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x 2013;15:31–5
The Obstetrician & Gynaecologist
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Please cite this paper as: Prakash A, Mathur R. Ovarian hyperstimulation syndrome. The Obstetrician & Gynaecologist 2013;15:31–5.
tends to be more severe than early OHSS and is poorly involvement of the arterial system with various case reports
predictable from the antecedent ovarian response to documenting ischaemic strokes, and carotid and vertebral
stimulation.4 There is no consensus on the most appropriate artery occlusions. Thrombosis often presents several weeks
classification of OHSS severity. The scheme put forward by after the apparent resolution of OHSS, making it important
Mathur et al.5 represents an evolution of previous to have a high degree of suspicion for this complication,
classifications and aims to identify patients most in need of particularly in women presenting with atypical features
close monitoring and treatment (Box 1). Furthermore, it is including visual and neurological symptoms.
important to realise that OHSS is a dynamic condition and
the level of severity may change over time and hence all Risk factors and prediction
patients should be counselled regarding warning symptoms.
A number of pretreatment patient characteristics and ovarian
response parameters have been studied as predictors of OHSS.
Box 1 Classification of ovarian hyperstimulation syndrome (OHSS) Younger age, presence of polycystic ovaries (PCO) and a past
(Mathur et al. 20055). OHSS may be early onset (within 9 days of history of OHSS all increase the risk of OHSS.2
human chorionic gonadotrophin [hCG] trigger) or late onset (after
9 days from HCG trigger) with severity as indicated below
During ovarian stimulation, high serum estradiol (E2)
concentrations, a rapid rise in serum E2, high follicle numbers
Mild OHSS and increased egg numbers have been correlated with
Abdominal bloating increased risk of developing OHSS. However, there is no
Mild abdominal pain
clear agreement in the literature on the cut-offs used to
Ovarian size usually <8 cm*
Moderate OHSS determine increased risk. The predictive value of these
Moderate abdominal pain parameters is poor, especially for late OHSS.4 Around a
Nausea vomiting third of cases of severe OHSS occur in cycles that would not be
Ultrasound evidence of ascites
Ovarian size usually 8–12 cm*
considered ‘high-risk’ on the basis of these parameters,
Severe OHSS whilst the majority of cycles identified as being ‘high-risk’
Clinical ascites (occasionally hydrothorax) do not result in OHSS. In cycles where the ovarian
Oliguria response has exceeded limits thought to be safe, serum
Haemoconcentration Haematocrit >45%
Hypoproteinaemia
VEGF concentrations prior to the onset of OHSS do not
Ovarian size usually >12 cm* distinguish between cycles that result in OHSS and cycles that
Critical OHSS do not. Prestimulation levels of anti-m€ ullerian hormone may
Tense ascites or large hydrothorax be useful predictors of OHSS risk.6 However, more work is
Haematocrit >55%
White cell count >25 000 ml 1
required to determine cut off levels and ascertain predictive
Oligo/anuria values. At present there is no single parameter, or combination
Thromboembolism of parameters, that offers reliable prediction of OHSS.
Adult respiratory distress syndrome (ARDS)
*Ovarian size may not correlate with severity of OHSS in cases of Prevention (Box 2)
assisted reproduction because of the effect of follicular aspiration
The risk of OHSS is one of the reasons why alternative
treatments that do not require ovarian stimulation should be
Abdominal distension and discomfort are the common initial considered where clinically appropriate. Weight optimisation
symptoms of OHSS, reflecting ovarian enlargement and the intervention for women who are obese or underweight
beginning of fluid accumulation in the peritoneal cavity. Severe should form first-line treatment. Anti-estrogens, dopamine
pain is uncommon and its presence should lead to a suspicion of agonists and gonadotrophin-releasing hormone (GnRH)
a co-incident complication, such as ovarian torsion or ectopic pump may have a role in certain cases and are all
pregnancy. Increasing severity leads to clinically detectable associated with a lower risk of OHSS than ovarian
ascites, which may eventually progress to pleural and pericardial stimulation. Laparoscopic ovarian diathermy may be an
effusions. Respiratory discomfort and dyspnoea result from effective alternative to gonadotrophin ovulation induction in
effusions and the splinting effect of ascites on the diaphragm. women with PCOS who do not conceive with clomifene.
