Human Fertility

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British Fertility Society Policy and Practice

Committee: Prevention of Ovarian
Hyperstimulation Syndrome

R. S. Mathur & B. K. Tan

To cite this article: R. S. Mathur & B. K. Tan (2014) British Fertility Society Policy and Practice
Committee: Prevention of Ovarian Hyperstimulation Syndrome, Human Fertility, 17:4, 257-268,
DOI: 10.3109/14647273.2014.961745

To link to this article: https://doi.org/10.3109/14647273.2014.961745

Published online: 07 Nov 2014.

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Human Fertility, 2014; 17(4): 257–268
© 2014 The British Fertility Society
ISSN 1464-7273 print/ISSN 1742-8149 online
DOI: 10.3109/14647273.2014.961745

POLICY AND PRACTICE

British Fertility Society Policy and Practice Committee: Prevention

of Ovarian Hyperstimulation Syndrome

R. S. MATHUR1 & B. K. TAN2

1
Cambridge IVF, Box 123 Addenbrooke’s Hospital, Cambridge, UK and 2Associate Clinical Professor of Obstetrics and
Gynaecology, University of Warwick, Coventry, CV4 7AL, UK

Introduction et al., 2000). ‘Early’ OHSS occurs within 9 days of hCG

Ovarian hyperstimulation syndrome (OHSS) is a poten-
tially serious iatrogenic complication of supraphysiologi-
cal ovarian stimulation, occurring most often in assisted
conception cycles where the ovaries are stimulated to
promote the development of multiple ovarian follicles
and thereby increase the number of oocytes available.
The incidence of moderate or severe OHSS has been
reported to lie between 3.1% and 8% of IVF cycles
(Delvigne & Rozenberg, 2002a). Much less commonly,
OHSS may develop following ovulation induction with
gonadotrophins or clomifene. A study utilising hospital
discharge statistics from Finland in the period 1996 and
1998 identified hospitalisation due to OHSS following
0.04% of ovulation induction cycles and 0.9% of IVF
cycles (Klemetti et al., 2005).
This review examines the evidence for various
methods of prevention of OHSS. Awareness of the
pathogenesis of OHSS underpins effective prevention
– a separate review discusses pathophysiology, clinical
features and management of OHSS (Tan & Mathur,
2013). In particular, the critical role of human chorionic
gonadotrophin (hCG) as the trigger for OHSS is well-
recognised. The action of HCG on ovarian granulosa
cells, on a background of increased ovarian sensitivity
and/or excessive ovarian response, leads to the excessive
release of vascular endothelial growth factor (VEGF)
and a variety of pro-inflammatory cytokines, which act
as effector molecules to produce the characteristic fea-
tures of OHSS. Exogenous HCG is commonly used as a
surrogate for luteinising hormone (LH) to achieve final
follicular maturation. Endogenous HCG arises from
the trophoblast in cycles where conception occurs. The
time of onset of OHSS reflects the effect of hCG expo-
sure at different stages of the treatment process and may
identify two distinct clinical presentations with different
predictive factors and potential for severity (Mathur
administered for final follicular maturation and reflects
the effect of exogenous hCG on a background of exces-
sive ovarian response to FSH. ‘Late’ OHSS occurs 10
or more days after the ovulatory dose of hCG and, in
the absence of luteal hCG administration, reflects the
effect of endogenous hCG from an early pregnancy.
‘Late’ OHSS is significantly more likely to be severe
than ‘early’ OHSS (Mathur et al., 2000).
Prediction of OHSS
Pre-treatment patient characteristics
Young age, polycystic ovaries and a previous history
of OHSS have all been considered to increase the risk
of developing OHSS (Delvigne & Rozenberg 2002a;
Enskog et al., 1999; Navot et al., 1992). Navot et al.
(1992) noted a lower mean body weight among women
with OHSS compared to controls, but this was not con-
firmed by a larger study (Delvigne et al., 1993).
More recently, the development of accurate ovar-
ian reserve parameters provides further opportunity to
identify patients at increased risk of developing OHSS.
Serum concentrations of anti-Mullerian hormone
(AMH) are closely predictive of the ovarian response
to stimulation with exogenous gonadotrophins. La
Marca et al. (2007) found that patients who had cycle
cancellation due to a perceived high risk of OHSS had
AMH levels in the highest quartile for their popula-
tion. Nardo et al. (2009) found serum AMH to have
a moderate degree of predictive ability for extremes of
ovarian response. Lee et al. (2008) examined the abil-
ity of AMH to predict OHSS in a study of 274 GnRH
agonist cycles with HCG luteal support. They showed
that serum AMH concentrations were better predic-
tive of the risk of developing OHSS than patient age,
BMI or ovarian response parameters. The best balance

