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DOI: 10.1111/j.1744-4667.2012.00153.

2013;15:315

The Obstetrician & Gynaecologist

Review

http://onlinetog.org

Ovarian hyperstimulation syndrome


Alka Prakash

MRCOG MD,

Raj Mathur

FRCOG MD

b,

Consultant in Gynaecology and Reproductive Medicine and Surgery, Cambridge IVF and Addenbrookes Hospital, Hills Road, Cambridge
CB2 0QQ, UK
b
Consultant in Reproductive Medicine and Surgery, Cambridge IVF and Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK
*Correspondence: Raj Mathur. Email: r.mathur@addenbrookes.nhs.uk
Accepted on 10 February 2012

Key content

Learning objectives

Ovarian hyperstimulation syndrome (OHSS) is characterised by


ovarian enlargement, increased vascular permeability and fluid
shift.
 Patients with polycystic ovary syndrome (PCOS) or previous
history of OHSS are at increased risk.
 A reduced risk of OHSS is seen with use of gonadotrophinreleasing hormone antagonist instead of agonist, coasting of
overstimulated cycles, metformin in women with PCOS and
dopamine agonists.
 OHSS is likely to be more severe and prolonged in cycles where
conception occurs.
 Patients of severe OHSS require close monitoring of fluid balance,
thromboprophylaxis and attention to effusions.

To identify patients and cycles at high risk of OHSS and apply


preventative measures.
 To assess and classify the severity of OHSS.
 To manage cases of severe OHSS.
Ethical issues


How do we counsel patients about the risk of an uncommon


serious complication of fertility treatment in the face of an
overwhelming desire to have a family?
 Should the risk of OHSS be considered a reason to restrict funding
for assisted conception treatment?
Keywords: coasting / in vitro fertilisation / ovarian

hyperstimulation syndrome / polycystic ovary syndrome

Please cite this paper as: Prakash A, Mathur R. Ovarian hyperstimulation syndrome. The Obstetrician & Gynaecologist 2013;15:315.

Introduction
Assisted conception is an integral part of mainstream medical
practice, with over 44 000 cycles of in vitro fertilisation (IVF)
carried out annually in the UK, leading to over 10 000 births.1
Ovarian stimulation, designed to increase the number of eggs
and embryos available, is used in the vast majority of these cycles.
The most significant short-term complication associated with
ovarian stimulation is ovarian hyperstimulation syndrome
(OHSS), with moderate or severe OHSS reported in 38% of
IVF cycles.2 In this review, the authors highlight the clinical
presentation, prevention and management of OHSS. The
iatrogenic nature and potential severity of OHSS emphasises
the importance of ethical considerations in modern reproductive
medicine practice. The purpose of fertility treatment is to create
new life rather than save lives, making it especially important that
clinicians remember the principle of first do no harm and seek
to minimise the risk of serious complications occurring as a
result of treatment. This is a specially marked responsibility when
looking after women who only undergo ovarian stimulation in
order to donate eggs for the treatment of others.
The characteristic feature of the pathophysiology of OHSS is
increased vascular permeability. This is mediated by vasoactive
substances derived from the hyperstimulated ovary following

2013 Royal College of Obstetricians and Gynaecologists

the action of human chorionic gonadotrophin (hCG) or


luteinising hormone (LH). Vascular endothelial growth factor
(VEGF) appears to play a critical role in the development of
OHSS.3 In vitro studies have shown hCG to be a potent
stimulator for granulosa cell VEGF production, which may
explain the clinically observed link between hCG exposure and
the development of OHSS. Increased vascular permeability is
most marked in the peritoneal surfaces nearest the ovary,
leading to ascites, but may also affect pleural and pericardial
cavities and the systemic circulation. Loss of fluid into the third
space causes hypovolaemia and effusions.