Pulmonary oedema is a rare but serious complication associated
with vigorous intravenous fluid therapy.
Ovulation induction
Intravascular dehydration and the specific effect of
cytokines such as VEGF increase the risk of thrombosis in In anovulatory women, mono-follicular ovulation induction
women with OHSS. Thrombosis in this condition differs using gonadotrophins in a chronic low-dose step-up regimen
from that commonly seen in gynaecological practice, in that carries a lower risk of over-stimulation and cycle cancellation
there is a preponderance of upper body sites and frequent than a step-down regimen.7
any effect on blastocyst development when used after avoided as they may compromise renal function. Anti-
hCG administration.16 emetics 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
Management
prolonged if pregnancy occurs and there is a risk of increased
OHSS arises from fertility treatments often carried out in severity due to endogenous hCG stimulation.
free-standing units, which may not have the facilities to look Patients of severe OHSS and those with significant pain or
after patients with severe OHSS. Hence, close liaison is called nausea limiting oral intake are usually managed as inpatients.
for between fertility units and acute hospitals where patients Monitoring and supportive care while awaiting spontaneous
with OHSS may present. All units that may potentially see improvement is the mainstay of management. This involves a
patients with OHSS should put in place protocols for strict fluid balance record, 4 hourly pulse and blood pressure
managing such patients and have access to specialised measurement, daily weight and abdominal girth measurement
expertise in an emergency. Patient awareness regarding the and daily assessment of electrolytes, liver function and full
symptoms of OHSS is key and all patients should have access blood count. Catheterisation is sometimes required for
to an emergency contact out of hours. The RCOG has accurate monitoring of fluid balance. Clinical assessment of
produced a patient information leaflet on OHSS which can respiratory function is prudent as pleural effusion is not
be used to educate patients and provide necessary advice, uncommon in patients with severe OHSS. Respiratory rate
including symptoms indicative of worsening OHSS that and oxygen saturation values form a basic part in monitoring
should prompt urgent medical attention.17 these women and if abnormal, chest X-ray may be indicated.
The management of OHSS depends on the severity of the OHSS appears to cause a fundamental alteration in osmo-
condition (Table 1). Symptomatic patients should be seen to regulation18 which makes management of fluid balance in
establish a diagnosis and assess the severity of OHSS. such individuals difficult. Characteristic problems of
Diagnostic confusion may arise between OHSS and other electrolyte imbalance include hyponatraemia and
causes of abdominal pain and distension. It should be kept in hyperkalaemia in about 50% of women with severe OHSS.
mind that uncomplicated OHSS is not commonly associated These usually respond to correction of dehydration. Oral fluid
with severe pain. The presence of significant pain and intake, guided by the patient’s thirst, is a physiological
tenderness should lead to a suspicion of co-existing problems approach to fluid replacement and is the preferred method of
such as pelvic infection, ovarian torsion and ectopic pregnancy. fluid management. Pain relief and anti-emetic therapy may be
Patients with mild OHSS can be managed on an outpatient required to help the patient achieve oral hydration.