Correspondence: Mr Raj Mathur, Cambridge IVF, Box 123 Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK. Tel: ⫹ 44 (0)1223-349010. Fax: ⫹ 44
(0)1223-348202. E-mail: rmathur@nhs.net
257
258 R. S. Mathur & B. K. Tan
of sensitivity and specificity was obtained by an AMH
concentration of 3.36 ng/ml (DSL assay) (sensitivity
90.5%, specificity 81.3%, positive predictive value 29.7
and negative predictive value 99.0) (Lee et al., 2008).
Recognition of the predictive value of pre-treatment se-
rum AMH concentrations has led to the development
of AMH-based tailored ovarian stimulation protocols.
Yates et al. (2011) and Nelson et al. (2009) described
their results using serum AMH to select women with
a high risk of developing OHSS for GnRH antagonist
protocols with a starting dose of 150 IU FSH daily.
Nelson et al. (2009) carried out a prospective cohort
study between two centres, one of which used GnRH
agonist and the other GnRH antagonist to control LH
during ovarian stimulation with high AMH concentra-
tions. Hospitalisation for OHSS was required in 20 out
of 148 women receiving GnRH agonist (13.9%) com-
pared to 0 out of 34 women receiving GnRH antago-
nist, albeit in a different centre. The authors concluded
that pre-treatment serum AMH levels could be used to
individualise the treatment regime and thereby reduce
the risk of OHSS. Yates et al. compared retrospectively
346 cycles of IVF based on a conventional protocol us-
ing serum FSH and age to guide stimulation, with 423
cycles using an AMH-guided stimulation protocol. In
the conventional group, long protocol GnRH agonist
was used in most cases, while, in the AMH-guided
group, women with high AMH levels received GnRH
antagonist and 150 IU FSH daily. The introduction of
AMH-guided ovarian stimulation was associated with
a reduced incidence of cycle cancellation or ‘freeze-all’
due to a perceived risk of OHSS, although the inci-
dence of hospital admission due to severe OHSS did
not differ significantly between the two groups.
The number of small antral follicles visible on
transvaginal ultrasound scan (antral follicle count
(AFC)) has also been shown to correlate with the
ovarian response to stimulation and the risk of devel-
oping OHSS. A prospective single-centre study found
that the incidence of OHSS was 2.2% in women with
an AFC ⬍ 24 and 8.6% in women with AFC ⱖ 24
(Jayaprakasan et al., 2012). The efficacy of AFC in
predicting excessive ovarian response (defined as
the collection of 20 or more oocytes) was identified
by Kwee et al. (2007), who found that an AFC of 14
yielded the best combination of sensitivity (82%) and
sensitivity (89%) with a positive predictive value of 58.
Analogous to the situation with AMH, AFC has been
studied as a guide to individualising ovarian stimula-
tion regimes (Yovich et al., 2012), although prospec-
tive randomised data are similarly lacking.
Ovarian response parameters
Monitoring of the ovarian response to stimulation dur-
ing a treatment cycle may provide an additional oppor-
tunity to identify cycles at high risk of developing OHSS.
Among the features reported to be associated with a
high risk of OHSS are high serum concentrations of
oestradiol (E2) (Enskog et al., 1999; Asch et al., 1991),
large numbers of follicles (Blankstein et al., 1987;
Enskog et al., 1999) and a large number of oocytes
retrieved (Asch et al., 1991). However, despite their
widespread use in clinical practice, ovarian response
parameters have modest predictive value and there
is significant variation between clinicians concerning
cut-off levels to guide practice. A significant propor-
tion of cases of severe OHSS occur in cycles where no
risk factors were identified in the antecedent treatment
cycle or patient characteristics (Delvigne et al., 1997),
while the incidence of severe OHSS in cycles consid-
ered ‘high-risk’ by commonly used predictive variables
is around 20% (Orvieto, 2005). Hence, any treatment
cycle in which supraphysiological ovarian stimulation
is used should be considered at risk of OHSS. Where
ovarian response parameters are used to target preven-
tative measures, it should be recognised that these pa-
rameters are unable to predict all cases of severe OHSS
and that the cut-offs used are often arbitrary.
Preventative measures
Alternatives to gonadotrophins
As gonadotrophin therapy inevitably carries an ele-
ment of risk of OHSS, an important aspect of preven-
tion of OHSS is to consider alternative management
options, depending on the clinical features. In cases
of ovulatory dysfunction, life style modification may
be appropriate to optimise weight or avoid exces-
sive exercise. Clomifene, insulin-sensitising agents,
aromatase inhibitors, laparoscopic ovarian diathermy,
gonadotrophin-releasing hormone pump and anti-
dopaminergic agents are appropriate in certain cases.
The risk of OHSS is a further reason not to progress
to IVF until indicated and only after consideration of
other treatments.
In vitro maturation of oocytes obtained from unstim-
ulated ovarian follicles is an alternative to ovarian stim-
ulation with gonadotropins in some women with PCOS.
The avoidance of exogenous gonadotrophin (apart from
a single dose of HCG 34–36 h prior to oocyte retrieval)
makes the process much safer than standard IVF with
regard to the risk of OHSS. However, the efficacy of
IVM in terms of achieving a live birth remains lower
than stimulated IVF in women with PCO (Gremeau
et al., 2012; de Ziegler et al., 2012).
Monofollicular ovulation induction
Ovulation induction protocols should be individualised
and monitored to achieve monofollicular development.
Patients with PCOS display high sensitivity to gonado-
trophins putting them at increased risk of OHSS. If
the gonadotrophin dose oversteps the threshold of
the polycystic ovary, this increases the risk of multi-
follicular development and hence OHSS (Homburg &
Howles, 1999).
Human Fertility