Clinical features and classication


OHSS occurs in two distinct time frames, reflecting the effects
of hCG exposure at different stages of treatment. Early and late
OHSS are distinct entities with different predisposing factors
and differ in their potential for severity. Early OHSS occurs
soon after oocyte retrieval and reflects the effect of exogenous
hCG administered for final follicular maturation on a
background of excessive 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, is precipitated by the
effect of endogenous hCG from an early pregnancy. Late OHSS

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Ovarian hyperstimulation syndrome

tends to be more severe than early OHSS and is poorly


predictable from the antecedent ovarian response to
stimulation.4 There is no consensus on the most appropriate
classification of OHSS severity. The scheme put forward by
Mathur et al.5 represents an evolution of previous
classifications and aims to identify patients most in need of
close monitoring and treatment (Box 1). Furthermore, it is
important to realise that OHSS is a dynamic condition and
the level of severity may change over time and hence all
patients should be counselled regarding warning symptoms.
Box 1 Classication of ovarian hyperstimulation syndrome (OHSS)
(Mathur et al. 20055). OHSS may be early onset (within 9 days of
human chorionic gonadotrophin [hCG] trigger) or late onset (after
9 days from HCG trigger) with severity as indicated below
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 812 cm*
Severe OHSS
Clinical ascites (occasionally hydrothorax)
Oliguria
Haemoconcentration Haematocrit >45%
Hypoproteinaemia
Ovarian size usually >12 cm*
Critical OHSS
Tense ascites or large hydrothorax
Haematocrit >55%
White cell count >25 000 ml 1
Oligo/anuria
Thromboembolism
Adult respiratory distress syndrome (ARDS)
*Ovarian size may not correlate with severity of OHSS in cases of
assisted reproduction because of the effect of follicular aspiration

Abdominal distension and discomfort are the common initial


symptoms of OHSS, reflecting ovarian enlargement and the
beginning of fluid accumulation in the peritoneal cavity. Severe
pain is uncommon and its presence should lead to a suspicion of
a co-incident complication, such as ovarian torsion or ectopic
pregnancy. Increasing severity leads to clinically detectable
ascites, which may eventually progress to pleural and pericardial
effusions. Respiratory discomfort and dyspnoea result from
effusions and the splinting effect of ascites on the diaphragm.
Pulmonary oedema is a rare but serious complication associated
with vigorous intravenous fluid therapy.
Intravascular dehydration and the specific effect of
cytokines such as VEGF increase the risk of thrombosis in
women with OHSS. Thrombosis in this condition differs
from that commonly seen in gynaecological practice, in that
there is a preponderance of upper body sites and frequent

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involvement of the arterial system with various case reports


documenting ischaemic strokes, and carotid and vertebral
artery occlusions. Thrombosis often presents several weeks
after the apparent resolution of OHSS, making it important
to have a high degree of suspicion for this complication,
particularly in women presenting with atypical features
including visual and neurological symptoms.

Risk factors and prediction


A number of pretreatment patient characteristics and ovarian
response parameters have been studied as predictors of OHSS.
Younger age, presence of polycystic ovaries (PCO) and a past
history of OHSS all increase the risk of OHSS.2
During ovarian stimulation, high serum estradiol (E2)
concentrations, a rapid rise in serum E2, high follicle numbers
and increased egg numbers have been correlated with
increased risk of developing OHSS. However, there is no
clear agreement in the literature on the cut-offs used to
determine increased risk. The predictive value of these
parameters is poor, especially for late OHSS.4 Around a
third of cases of severe OHSS occur in cycles that would not be
considered high-risk on the basis of these parameters,
whilst the majority of cycles identified as being high-risk
do not result in OHSS. In cycles where the ovarian
response has exceeded limits thought to be safe, serum
VEGF concentrations prior to the onset of OHSS do not
distinguish between cycles that result in OHSS and cycles that
do not. Prestimulation levels of anti-m
ullerian hormone may
be useful predictors of OHSS risk.6 However, more work is
required to determine cut off levels and ascertain predictive
values. At present there is no single parameter, or combination
of parameters, that offers reliable prediction of OHSS.

Prevention (Box 2)
The risk of OHSS is one of the reasons why alternative
treatments that do not require ovarian stimulation should be
considered where clinically appropriate. Weight optimisation
intervention for women who are obese or underweight
should form first-line treatment. Anti-estrogens, dopamine
agonists and gonadotrophin-releasing hormone (GnRH)
pump may have a role in certain cases and are all
associated with a lower risk of OHSS than ovarian
stimulation. Laparoscopic ovarian diathermy may be an
effective alternative to gonadotrophin ovulation induction in
women with PCOS who do not conceive with clomifene.