basis, with symptomatic relief, monitoring, counselling and Intravenous fluid therapy in the presence of increased
support. Analgesia is provided by paracetamol and codeine. capillary permeability carries a risk of increasing ascites and
Non-steroidal anti-inflammatory medications should be effusions. However, intravenous fluids have a role where the
patient is unable to drink, or for initial rehydration when the
Table 1. Inpatient management of severe ovarian hyperstimulation patient presents with severe haemoconcentration. Initial fluid
syndrome
replacement is usually with crystalloids. Initial crystalloid
Monitoring Daily: weight, abdominal girth, intake/output, rehydration not followed by improvement in
full blood count, haematocrit, electrolytes, haemoconcentration (haematocrit >45%) or persistent
liver and renal function tests
oliguria (urine output <30 ml/hr) warrants a reassessment
As indicated by clinical features: pelvic,
abdominal and chest ultrasound, ECG, blood of the situation; colloids such as albumin or hydroxyethyl
gases, chest X-ray starch should then be considered. Diuretics should generally
Analgesia Avoid non steroidal anti-inflammatory agents, be avoided as they may worsen hypovolaemia, although there
consider other causes of pain, such as, torsion
or ectopic pregnancy
may be a role for diuretic use in a high-dependency setting if
Fluid balance Encourage oral intake to thirst, crystalloids for urine output remains poor despite adequate fluid replacement
initial rehydration, colloids for volume (as judged by invasive hemodynamic monitoring such as
expansion, and consider paracentesis, avoid central venous pressure measurements) and paracentesis.
diuretics
Thromboprophylaxis Low molecular weight heparin, mobilisation, be
Paracentesis should be considered in patients with
aware of atypical presentations with arterial respiratory embarrassment due to abdominal distension and
thrombosis and upper body involvement in those who remain oliguric despite adequate rehydration,
Third space fluid Paracentesis of tense ascites, drainage of pleural which occurs due to a reduction of renal preload. This should
collections effusions
Surgery If coexistent torsion or ectopic pregnancy be done under ultrasound guidance to avoid injury to the
Intensive care For critical OHSS enlarged ovaries. There is some evidence that paracentesis
shortens the course of the disease and there may be a role for
ECG = electrocardiogram
this in patients with a prolonged course of OHSS.19 Rarely,
pleural effusions causing respiratory compromise unresolved 2 Delvigne A, Rozenberg S. Systematic review of data concerning
etiopathology of ovarian hyperstimulation syndrome. Int J Fertil
by ascitic tap may need to be drained separately.
Womens Med 2002;47:211–26.
Thrombosis is a serious complication of OHSS with a 3 McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr,
reported incidence of 0.7–10%. A recent review suggested that et al. Vascular endothelial growth factor as capillary permeability
arterial thrombosis usually occurs with the clinical agent in ovarian hyperstimulation syndrome. Lancet 1994;344:235–6.
4 Mathur RS, Akande AV, Keay SD, Hunt LP, Jenkins JM. Distinction
manifestation of OHSS while venous thrombosis may occur
between early and late ovarian hyperstimulation syndrome. Fertil Steril
weeks after apparent resolution of symptoms.20 2000;73:901–7.
Thromboembolism may be a life threatening complication of 5 Mathur R, Evbuomwan I, Jenkins J. Prevention and management of
severe OHSS and prophylactic measures are warranted despite ovarian hyperstimulation syndrome. Curr Obstet Gynaecol
2005;15:132–8.
the lack of clinical studies on the value of thromboprophylaxis. 6 Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-
Venous support stockings and prophylactic low molecular Mullerian hormone and estradiol levels as predictors of ovarian
weight heparin should be used in all women with severe OHSS hyperstimulation syndrome in assisted reproduction technology cycles.
and those who are admitted to hospital or have reduced mobility. Hum Reprod 2008;23:160–7.
7 Homburg R, Levy T, Ben-Rafael Z. A comparative prospective study of
Current RCOG guidance21 suggests consideration for continuing conventional regimen with chronic low-dose administration of follicle-
prophylactic heparin until the end of the first trimester of stimulating hormone for anovulation associated with polycystic ovary
pregnancy. However, patients should be individualised and syndrome. Fertil Steril 1995;63:729–33.
counselled depending on their risk factors and in some cases it 8 Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M,
Smit J, et al. Gonadotrophin-releasing hormone antagonists for
may be reasonable to continue thromboprophylaxis for the assisted conception. Cochrane Database Syst Rev 2006;(3):CD001750.
duration of pregnancy if complicated by other thrombophilic 9 Tan SL, Child TJ. In-vitro maturation of oocytes from unstimulated
conditions. In women who do not conceive, polycystic ovaries. Reprod Biomed Online 2002;4(Suppl 1):18–23.
