnancy rates appear to decrease while coasting during
prolonged gonadotropin-free periods.
Explanation for lower LBR:
because suspending gonadotropins may starve the granulosa
cells at a critical time of oocyte development when LH is
necessary.

D’Angelo et al., in their Cochrane Review, identified 4
RCTs which highlighted that there was no difference in
the incidence of moderate and severe OHSS with
coasting.
A lower number of oocytes were retrieved from the
coasting group, so they recommend that there was no
benefit of coasting in comparison to other interventions.

An earlier meta-analysis also came to the conclusion that
coasting may decrease the risk of OHSS in high risk
women but does not completely prevent it.
Coasting, however, seems to have no effect on live birth
rates and clinical pregnancy rates

Cryopreservation of Embryos
During cryopreservation, COS and subsequent oocyte
retrieval is performed followed by the cryopreservation
of embryos.
These are then transferred in a subsequent unstimulated
IVF cycle where the woman’s ovarian response to hCG
has normalized.
A Cochrane Review only identified 2 RCTs for analysis
and came to the conclusion that there was insufficient
evidence to support routine cryopreservation.

Recent evidence however strongly supports the use of a
GnRHa trigger followed by cryopreservation as being the
most effective method in preventing OHSS, best
illustrated by Devroey and colleagues through their
OHSS-Free Clinic.

A problem with cryopreserved embryos was the lower
pregnancy rates in contrast to fresh embryo transfers
related to older slow freezing methods.
With the modern techniques such as vitrification, there
is convincing evidence to suggest that cryopreservation
has better pregnancy rates than fresh embryo transfer as
well.
Based on these findings, the use of a GnRHa trigger
followed by cryopreservation is highly recommended for
prevention of OHSS.

Cycle Cancellation
Cycle cancellation and withholding of hCG are the only
definite methods of preventing OHSS.
However, it must be taken in context with the high
financial impact and psychological distress that it causes
to women.
It is the last resort for clinicians to prevent OHSS.

Alternative Methods of Prevention of OHSS
1. Cabergoline.
2. Colloid Infusion:
A. Albumin.
B. Hydroxyethyl Starch (HES).
3. IV calcium infusion.
4. Aspirin.
5. Vasopressin V1a receptor antagonist (relcovaptan).
6. In vitro maturation ( IVM).

Cabergoline.
It is a dopamine antagonist which prevents the excessive
increase in VEGF mediated vascular permeability
encountered with OHSS through its antiangiogenic
properties.
Tang et al., in their Cochrane Review of 230 women in 2
RCTs found cabergoline to be effective in significantly
reducing the incidence of moderate OHSS with no
significant effect on clinical pregnancy rate and
miscarriage rates.
This protective effect, however, did not extend to severe OHSS, possibly
due to the number of studies available for comparison.

A recent systemic review by Leitao at el., which took 7
RCTs into consideration, has further established its
efficacy in preventing the occurrence of moderate and
severe OHSS as well as without a negative impact on
clinical pregnancy or oocytes retrieved.
Therefore, the use of cabergoline is recommended and it
is suggested that treatment be commenced on the day
of hCG trigger at a dose of 0.5mg for 8 days.

Colloid Infusion
Colloid infusions are administered around the time of
oocyte retrieval as they are suspected to prevent OHSS
by binding to and deactivating the vasoactive mediators
of OHSS.

Albumin.
A Cochrane Review by Youssef et al. noted that there was
borderline statistically lower incidence of severe OHSS with
albumin utilization but there was marked heterogeneity in the
studies.
Another systematic review by Jee et al. also found that IV
albumin did not reduce the rate of severe OHSS and also
raised concerns regarding significantly reduced pregnancy
rates.
Factors such as the possibility of transmission of viral
infections (i.e., hepatitis B/C/HIV) and anaphylactic reactions
are risks that should not be overlooked.
On the basis of these factors, the routine use of IV albumin to prevent OHSS cannot be
recommended.

Hydroxyethyl Starch (HES).
HES is a plasma expander that has been used as an
alternative to albumin as it is non-biological and
therefore avoids the risks associated with albumin use.
The Cochrane Review by Youssef et al. found a
statistically significant decrease in severe OHSS with HES
use without any effect on pregnancy rates.
These findings were based on only 3 RCTs, so we need
more evidence to recommend its routine use.

IV calcium
Increased calcium inhibits cAMP- stimulated renin
secretion, which decreases angiotensin II synthesis and
subsequent effect on VEGF production.
10 ml of 10% Ca gluconate in 200 ml normal saline on
the day of OR and days 1, 2 and 3 after OR.
Little evidence available.

Aspirin
Increased platelet activation due to VEGF leads to the
release of many substances that can potentiate the
cascade of OHSS.
The use of 100 mg aspirin daily from the first day of
stimulation till day of pregnancy test or cardiac pulsation
detection can lower the incidence of severe OHSS.
No difference in pregnancy outcomes.
Low evidence available.

Vasopressin V1a receptor antagonist
(relcovaptan)
It inhibits VEGF by modulating vasoconstriction and vascular
smooth muscle proliferation.
In the hyperstimulated rat model, lower concentrations of
VEGF-A in the peritoneal fluid and lesser ovarian weight gain
and significant decreases in the number of corpora lutea in
contrast to control groups.
Further research is promising and may change the
management protocols for OHSS.
Not yet available for clinical use.

In vitro maturation (IVM)
IVM may be another primary preventive strategy for women
with high OHSS risk.
In contrast to the conventional IVF/ICSI-procedure, immature
oocytes are used for artificial reproductive techniques with IVM.
After a short FSH-priming, all antral follicles are punctured. All
mature oocytes are used for IVF/ ICSI at the day of oocyte
retrieval and immature oocytes after in vitro maturation in a
specific IVM-medium at the following day.
Although RCTs focusing on the use of IVM in women with PCOS
are currently in process, still no clear data are existent on the
value of IVM.

Conclusions
1. OHSS is an iatrogenic problem.
2. OHSS occurs when hCG is given.
3. Prediction and prevention should be always our goal.
4. Step-up protocol is better than step-down.
5. Antagonist protocol is better than agonist.
6. Metformin should be given for all PCOs patients.
7. GnRHa is better for ovulation triggering but together
with low dose hCG or freeze all.

Conclusions
8. Coasting needs more research to prove efficacy and
establish regimen.
9. Cryopreservation is recommended for high risk patients.
10. Cycle cancellation is the last resort if all measures
failed.
11. Cabergoline is recommended for prevention.
12. OHSS is a self- limited condition, but resolution is
delayed if pregnancy occurred.

Prevention of ovarian hyperstimulation syndrome

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