Ovulation induction
In anovulatory women, mono-follicular ovulation induction
using gonadotrophins in a chronic low-dose step-up regimen
carries a lower risk of over-stimulation and cycle cancellation
than a step-down regimen.7

2013 Royal College of Obstetricians and Gynaecologists

Prakash and Mathur

Box 2 Strategies to prevent ovarian hyperstimulation syndrome


1 Choice of treatment
2 Ovulation induction
3 In vitro fertilisation regimens
GnRH (gonadotrophin-releasing hormone) antagonist
Coasting
Triggering oocyte maturation with GnRH agonist in antagonist
cycles
4 Single embryo transfer, blastocyst transfer and elective
cryopreservation
5 Luteal phase support: human chorionic gonadotrophin versus
progesterone
6 Other agents, such as metformin, dopamine agonist
7 Cycle cancellation

Ovarian stimulation regimens for IVF


GnRH antagonists are able to provide suppression of
endogenous gonadotrophin release without impairing
pituitary sensitivity to GnRH during ovarian stimulation
for IVF. Regimens using GnRH antagonists yield fewer
oocytes and lower E2 levels compared with GnRH agonist
regimens, and there is evidence from meta-analysis that the
risk of severe OHSS is also lower with GnRH antagonists.8
There may be a specific role for GnRH antagonist regimens in
women thought to be at high risk of OHSS, for instance due
to PCOS or a previous history of OHSS. These groups are at
particularly high risk for developing OHSS and a cautious
regimen for ovarian stimulation, using a low starting dose of
follicle-stimulating hormone (FSH), is appropriate for them.
In women with PCOS who exhibit the highest sensitivity to
exogenous gonadotrophins, in vitro maturation of oocytes
from unstimulated ovaries or following priming with lowdose gonadotrophins, is an increasingly viable option that
avoids OHSS.9

in high-risk cycles managed by coasting,12 but evidence from


randomised trials is lacking. Coasting for periods of greater
than 3 days may be associated with a reduction in pregnancy
rate; hence, if the ovarian response has not settled sufficiently
in such circumstances, cycle cancellation should be discussed
with the patient.

Reducing hCG exposure


The pivotal role of hCG in precipitating OHSS is demonstrated
by in vitro studies and epidemiological data showing a
significantly higher risk of OHSS in IVF cycles with increased
hCG exposure (cycles with conception, multiple pregnancy or
hCG used for luteal support). Complete avoidance of both
hCG and endogenous LH achieved by stopping all
stimulation and continuing pituitary down-regulation
abolishes the risk of OHSS, albeit at the cost of wasting a
treatment cycle. Short of this, measures can be taken to reduce
the hCG exposure to the extent possible. Recombinant LH may
be used in place of hCG for inducing final follicular
maturation, but studies have failed to show a reduced risk of
OHSS, despite the shorter half-life and less marked
luteotrophic effect of LH compared with hCG. An alternative
to hCG in GnRH antagonist cycles is the use of GnRH agonist
to cause an endogenous LH surge. Further research is required
on the optimum method of luteal support if this approach is
used, to obviate the effect of inadequate corpus luteum
development. An alternative to cancellation in cycles with an
excessive ovarian response is elective cryopreservation of all
embryos, thereby avoiding endogenous hCG. This clearly
avoids the risk of late OHSS, but early OHSS risk is unaffected.
Finally, progesterone is as effective as hCG for luteal support
with a lower risk of OHSS and should be the recommended
form of luteal phase support.13

Adjuvants
Coasting
During the course of IVF cycles, an excessive ovarian
response can be managed by stopping gonadotrophin
injections while continuing pituitary suppression, a process
referred to as coasting. This leads to atresia of small and
intermediate-sized follicles, while larger follicles with a
degree of FSH independence continue to grow. The
proposed mechanism for the protective effect of coasting is
through a reduction in the granulosa cell production of
vasoactive mediators, such as VEGF. Serum E2
concentrations continue to rise for 24 to 48 hours, before
falling. When the E2 reaches a safe level, final follicular
maturation is induced and the cycle resumed. Most studies
quote E2 levels of 3000 pg/ml as the safe level of E2 when
they would proceed with triggering ovulation.10,11 A number
of observational studies show a reduced incidence of OHSS

