TOG 2017
Ovarian Hyperstimulation syndrome
approximately 2% of births in the United Kingdom now resulting from in vitro fertilisation.
based on its severity into
mild, moderate, severe and critical.
It can also be divided into early (presenting within 7 days of oocyte retrieval) and late (from 10 days after oocyte retrieval) depending on the period of onset.
Early onset OHSS occurs as a result of exogenous hCG administration for egg maturation in patients with excessive ovarian response to the stimulation.
Late onset OHSS occurs as a result of endogenous hCG from an early pregnancy.
Pathophysiology
physiological change underlying the clinical manifestation of OHSS is increased vascular permeability. This leads to extravasation of fluid from the intravascular compartment into the third space.
Vascular endothelial growth factor (VEGF) is a vasoactive glycoprotein secreted by the granulosa cells of the hyper stimulated ovaries.
VEGF is known to stimulate vascular endothelial cell proliferation, promote ovarian angiogenesis and increase vascular permeability partially mediated through the nitric oxide pathway.
levels of VEGF are directly correlated with the severity of OHSS.
Human chorionic gonadotropin (hCG) is thought to be a crucial mediator of OHSS by activation of the intra ovarian renin-angiotensin system, which plays a role in regulating vascular permeability, endothelial proliferation, angiogenesis and prostaglandin release.
In addition to this, hCG exposure increases the release of VEGF-A by interacting with VEGF receptor 2.
Fluid shift into the third space may cause profound intravascular depletion and haemoconcentration.
Electrolyte imbalance including hyponatremia, hyperkalaemia and hypo osmolality ensues.
Hypovolaemia leads to reduced renal and liver perfusion resulting in oliguria/anuria and alterations of the coagulation cascade.
Intravascular haemoconcentration and the hyper-oestrogenic state significantly increase the risk of thromboembolism.
African American women are at high risk compared to other ethnic groups.
High levels of anti-Mullerian hormone (AMH) produced by the granulosa cells are a better predictor. A high antral follicle count (AFC) >24 is a risk factor, however it is prone to inter-observer variability.
A rapidly increasing level of oestradiol, large number of follicles (>14 with a diameter of 8-12 mm) noted during treatment, large numbers of oocytes retrieved (>20) and usage of hCG for luteal support compared to progesterone are other risk factors.
Preventive measures
Primary prevention
Metformin therapy for Polycystic Ovary Syndrome (PCOS):
metformin is a safe and effective insulin sensitising agent which reduces the risk of OHSS by inhibiting the secretion of VEGF.
A recent Cochrane review has shown that metformin reduces the risk of OHSS by 63% and increases the clinical pregnancy rate without altering the live birth rate.
A daily dose of 500-2000 mg, 4 months prior to the ovarian stimulation, and maintenance of the dosage until oocyte retrieval, pregnancy test or up until 12 weeks’ gestation, is recommended.
Reducing the gonadotropin dose (IUI cycles)
PCOS is a known risk factor for OHSS and aiming for unifollicular ovulation in stimulated cycles will limit the incidence of OHSS.
The dose of gonadotropins used is reduced to 75 IU daily for the first 13 days.
This is followed by a small increase of 37.5 IU for a period of 7 days, or until an ovarian response is noted.
This is called as a step-up regimen and is associated with low risk of OHSS, low risk of cycle cancellation and an increased rate of unifollicular development.
Limiting stimulation so as to keep the lead follicle no more than 12 mm is also associated with a reduced incidence of OHSS.
Reducing the gonadotropin duration in IVF/ICSI cycles
this is achieved by the use of mild stimulation protocols, where the FSH administration is delayed until the mid-late follicular phase.
Administration of FSH on the day of the hCG induction increases the risk of OHSS and should be avoided.
GnRH antagonist protocols
a recent Cochrane review of 2016 showed that antagonist protocols are associated with a reduced risk of OHSS without a significant difference in the live birth rate when compared with agonist cycles.
A meta-analysis in 2014 examining the effect of GnRH antagonist protocols in women with PCOS did not show an overall difference in the incidence of OHSS between antagonist and agonist groups, however a reduction was noted when mild OHSS was excluded from the analysis and cases of moderate and severe OHSS were combined together.