Regimes for monofollicular ovulation induction
In the step-up protocol, stimulation is initiated with
a low dose of FSH, for example 75 IU for 14 days
followed by incremental increases of 37.5 IU every 7
days if there is no ovarian response (no follicle ⬎ 10 mm
diameter) (Balasch et al., 2001) or 50 IU daily for 14
days, followed by increments of 25 IU every 7 days if
no response is obtained (Christin-Maitre & Hugues,
2003). The dose that initiates follicular development
is continued until the criteria for giving hCG are at-
tained. In the step-down protocol, the starting dose is
higher (for instance, 150 IU) and is decreased once
ovarian response is. Randomised trials show a lower
risk of overstimulation with the step-up as compared to
the step-down protocol (Balasch et al., 2001; Christin-
Maitre & Hugues, 2003). In a randomised control study
of 83 women with clomifene-resistant PCOS (Christin-
Maitre & Hugues, 2003), the step-up protocol was more
efficient in obtaining a monofollicular development and
ovulation than the step-down protocol. Although the
duration of stimulation was longer, overstimulation was
significantly less frequent using the step-up protocol
(4.7% vs 36%, p ⬍ 0.0001). This is distinct from the risk
of actual OHSS, for which comparative data are scant,
although there is a reasonable expectation that the lower
risk of ovarian overstimulation with the step-up proto-
col will be reflected in a lower risk of OHSS.
A systematic review found a reduction in the inci-
dence of OHSS with the use of purified urinary-derived
FSH (uFSH) compared to hMG in ovulation induction
cycles without the concomitant use of a GnRH ago-
nist (OR 0.20, 95% CI 0.08–0.46) and a higher over-
stimulation rate when a GnRH-agonist was added to
gonadotrophins (OR 3.15, 95% CI 1.48–6.70) (Nugent
et al., 2000). A systematic review of three randomised
trials in clomifene-resistant, anovulatory women found
no significant difference in the occurrence of OHSS be-
tween recombinant FSH and uFSH (OR 1.55,95% CI
0.50–4.84) (Bayram et al., 2001).
Prevention of OHSS in IVF treatment
Laparoscopic ovarian diathermy
Laparoscopic ovarian diathermy has been studied as a
measure to prevent OHSS in women with PCOS under-
going IVF. A controlled trial in women with ultrasound
evidence of PCO found a lower risk of cancellation due
to over-response, but no difference in the incidence of
OHSS, with the use of laparoscopic ovarian diathermy
carried out 1 week prior to the start of gonadotrophin
stimulation in GnRH agonist cycles (Rimington et al.,
1997). Similar results were found in a retrospective
study by Tozer et al. (2001). The specific role of this
invasive procedure to prevent OHSS in IVF is unclear.
At present, data do not justify routine use of ovarian
diathermy for the sole indication of prevention of OHSS
in future IVF treatment.
© 2014 The British Fertility Society
Prevention of OHSS 259
Ovarian stimulation regimes
Starting dose of FSH
The starting dose of FSH for controlled ovarian hy-
perstimulation should take into account factors that
may increase the risk of evoking an excessive ovarian
response, including the presence or absence of PCO,
previous history of OHSS and young age. The value of
AMH and AFC in determining the appropriate start-
ing dose and regime is described above. There are no
randomised trials examining a lower starting dose of
FSH for patients with risk factors for excessive ovarian
response undergoing IVF. Marci et al. (2001) observed
a significant reduction in cycle cancellation rate with
a starting dose of 75 IU rFSH in 61 women who had
previously responded excessively to a starting dose of
150–225 IU hMG. The incidence of OHSS was not re-
ported in the study, but commonly used risk parameters
(peak oestradiol and number of oocytes) were reduced
in the group with the lower starting dose.
Choice of FSH
Meta-analysis of 32 trials with 7740 patients shows that
the risk of OHSS in IVF cycles using urinary FSH is not
significantly different to the risk in cycles using recom-
binant FSH (OR 1.18, 95% CI 0.86–1.61) (van Wely
et al., 2011).
GnRH agonist versus GnRH antagonist
Prevention of a spontaneous LH surge in assisted con-
ception cycles can be achieved either with gonadotrophin-
releasing hormone agonists (GnRH-a) or antagonists.
GnRH antagonists are associated with a shorter duration
of stimulation, lower oestradiol levels and smaller num-
bers of follicles recruited (Tarlatzis et al., 2006). Al-Inany
et al. (2011) performed a meta-analysis of randomised
controlled trials comparing GnRH antagonist with long
protocol GnRH agonist treatment cycles. OHSS was a
secondary outcome in the studies included in the meta-
analysis and there was no standard definition of OHSS
between studies. GnRH antagonist was administered by
any of three types of protocols – single dose, multiple
dose flexible and multiple dose fixed. In women ran-
domised to GnRH antagonist, ovarian stimulation was
started on day 2 or 3 of the menstrual cycle and the
antagonist started in most trials on stimulation day 6.
Final follicular maturation was induced with 10,000 IU
HCG. No significant difference in ongoing pregnancy
or live birth rates was observed between GnRH antago-
nist and GnRH agonist cycles. Information on the inci-
dence of severe OHSS was available in 29 studies with
a total of 5417 subjects. The incidence of severe OHSS
was significantly lower in GnRH antagonist cycles
compared to GnRH agonist cycles (2.65% vs 6.61%;
R.D ⫽ ⫺ 0.03, 95% CI ⫽ ⫺ 0.05 to ⫺ 0.02; p ⬍ 0.00001;
I2 ⫽ 67.68%, 95% CI ⫽ 52.50–78.02%). In the overall
study population, the risk of OHSS was 60% lower in
260 R. S. Mathur & B. K. Tan
women receiving GnRH antagonist, with an absolute
risk reduction of 4% and a corresponding number
needed to harm of 25. When women with PCOS were
considered separately (8 trials, 783 women), the effect