2013 Royal College of Obstetricians and Gynaecologists

The elevated risk of OHSS in women with PCOS may be


related to increased VEGF activity. Insulin is known to
stimulate VEGF protein expression and secretion. Coadministration of metformin for women with PCOS
undergoing IVF shows a reduced incidence of OHSS
(pooled odds ratio [OR] 0.27, 95% confidence interval [CI]
0.160.47).14 Dopamine agonists, cabergoline and
quinagolide have been studied as preventative measures,
having been found to exert a specific effect on vascular
permeability without affecting luteal angiogenesis.15
However, the magnitude of protection and whether or not
dopamine agonists protect against late OHSS is not clear.
Future developments may include applications for specific
antagonists for VEGF and hCG. In the animal model,
hCG antagonist reduces vascular permeability and VEGF
expression dramatically and does not appear to have

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Ovarian hyperstimulation syndrome

any effect on blastocyst development when used after


hCG administration.16

Management
OHSS arises from fertility treatments often carried out in
free-standing units, which may not have the facilities to look
after patients with severe OHSS. Hence, close liaison is called
for between fertility units and acute hospitals where patients
with OHSS may present. All units that may potentially see
patients with OHSS should put in place protocols for
managing such patients and have access to specialised
expertise in an emergency. Patient awareness regarding the
symptoms of OHSS is key and all patients should have access
to an emergency contact out of hours. The RCOG has
produced a patient information leaflet on OHSS which can
be used to educate patients and provide necessary advice,
including symptoms indicative of worsening OHSS that
should prompt urgent medical attention.17
The management of OHSS depends on the severity of the
condition (Table 1). Symptomatic patients should be seen to
establish a diagnosis and assess the severity of OHSS.
Diagnostic confusion may arise between OHSS and other
causes of abdominal pain and distension. It should be kept in
mind that uncomplicated OHSS is not commonly associated
with severe pain. The presence of significant pain and
tenderness should lead to a suspicion of co-existing problems
such as pelvic infection, ovarian torsion and ectopic pregnancy.
Patients with mild OHSS can be managed on an outpatient
basis, with symptomatic relief, monitoring, counselling and
support. Analgesia is provided by paracetamol and codeine.
Non-steroidal anti-inflammatory medications should be
Table 1. Inpatient management of severe ovarian hyperstimulation
syndrome
Monitoring

Analgesia

Fluid balance

Thromboprophylaxis

Third space uid


collections
Surgery
Intensive care

Daily: weight, abdominal girth, intake/output,


full blood count, haematocrit, electrolytes,
liver and renal function tests
As indicated by clinical features: pelvic,
abdominal and chest ultrasound, ECG, blood
gases, chest X-ray
Avoid non steroidal anti-inammatory agents,
consider other causes of pain, such as, torsion
or ectopic pregnancy
Encourage oral intake to thirst, crystalloids for
initial rehydration, colloids for volume
expansion, and consider paracentesis, avoid
diuretics
Low molecular weight heparin, mobilisation, be
aware of atypical presentations with arterial
thrombosis and upper body involvement
Paracentesis of tense ascites, drainage of pleural
effusions
If coexistent torsion or ectopic pregnancy
For critical OHSS