10 Mansour R, Aboulghar M, Serour G, Amin Y, Abou-Setta AM. Criteria
thromboprophylaxis is usually discontinued at the time of the
of a successful coasting protocol for the prevention of severe ovarian
withdrawal bleed. Signs and symptoms of thromboembolism hyperstimulation syndrome. Hum Reprod 2005;20:3167–72.
demand prompt additional diagnostic measures (arterial 11 Levinsohn-Tavor O, Friedler S, Schachter M, Raziel A, Strassburger D,
blood gas measurements, ventilation/perfusion scan) and Ron-El R. Coasting-what is the best formula? Hum Reprod
2003;18:937–40.
therapeutic anticoagulation when the diagnosis is confirmed
12 Al-Shawaf T, Zosmer A, Hussain S, Tozer A, Panay N, Wilson C, et al.
or strongly suspected. Atypical presentations of thrombosis Prevention of severe ovarian hyperstimulation syndrome in IVF with or
should be kept in mind in women with OHSS, with frequent without ICSI and embryo transfer: a modified ‘coasting’ strategy based
involvement of the arterial system and upper body vessels. on ultrasound for identification of high-risk patients. Hum Reprod
2001;16:24–30.
Enlarged ovaries are normal in OHSS and do not require 13 van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M.
surgery. Indications for surgery in women with OHSS Luteal phase support for assisted reproduction cycles. Cochrane
include coincidental ovarian torsion and ectopic pregnancy. Database Syst Rev 2011;(10):CD009154.
Hyperstimulated ovaries are very friable and vascular; hence 14 Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin
treatment before and during IVF or ICSI in women with polycystic ovary
any surgery if required should only be undertaken by an syndrome. Cochrane Database Syst Rev 2009;(2):CD006105.
experienced surgeon. 15 Garcia-Velasco JA. How to avoid ovarian hyperstimulation syndrome: a
new indication for dopamine agonists. Reprod Biomed Online
2009;18(Suppl 2):71–5.
Conclusion 16 Vardhana PA, Julius MA, Pollak SV, Lustbader EG, Trousdale RK, Lustbader
JW. A unique hCG-antagonist suppresses ovarian hyperstimulation
Close monitoring of patients of severe OHSS and the use of a syndrome (OHSS) in rats. Endocrinology 2009;150:3807–14.
modified early warning score chart may help identify 17 Royal College of Obstetricians and Gynaecologists. Ovarian
deteriorating patients who need high-dependency care. Hyperstimulation Syndrome: What You Need to Know. London:
RCOG; 2007 [http://www.rcog.org.uk/womens-health/clinical-
Women with critical OHSS may require management in an guidance/ovarian-hyperstimulation-syndrome-what-you-need-know].
intensive-care setting. A gynaecologist with specialist knowl- 18 Evbuomwan IO, Davison JM, Murdoch AP. Coexistent
edge and experience of OHSS should coordinate care, which hemoconcentration and hypoosmolality during superovulation and in
usually requires multidisciplinary input from physicians, renal severe ovarian hyperstimulation syndrome: a volume homeostasis
paradox. Fertil Steril 2000;74:67–72.
specialists and intensivists. 19 Levin I, Almog B, Avni A, Baram A, Lessing JB, Gamzu R. Effect of
paracentesis of ascitic fluids on urinary output and blood indices in
Conflict of interest patients with severe ovarian hyperstimulation syndrome. Fertil Steril
None declared. 2002;77:986–8.
20 Chan WS. The ‘ART’ of thrombosis: a review of arterial and venous
thrombosis in assisted reproductive technology. Curr Opin Obstet
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