was even more marked. The incidence of severe OHSS
among women with PCOS was significantly lower
with the use of GnRH antagonist (3.44% vs 15.02%;
R.D ⫽ ⫺ 0.10, 95% CI ⫽ ⫺ 0.14 to ⫺ 0.07; p ⬍ 0.00001;
I2 ⫽ 82.05%, 95% CI ⫽ 65.82%–90.57%). A separate
meta-analysis by Pundir et al. (2011) also showed a
significant reduction in the risk of OHSS with the use
of GnRH antagonist protocol in women with PCOS,
when moderate and severe OHSS were pooled but not
when either moderate or severe OHSS cases were con-
sidered separately. The incidence of coasting or cycle
cancellation due to a perceived risk of OHSS was also
significantly lower in GnRH antagonist cycles, lending
further plausibility to the reduced incidence of OHSS
with this method of treatment (Al-Inany et al., 2011).
Despite evidence supporting a role for GnRH an-
tagonists in reducing the risk of OHSS, the uptake of
this method of controlling endogenous LH remains
non-uniform. One reason for this may be that clinicians
fear a reduction in IVF live birth rates if they change
to a new regime. Several authors describe a ‘learning
curve’ in the application of GnRH antagonist and we
surmise that this may have inhibited wider adoption
of this risk-reduction strategy (Merviel et al., 2005;
Kamath et al., 2008; Al-Inany et al., 2011). It should be
recognised also that the use of GnRH antagonist with
a conventional HCG trigger does not abolish the risk
of OHSS. In a large cohort of 2524 GnRH antagonist
cycles in 1801 women, Papanikolaou et al. (2006) noted
an incidence of hospitalisation for OHSS of 2.1% per
cycle, which is broadly comparable to the incidence
of OHSS of all grades of 3.3% noted by Mathur et al.
(2000) in a series of 2362 consecutive GnRH agonist
cycles in 1565 women.
GnRH agonist for final follicular maturation
in GnRH antagonist cycles
In women receiving GnRH antagonist, the pituitary
gonadotrophs retain their sensitivity to GnRH. Hence,
administration of GnRH agonist to a woman receiv-
ing GnRH antagonist can induce an endogenous LH
surge by their initial ‘flare’ effect. This surge may be
sufficient for final follicular maturation, while carry-
ing a lower risk of inducing OHSS than an injection of
HCG, which has a longer half-life and produces more
sustained luteotrophic stimulation than LH (Humaidan
et al., 2012). Several trials in women undergoing IVF
using a GnRH antagonist regime have compared the
efficacy and safety of a GnRH agonist trigger to com-
plete follicular maturation against a conventional HCG
trigger. A meta-analysis of five randomised controlled
trials comprising 504 fresh autologous cycles found a
significantly lower risk of OHSS with a GnRH agonist
trigger compared with HCG trigger (OR 0.10, 95% CI
0.01–0.82), suggesting that for a population with an
OHSS incidence of 3% using HCG trigger, the inci-
dence using GnRH agonist trigger would be 0–2.6%.
The incidence of OHSS in egg donation cycles (3 trials,
342 cycles) was also significantly lower with GnRH ago-
nist trigger compared to HCG trigger (OR 0.06, 95%
CI 0.01–0.31) (Youssef et al., 2011a). However, the
meta-analysis also found significantly lower live birth
rates (OR 0.44, 95% CI 0.29–0.68; 4 trials comprising
497 cycles) and increased risk of miscarriage (OR 1.89,
95% CI 1.11–3.21; 8 trials comprising 713 cycles) with
GnRH agonist trigger compared to HCG trigger in au-
tologous IVF cycles. No difference was found in ongo-
ing pregnancy or live birth rates in egg donation cycles
indicating that where the transfer of fresh autologous
embryos is not planned, GnRH agonist trigger has an
advantage over HCG trigger in women undergoing IVF
with GnRH antagonist.
The lower clinical pregnancy rate following fresh
autologous embryo transfer in GnRH antagonist cycles
with GnRH agonist trigger is probably related to luteal
insufficiency caused by reduced LH concentrations in
the early and mid-luteal phase (Humaidan et al., 2012)
and is a major factor limiting the uptake of this strategy
to prevent OHSS. Attempts have therefore been made
to develop luteal phase regimes that aim to correct this
defect. One approach has been to use a small dose of
HCG either at the time of GnRHa trigger (so-called ‘dual
trigger’) or at the time of egg retrieval. In a randomised
controlled trial of 302 patients, Humaidan et al. (2010)
found that 1500 IU HCG administered 35 h after the
GnRHa trigger was associated with no cases of OHSS
and live birth rates comparable to a conventional HCG
trigger in unselected women undergoing IVF with a
GnRH antagonist regime. However, the safety of HCG
administration, even in small doses, in women at high
risk of OHSS may cause unease to clinicians. A recent
retrospective study of 23 women at increased risk of
OHSS (mean oestradiol level 4891 ⫾ 2214 pg/ml, mean
number of ⬎ 12 mm follicles 20 ⫾ 6 on the day of trig-
ger) found severe early OHSS in six patients (26%) with
the use of GnRH agonist trigger and 1500 IU HCG
luteal rescue (Seyhan et al., 2013). In contrast, a retro-
spective report of GnRH agonist trigger with 1500 IU
HCG administered after oocyte retrieval in 275 cycles
in women judged to be at high risk of OHSS from as-
sessment of baseline characteristics found severe OHSS
in 2 cycles (0.72%) and a pregnancy rate of 41.8%
(Iliodromiti et al., 2013).
Other regimes to correct the luteal phase defect fol-
lowing GnRh agonist trigger include intensive steroid
replacement (intramuscular progesterone and transder-
mal or oral oestradiol) (Babayof et al., 2006; Engmann
et al., 2008), recombinant LH injections during the
luteal phase (Papanikolaou et al., 2011) and daily in-
tranasal GnRH agonist during the luteal phase (Pirard
et al., 2006). The present literature does not provide
sufficient evidence of the efficacy and safety of any
one regime (Humaidan et al., 2011; Humaidan et al.,
Human Fertility