ECG = electrocardiogram

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avoided as they may compromise renal function. Antiemetics may be needed to allow oral intake guided by thirst.
Resolution of symptoms usually occurs in 7 to 10 days if
treatment has not resulted in pregnancy. The course may be
prolonged if pregnancy occurs and there is a risk of increased
severity due to endogenous hCG stimulation.
Patients of severe OHSS and those with significant pain or
nausea limiting oral intake are usually managed as inpatients.
Monitoring and supportive care while awaiting spontaneous
improvement is the mainstay of management. This involves a
strict fluid balance record, 4 hourly pulse and blood pressure
measurement, daily weight and abdominal girth measurement
and daily assessment of electrolytes, liver function and full
blood count. Catheterisation is sometimes required for
accurate monitoring of fluid balance. Clinical assessment of
respiratory function is prudent as pleural effusion is not
uncommon in patients with severe OHSS. Respiratory rate
and oxygen saturation values form a basic part in monitoring
these women and if abnormal, chest X-ray may be indicated.
OHSS appears to cause a fundamental alteration in osmoregulation18 which makes management of fluid balance in
such individuals difficult. Characteristic problems of
electrolyte imbalance include hyponatraemia and
hyperkalaemia in about 50% of women with severe OHSS.
These usually respond to correction of dehydration. Oral fluid
intake, guided by the patients thirst, is a physiological
approach to fluid replacement and is the preferred method of
fluid management. Pain relief and anti-emetic therapy may be
required to help the patient achieve oral hydration.
Intravenous fluid therapy in the presence of increased
capillary permeability carries a risk of increasing ascites and
effusions. However, intravenous fluids have a role where the
patient is unable to drink, or for initial rehydration when the
patient presents with severe haemoconcentration. Initial fluid
replacement is usually with crystalloids. Initial crystalloid
rehydration
not
followed
by
improvement
in
haemoconcentration (haematocrit >45%) or persistent
oliguria (urine output <30 ml/hr) warrants a reassessment
of the situation; colloids such as albumin or hydroxyethyl
starch should then be considered. Diuretics should generally
be avoided as they may worsen hypovolaemia, although there
may be a role for diuretic use in a high-dependency setting if
urine output remains poor despite adequate fluid replacement
(as judged by invasive hemodynamic monitoring such as
central venous pressure measurements) and paracentesis.
Paracentesis should be considered in patients with
respiratory embarrassment due to abdominal distension and
in those who remain oliguric despite adequate rehydration,
which occurs due to a reduction of renal preload. This should
be done under ultrasound guidance to avoid injury to the
enlarged ovaries. There is some evidence that paracentesis
shortens the course of the disease and there may be a role for
this in patients with a prolonged course of OHSS.19 Rarely,

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Prakash and Mathur

pleural effusions causing respiratory compromise unresolved


by ascitic tap may need to be drained separately.
Thrombosis is a serious complication of OHSS with a
reported incidence of 0.710%. A recent review suggested that
arterial thrombosis usually occurs with the clinical
manifestation of OHSS while venous thrombosis may occur
weeks after apparent resolution of symptoms.20
Thromboembolism may be a life threatening complication of
severe OHSS and prophylactic measures are warranted despite
the lack of clinical studies on the value of thromboprophylaxis.
Venous support stockings and prophylactic low molecular
weight heparin should be used in all women with severe OHSS
and those who are admitted to hospital or have reduced mobility.
Current RCOG guidance21 suggests consideration for continuing
prophylactic heparin until the end of the first trimester of
pregnancy. However, patients should be individualised and
counselled depending on their risk factors and in some cases it
may be reasonable to continue thromboprophylaxis for the
duration of pregnancy if complicated by other thrombophilic
conditions. In women who do not conceive,
thromboprophylaxis is usually discontinued at the time of the
withdrawal bleed. Signs and symptoms of thromboembolism
demand prompt additional diagnostic measures (arterial
blood gas measurements, ventilation/perfusion scan) and
therapeutic anticoagulation when the diagnosis is confirmed
or strongly suspected. Atypical presentations of thrombosis
should be kept in mind in women with OHSS, with frequent
involvement of the arterial system and upper body vessels.
Enlarged ovaries are normal in OHSS and do not require
surgery. Indications for surgery in women with OHSS
include coincidental ovarian torsion and ectopic pregnancy.
Hyperstimulated ovaries are very friable and vascular; hence
any surgery if required should only be undertaken by an
experienced surgeon.

Conclusion
Close monitoring of patients of severe OHSS and the use of a
modified early warning score chart may help identify
deteriorating patients who need high-dependency care.
Women with critical OHSS may require management in an
intensive-care setting. A gynaecologist with specialist knowledge and experience of OHSS should coordinate care, which
usually requires multidisciplinary input from physicians, renal
specialists and intensivists.

Conflict of interest
None declared.

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