Alternative drugs for triggering ovulation
use of hCG to trigger ovulation and its association with the risk of OHSS is now well established.
This risk is same for both urinary and recombinant hCG.
Even at a low dose of 5000 IU the risk of OHSS cannot be excluded.
There are alternatives to hCG for triggering ovulation;
- GnRH agonists
a recent meta-analysis has shown a positive effect on the reproductive outcome without an increase in the incidence of OHSS.
However, the optimal luteal phase support is still to be established.
Until this is known, the safe alternative after triggering ovulation with GnRH agonists is to electively freeze all embryos and transfer in the subsequent natural or stimulated cycle.
There is added cost and patient inconvenience to this treatment choice.
- Recombinant LH
use of recombinant LH in a recent Cochrane review did not reduce the incidence of severe OHSS. Furthermore, the pregnancy rate was lower and the costs higher.
Individualised treatment regimes:
this involves identifying the high risk population through the use of biomarkers, particularly a combination of both AMH levels and AFC. The treatment regimen is then tailored according to their levels thereby reducing the incidence of OHSS.
There is also evidence of good oocyte yield but there is no increase in the pregnancy rate. Avoidance of hCG for luteal phase support:
progesterone, when used instead of hCG, has shown to halve the risk of OHSS and significantly increase the live birth rate. Therefore use of progesterone instead of hCG is recommended for luteal phase support.
In Vitro Maturation:
IVM following the retrieval of immature oocytes is a safe alternative, but it is not widely used as the pregnancy and implantation rates are not as high as with IVF treatment.
However due to the recent advancements in cryopreservation techniques there has been an improvement in the clinical outcomes.
IVM is therefore a safe alternative to coasting (see later), embryo cryopreservation and cycle cancellation.
Aromatase inhibitors:
no difference in the incidence of OHSS was noted with the use of aromatase inhibitors such as letrezole, in a Cochrane review. Hence it is not routinely used.
Secondary prevention
Freezing all oocytes/embryos
this technique involves cryopreservation of all oocytes/embryos following oocyte retrieval and transfer at a later date in a non-stimulated cycle.
This will not reduce the number of cases of early-onset OHSS but cryopreservation will reduce the incidence of late onset OHSS.
Usage of GnRH agonists as an alternative for triggering ovulation along with cryopreservation eliminates the risk of OHSS.
There is evidence to show other advantages of transferring the embryo in a non-stimulated cycle including a reduced risk of preterm birth, small for gestational age fetus, low birth weight and perinatal mortality.
There is a small increase in the number of large for gestational age babies according to recent reports
Coasting:
coasting is a strategy where the administration of gonadotropins is withheld along with hCG for a few days until the levels of serum oestrogen have declined to acceptable levels.
As a result of this delay, a proportion of the granulosa-lutein cells will have become apoptotic and subsequent levels of VEGF will be lower.
The duration of the delay is usually 3-4 days and cycle cancellation should be considered when coasting for more than 4 days has failed to reach a safe position for triggering ovulation. Resulting oocytes following prolonged coasting are of poorer quality and subsequent implantation and pregnancy rates are lower.
Although widely used it is not a universally accepted technique.
A Cochrane review has shown no evidence of benefit in the use of coasting to prevent OHSS.
Cycle cancellation:
a guaranteed method of eliminating OHSS is cycle cancellation and the withholding of hCG administration.
There is an associated financial and emotional burden for the patient with this preventive strategy however.
Albumin and Hydroxyethyl starch (HES):
it has been postulated that the administration of 25% albumin at the time of oocyte retrieval may help to reduce the incidence of OHSS by binding to, and deactivating, vasoactive mediators.
A Cochrane review found only limited evidence of benefit and hence the routine use of intravenous albumin is not recommended.
HES is a safe alternative to albumin and a Cochrane meta-analysis suggested a statistically significant decrease in the incidence of severe OHSS.
Further research is needed before its routine use becomes a national recommendation. Dopamine agonists:
dopamine agonists act by inactivating VEGF receptor 2 and preventing the increase in vascular permeability.
Cabergoline 0.5 mg is taken daily from the day of hCG injection and continued for 8 days.
There is a moderate amount of evidence to show that dopamine agonists reduce the incidence but not the severity of OHSS, with similar pregnancy rate with routine use.