2012). Further large prospective studies are required
to determine the optimum regime to achieve a low risk
of OHSS and high clinical pregnancy rates in high-
risk women receiving GnRH agonist trigger in GnRH
antagonist cycles.
Recombinant LH for final follicular maturation
The luteotropic effect of hCG is more prolonged than
that of endogenous LH, hence it has been suggested
that using LH instead of hCG for final follicular matu-
ration may reduce the risk of OHSS. However, a meta-
analysis of 2 trials comprising 280 subjects comparing
recombinant LH with urinary hCG did not show any
difference in the risk of severe OHSS (OR 0.82, 95%
CI 0.39–1.69) (Youssef et al., 2011b). The incidence of
severe OHSS was quite high in both groups (10.3% in
the rLH group and 12.4% in u-hCG group). Further
trials are needed to assess the efficacy of rLH in reduc-
ing the risk of OHSS.
Recombinant hCG for final follicular maturation
Meta-analysis of 3 RCTs comprising 549 subjects
found no significant difference in the incidence of
severe OHSS between recombinant and urinary hCG
used for final follicular maturation (3.3% vs 1.9%, OR
1.49, 95% CI 0.37–4.10) (Youssef et al., 2011b).
Dose of hCG
Pregnancy rates and numbers of oocytes retrieved in
IVF treatment appear not to be different for doses of
HCG ⱖ 5000 IU (Abdalla et al., 1987). Given the cor-
relation between degree of HCG exposure and the risk
of OHSS (Mathur et al., 1995), it appears sensible to
use the lowest effective dose of HCG for final follicular
maturation in cycles considered at risk of OHSS.
Nargund et al. (2007) described the use of 2500 IU
HCG to induce final follicular maturation in a group
of 21 women thought to be at high risk of OHSS (⬎ 20
follicles in each ovary and E2 ⬎ 14000 pmol/l on the
day of HCG). Despite the transfer of fresh embryos, no
cases of moderate or severe OHSS were noted. Clinical
pregnancies occurred in 13 cycles (61%) with 2 twin
pregnancies. This small study suggests that, in cycles
with an excessive ovarian response, even a very low dose
of urinary HCG of 2500 IU may be sufficient to obtain
good clinical results with a low risk of significant OHSS.
A trial by Chang et al. (2001) in women receiving either
250 mcg or 500 mcg of recombinant HCG for follicular
maturation showed a lower risk of severe OHSS with
the 250 mcg dose.
Coasting
Coasting consists of withholding gonadotrophins while
maintaining pituitary suppression. Daily serum E2
estimation and follicular tracking are carried out until
E2 drops to a “safe” level. HCG is then administered,
followed by oocyte retrieval and embryo transfer.
© 2014 The British Fertility Society
Prevention of OHSS 261
Serum FSH levels decline significantly during the coasting
period. Larger follicles have a lower dependence on FSH
than smaller follicles and are capable of continuing their
growth and maturation, while small and intermediate
follicles undergo atresia (Benavida et al., 1997; Dhont
et al., 1998). FSH is a potent inhibitor of granulosa
cell apoptosis (Chun et al., 1996), which may increase
as FSH concentrations fall (Tortoriello et al., 1998).
Declining concentrations of vasoactive mediators of
ovarian origin, such as VEGF, may contribute to the
efficacy of coasting (Tozer et al., 2004).
A Cochrane review (D’Angelo et al., 2011) identi-
fied four randomised trials of coasting, but only one of
these compared coasting with no coasting, showing a
reduction in the risk of moderate or severe OHSS with
coasting (OR 0.17, 95% CI 0.03–0.88; P ⫽ 0.03). Other
trials either compared coasting with early follicular
aspiration or GnRH antagonist administration, and
no significant difference was found in the incidence of
OHSS in these comparisons. Owing to the comparison
with another preventative modality, these trials may
not be a true reflection of the value of coasting itself.
There are several retrospective studies examining the
value of coasting in preventing OHSS. In a qualitative
systematic review of 12 studies involving 493 patients,
the data were heterogenous with variable criteria being
employed for coasting. The fertilisation and pregnancy
rates were acceptable and 2.5% of patients required hos-
pitalisation for OHSS (Delvigne & Rozenberg, 2002b).
While it is clear that coasting does not abolish the risk
of OHSS, there does appear to be a lower incidence of
OHSS in coasted cycles than would be expected from
the literature (García-Velasco et al., 2006). Mansour
et al. (2005) reported their experience of a large ret-
rospective series of cycles in which coasting was initi-
ated if there were ⱖ 20 follicles and E2 ⱖ 3000 pg/ml.
Of 1223 cycles with coasting, 16 cases of severe OHSS
occurred (1.3%), all in cycles where hCG was admin-
istered prior to the E2 dropping below 3000 pg/ml.
A survey of 573 members of the European Society of
Human Reproduction and Embryology found coasting
to be the commonest preventive strategy used (Delvigne
& Rozenberg, 2001).
Coasting can be initiated once follicles are mature
(⬎ 15 mm). The criteria described for initiating coasting
are variable but are intended to identify cycles where
the ovarian response is so excessive that cycle cancel-
lation would otherwise be considered. Most investiga-
tors have recommended using E2 levels as one of the
criteria for initiating coasting, despite their relatively
modest predictive value for severe OHSS. Cut-off levels
have varied from 2500 pg/ml (Dhont et al., 1998) to
6000 pg/ml (Egbase et al., 1999). It is not possible to be
prescriptive about the precise E2 cut-off that should be
used for initiating coasting, hence the experience of the
individual centre and an overall assessment of the risk
of OHSS in any given treatment cycle should be taken
into account. The number of follicles is also a criterion
described by most investigators, with some variation in
262 R. S. Mathur & B. K. Tan
the cut-off numbers used and whether the total num-
ber of follicles or the number of mature follicles only is
considered.
Criteria for when coasting may cease, followed by the
administration of hCG usually relate to a drop in se-
rum E2 level to a ‘safe’ level, usually below 3500 pg/ml
(García-Velasco et al., 2006) or 3000 pg/ml (Mansour
et al., 2005). An abrupt drop in E2 or a level ⬍ 1000
pg/ml may be associated with poor outcome (García-
Velasco et al., 2006). Coasting for more than 3 or 4 days
may be associated with poorer cycle outcomes, although
clinical pregnancies are still achieved. In a retrospective
analysis of 1223 coasted cycles, Mansour et al. (2005)
found a lower clinical pregnancy rate following ICSI
in cycles that were managed with coasting for ⬎ 3 days
compared to cycles where E2 had declined to safe levels
within 3 days of coasting (36% vs 52%). García-Velasco
et al. (2006) found lower implantation rates in patients
who had been coasted for ⬎ 4 days (15.5% vs 28.5%).
However, a retrospective analysis of 1058 cycles where
coasting was applied did not find a reduction in live birth
rate with coasting up to 8 days. Neither peak oestradiol
concentration nor the drop in oestradiol with coasting
was predictive of cycle outcome (Abdalla & Nicopoul-
los, 2010). At present it is not possible to be prescriptive
about setting limits on coasting in terms of time or fall
in oestradiol concentration.
Avoiding HCG
Cycle cancellation
OHSS develops only in cycles with exposure to en-
dogenous or exogenous hCG. Consequently, the most
effective prevention is to withhold hCG in cycles at
risk of OHSS, thereby cancelling the treatment cycle.
The emotional and financial costs of this can be sig-
nificant, leading to an understandable reluctance on
the part of patients to let the ovarian response go to
waste. However, there remains a role for cancellation
in circumstances where the ovarian response is exces-
sive and embryo cryopreservation is not a viable option,
particularly if the gonadotrophin dose can be reduced
for future attempts. Patients need to be counselled with
regard to their individual risk of developing OHSS, with
its potential morbidity, as well as the risk of develop-
ing a similar ovarian response even with a lower dose of
gonadotrophins.
Cryopreservation of all embryos
Avoiding fresh embryo transfer eliminates exposure
to endogenous hCG of pregnancy and should thereby
eliminate the possibility of late OHSS. Clearly, it
cannot prevent early OHSS which is related to the
pre-ovulatory exogenous HCG. Despite its theoretical
value and widespread use in practice, cryopreservation
of all embryos has been poorly studied as a means of pre-
venting OHSS. A Cochrane review (D’Angelo & Amso,
2002) found only two studies suitable for inclusion,
of which one (Shaker et al., 1996) compared embryo
cryopreservation with intravenous albumin and subse-
quent fresh embryo transfer. The only trial comparing
cryopreservation of all embryos with fresh embryo
transfer alone (Ferraretti et al., 1999) found a lower
incidence of OHSS in the group where all embryos
were cryopreserved compared to the fresh embryo
transfer group (0/58 vs 4/67), but the difference did
not reach statistical significance. All patients in this
trial received 20 g albumin intravenously on the day
of oocyte retrieval. Endo et al. (2002) in a controlled
trial of 138 women undergoing elective cryopreserva-
tion of all embryos due to excessive ovarian response
found that the incidence of OHSS was reduced by the
continuation of GnRH agonist for 1 week after hCG
injection.
Increased application of blastocyst culture and
vitrification may allow clinicians more time to observe
the patient for signs of early OHSS before a decision
needs to be made between freezing all embryos and
fresh embryo transfer. A step-by-step algorithmic ap-
proach has been proposed (D’Angelo, 2010).
Adjuvant treatments
Metformin co-treatment during gonadotrophin stimulation
The elevated risk of OHSS following ovarian stimu-
lation in women with PCOS has been correlated to
elevated VEGF activity (Peitsidis & Agrawal, 2010).
Studies on cultured vascular smooth muscle cells reveal
that insulin stimulates VEGF protein expression and
secretion (Doronzo et al., 2004), pointing to a possible
pathophysiologic link between insulin resistance and
OHSS in women with PCOS. Investigators have stud-
ied the use of metformin co-treatment during ovarian
stimulation in order to improve the ovarian response
and reduce the risk of OHSS. In oocytes retrieval to
women with PCOS undergoing IVF. Coasting was not
carried out and embryo cryopreservation with delayed
transfer was offered if 30 or more oocytes were ob-
tained. The incidence of severe OHSS was significantly
reduced in the metformin group (2/52 vs 10/49; OR
0.15, 95% CI ⫽ 0.03–0.76). A systematic review pool-
ing data from five RCTs in women with PCOS under-
going a randomised controlled trial, Tang et al. (2006)
administered placebo or Metformin 850 mg twice daily
from the first day of down-regulation to the day of IVF
(Tso et al., 2009) showed a significant reduction in the
incidence of OHSS with the use of metformin (13/227
vs 47/222; OR 0.27, 95% CI ⫽ 0.16–0.47), without
significant statistical heterogeneity. There was no sta-
tistically significant difference in markers of ovarian
response or treatment outcome with the use of met-
formin. Only one trial (Doldi et al., 2006) examined
the use of metformin in combination with a GnRH
antagonist regime, studying 40 women with PCOS ran-
domised to no pre-treatment or metformin 1.5 g daily
for 2 months prior to the start of IVF. The incidence of
Human Fertility

OHSS was 5% in the metformin group vs 15% in the
placebo group (p ⬍ 0.05).
Dopamine agonists
Dopamine agonists have been proposed as a preventa-
tive measure for OHSS, based on the action of dopamine
in antagonising the vascular permeability-enhancing
effect of VEGF through the dopamine receptor type 2.
Initial studies in rats were followed by a trial in oocyte
donors (Alvarez et al., 2007a), which showed a reduced
incidence of moderate, but not severe, OHSS in oocyte
donors receiving 0.5 mg cabergoline daily from the day
of HCG administration for 8 days. Cabergoline appears
to inhibit the permeability-enhancing effect of VEGF
without affecting neo-vascularisation, enabling implan-
tation to occur (Alvarez et al., 2007b).
Carizza et al. (2008) carried out a randomised con-
trolled trial of cabergoline 0.5 mg orally daily from the
day after oocyte retrieval for 21 days versus no treat-
ment in 166 women with E2 levels ⬎ 4000 pmol/l on
the day of HCG administration. The incidence of early,
but not late, OHSS was significantly reduced in the
cabergoline group. A subsequent systematic review
(Youssef et al., 2010) confirmed a reduced risk of early,
but not late, OHSS in women treated with cabergoline
(OR 0.1, 95% CI 0.03–0.33). It should be noted that
late OHSS is more likely to be clinically severe and pro-
longed than the early form. A further randomised trial
comparing cabergoline and hydroxyl-ethyl starch with
hydroxyl-ethyl starch alone in women at increased risk
of OHSS did not find any difference in the incidence
or severity of OHSS between the two groups (Matorras
et al., 2013). At present, the data do not support a major
role for cabergoline in preventing severe or late OHSS,
which are the clinical groups of patients most at risk of
complications.
Intravenous albumin
Administration of intravenous albumin around the time
of oocyte retrieval has been proposed as a measure to
prevent OHSS, starting initially with a report of ef-
fectiveness in an uncontrolled case series (Asch et al.,
1993). This was followed by a number of randomised
controlled trials of small numbers of patients deemed to
be at risk of OHSS on the basis of parameters of ovar-
ian response, which appeared to show a reduction in
the incidence of severe OHSS in the group receiving
albumin. However, the evidence from meta-analysis of
randomised trial remains unclear. A Cochrane review
(Youssef et al., 2011c) found a lower incidence of OHSS
with the use of albumin (OR 0.67, 95% CI 0.45–0.99;
P ⫽ 0.01). However, a separate meta-analysis (Venetis
et al., 2011) did not show any difference in the incidence
of severe OHSS between women receiving intravenous
albumin and controls. The authors of the Cochrane re-
view acknowledged the presence of significant heteroge-
neity, methodological limitations in the studies assessed
and small numbers of subjects in individual trials. If
© 2014 The British Fertility Society
Prevention of OHSS 263
unpublished studies were excluded from the Cochrane
review, there was no significant difference in the risk of
OHSS between patients receiving intravenous albumin
and controls (OR 0.75, 95% CI 0.47–1.21).
The largest single-centre trial on this subject (Bellver
et al., 2003) reported on 976 women who had 20 or
more oocytes collected. Subjects were randomised to
receive 40 g intravenous albumin immediately after oo-
cyte retrieval or no treatment. Patients were followed
up until menstruation or the detection of foetal heart
activity. The incidence of moderate and severe OHSS or
severe OHSS alone did not differ significantly between
the two groups (7.1% moderate and severe and 5% se-
vere in the albumin group; 6.7% moderate and severe
and 4.7% severe in the control group). The study was
powered to detect a 50% reduction in the incidence of
severe OHSS with 95% confidence and a type 2 error
of ⫾ 2.4%.
The balance of the literature therefore does not
support a benefit for intravenous albumin adminis-
tered around the time of oocyte retrieval in preventing
OHSS. The proposed mechanism for the putative effect
of albumin in preventing OHSS is unclear: it has been
suggested that albumin may bind to vaso-active media-
tors, such as VEGF, but this has not been substantiated.
Serum VEGF levels on the day of embryo transfer did
not differ significantly between highly responsive pa-
tients who went on to develop OHSS and patients with
a similar ovarian response who did not develop OHSS
(Mathur et al., 2002). The effect of albumin in main-
taining plasma oncotic pressure and hence intravascular
volume may be useful in mitigating the pathophysiology
of established severe OHSS, but it is unclear how this
action would prevent the development of OHSS. Albu-
min is a blood-derived product with a significant cost.
Side-effects of albumin administration, though usually
mild, include allergic reactions, nausea and vomiting.
Given these factors it appears that the routine use of
albumin with the purpose of prevention of OHSS is not
justified.
Hydroxy-ethyl starch
Hydroxy-ethyl starch (HES) is a large molecular weight
synthetic compound used as an alternative plasma vol-
ume-expander to albumin. A group of investigators re-
ported its use to prevent OHSS in 100 high-risk women
who were administered 6% HES in the dose of 1000 ml
at the time of oocyte retrieval and 500 ml at embryo
transfer (Graf et al., 1997). There was no significant dif-
ference in the incidence of severe OHSS between the
treatment group and a historical control group with a
similar risk profile for OHSS, although the incidence of
moderate OHSS was reduced. A subsequent placebo-
controlled randomised trial assessed the effectiveness
of 1000 ml 6% HES administered at the time of em-
bryo transfer in women thought to be at high risk of
OHSS (König et al., 1998). The incidence of moderate
and severe OHSS in the control group was 13% (7/53),
264 R. S. Mathur & B. K. Tan
compared with 2% (1/51) in the treatment group,
with the difference just reaching statistical significance
(p ⫽ 0.03). The criteria for selecting patients for the
trial were an oestradiol level greater than 1500 pg/ml
(5505 pmol/l) or ⬎ 10 follicles on the day of hCG injec-
tion. Anecdotally, most UK clinics would not institute
specific preventative measures for OHSS at this level of
ovarian response. Gokmen et al. (2001) found albumin
and HES to both be superior to placebo in preventing
OHSS in women with oestradiol ⬎ 3000 pg/ml and ⬎ 20
follicles on the day of hCG. Although there was no sig-
nificant difference in the incidence of OHSS between
the albumin and HES groups, the authors preferred
HES on the grounds of cost and safety. Given the small
number of patients included in the trails involving HES
and the experience with regard to albumin (see above),
it seems prudent to await further research before HES is
accepted as a routine agent for preventing OHSS.
Follicle aspiration prior to hCG administration
It has been suggested that aspiration of some ovarian
follicles prior to hCG administration may reduce the
risk of OHSS by reducing the cohort of granulosa cells
able to respond to HCG. In a retrospective study of 13
patients returning for further IVF following previous
cycles complicated by OHSS, Zhu et al. (2005) found
that this approach was associated with a reduction in
the risk of OHSS. In contrast four of five patients devel-
oped severe OHSS following unilateral follicular aspira-
tion and continuation of stimulation leading to oocyte
retrieval (Schroder et al., 2003). No benefit was seen
for aspiration of all follicles from one ovary 6–8 h prior
to hCG in 16 high OHSS risk women compared to 15
matched controls who did not undergo the aspiration
(Egbase et al., 1997). In patients at high risk of OHSS
comparison between 15 coasting patients and 15 pa-
tients undergoing early aspiration revealed good preg-
nancy rates, but OHSS in 3 and 4 cases, respectively
(Egbase et al., 1999). The evidence regarding timed fol-
licular aspiration prior to hCG remains uncertain. The
strategy involves an extra invasive procedure which may
make it less acceptable to patients than coasting.
Choice of luteal support
HCG has a critical role in precipitating OHSS and may
worsen established OHSS. Progesterone is equally ef-
fective as hCG for luteal support and is associated with
a lower risk of OHSS (van der Linden et al., 2011).
Hence, luteal support should avoid hCG. The increased
risk of OHSS in multiple pregnancies (Mathur et al.,
1995) is further encouragement to adopt a policy of
single embryo transfer in younger, more fertile women,
who are also at a greater risk of OHSS.
Some researchers recommend high-dose progester-
one in the luteal phase as a means of steroidal ovarian
suppression, with a view to reducing the incidence of
OHSS (Schwarzler et al., 2003). In a study of 945 con-
secutive IVF cycles, patients were randomly allocated
to receive either hCG 5000 IU 4 and 8 days after em-
bryo transfer or intramuscular hydroxyl-progesterone
caproate 100 mg with oestradiol valerate 10 mg on days
2, 6, 10 and 14 after embryo transfer. The incidence
of OHSS was significantly higher in the hCG group
(30.5%) compared to the group that did not receive
hCG (5.4%). It is difficult to rationalise that this differ-
ence is due to a specific protective effect of progester-
one, rather than the impact of hCG on increasing the
risk of OHSS.
Conclusion
OHSS is a significant iatrogenic problem in women
undergoing ovarian stimulation for fertility treatment.
Predicting the risk of OHSS from patient characteristics
and ovarian response is associated with significant false
positives and false negatives. Of the number of measures
proposed to prevent OHSS in IVF cycles, evidence sup-
ports a role for GnRH antagonist (with GnRH agonist
trigger in cycles where fresh autologous embryo transfer
is not required), metformin co-treatment for women
with PCOS and the avoidance of hCG for luteal sup-
port. Coasting of overstimulated cycles and elective
cryopreservation of all embryos are associated with a
reduced risk of OHSS. However, no available method
guarantees complete avoidance of OHSS, and there is
little agreement on criteria for applying various pre-
ventative measures. Continued research is therefore
required in this area. Future developments in in vitro
maturation of oocytes, immunomodulation and a bet-
ter understanding of the pathophysiology of OHSS may
lead to an improvement in the ability to predict and
prevent OHSS.
Guidelines
See Figure 1 for classification of evidence levels
and grades of recommendations. Alternatives such
as lifestyle changes and clomifene should always be
considered before proceeding to gonadotrophin treat-
ment in suitable patients √
A low-dose step-up regime carries a lower risk of over-
stimulation compared with a step-down regime in women
undergoing monofollicular ovulation induction A
Ovarian stimulation regimes for IVF should be based
on the predicted ovarian reserve B
In women undergoing IVF, GnRH antagonist re-
gimes carry a lower risk of OHSS than the use of GnRH
agonist for pituitary suppression and should specially be
considered in women at high risk of OHSS A
In GnRH antagonist cycles where fresh autologous
embryos are not to be transferred (for instance, in oo-
cyte donors), final follicular maturation with GnRH
agonist carries a lower risk of inducing OHSS than the
use of HCG A
Human Fertility

Figure 1.Classification of evidence levels and grades of recommendations.
Metformin co-treatment should be considered in
women with PCOS undergoing IVF A
Coasting in cycles with an excessive ovarian response
is associated with a lower risk of OHSS. However, it is
not possible to be specific about criteria for initiating
and stopping coasting. B
In cycles with an excessive ovarian response or where
OHSS is manifest prior to embryo transfer, cryopreser-
vation of all embryos abolishes the risk of late, but not
early, OHSS. A
HCG should not be used for luteal support. A
Dopamine agonists may reduce the risk of early but
not late OHSS in high-risk women. A
Intravenous albumin or HES are not recommended
as routine measures to prevent OHSS. A
Cycle cancellation prior to HCG administration pro-
vides the only sure method of preventing OHSS. √
Declaration of interest: The authors report no decla-
rations of interest. The authors alone are responsible for
the content and writing of the paper.
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