Investigations
First line investigations
a pelvic ultrasound scan.
The blood investigations
should include haemoglobin, haematocrit, urea, creatinine, albumin, liver function test and CRP.
A haematocrit >45%, serum sodium 5.0 mmol/litre, and elevated creatinine indicate severe disease.
An ultrasound scan
to assess ovarian enlargement, size and number of luteal cysts and the degree of fluid accumulation in the pelvis/abdominal cavity.
A chest X ray is indicated
only in the presence of chest symptoms/signs and similarly less commonly an ECG and ECHO are performed to rule out pericardial effusion.
Outpatient management
Patients with mild to moderate OHSS are suitable for outpatient management.
Women should be given clear written information regarding when to seek assistance.
An appropriate outpatient set up with diligent protocols and careful patient selection are essential to provide safe care.
Patient counselling, support, oral analgesia and adequate hydration form the mainstay of the treatment.
Oral intake should be maintained at no less than 1 litre/day and there is no evidence to recommend electrolyte solutions over water for hydration.
Women are advised to drink to thirst and record their weight every day. Pain relief is managed with simple analgesia like paracetamol and codeine.
NonSteroidal Anti-Inflammatory Drugs (NSAIDS) should be avoided, as they may further impair renal function and can also interfere with implantation.
Nausea and vomiting should be managed with anti-emetic medications
Patients should be reviewed on a regular basis.
Women should be made aware that their symptoms may extend if a pregnancy occurs, due to the endogenous hCG production.
Prolonged bed rest increases the risk of thromboembolism and should be avoided.
Inpatient management
The indications for admission include intractable vomiting, abdominal pain not relieved by simple analgesia, worsening abdominal distension, respiratory compromise, oliguria andworsening of blood markers, mainly a haematocrit >45%.
Analgesia and antiemetic are similar to outpatient management and can also be administered via the parenteral route.
IV Fluid management
In order to prevent multi system organ failure and to ensure tissue and organ perfusion, adequate intravascular volume must be maintained.
There is an acute need for volume replacement in patients admitted to hospitals, however fluid administration may contribute to the accumulation of ascites.
Therefore, strict monitoring of fluid intake and urine output is essential.
Initial hydration may begin with a rapid bolus of 1000 ml of normal saline followed by dextrose saline if there is adequate urine output and a normalisation of the haemoconcentration.
The fluid therapy is maintained at a rate of 125-150 ml/hour,
to ensure an adequate urine output of >20-30 ml/hour.
If intravenous crystalloids fail to maintain adequate urine output, they may be replaced by plasma expanders.
The most commonly used plasma expander is 25% albumin in a dose of 50 g, infused over 4 hours.
[This can be repeated at 4-12 hour intervals as necessary.
Dextran is associated with the development of ARDS and hence is best avoided.
Diuretics in combination with colloids may be considered once adequate intravascular volume has been replaced and the haematocrit is <38%.
Paracentesis
Paracentesis is an important treatment option in severe OHSS resistant to medical management.
Ultrasound guided paracentesis either via the transabdominal or transvaginal route has shown to reduce the duration of hospital stay.
Paracentesis reduces intra-abdominal pressure and improves organ perfusion.
Placement of a catheter permits complete drainage and avoids repeated paracentesis.
Thoracentesis is considered after careful assessment of the degree of respiratory compromise.
Rarely a chest drain insertion may be needed for treatment of a pleural effusion.
Early removal of fluid accumulation and oxygen supplementation reduces the risk of hypoxia.
Thromboprophylaxis
Women with severe OHSS are at increased risk of thromboembolism.
OHSS in the first trimester has a risk score of 4 as per the RCOG GTG no 37a, and therefore warrants thromboprophylaxis.
Thromboprophylaxis includes mobilisation, avoidance of dehydration, use of full-length graduated compressing stockings and administration of low molecular weight heparin.
Use of intermittent pneumatic compression devices should be considered for patients confined to bed.
The optimal duration of treatment is still unclear and therefore needs to be individualised.
Intensive care
Critical OHSS requires multi-disciplinary involvement and intensive care support for managing renal failure or pulmonary complications.
Management of critical OHSS includes monitoring of central venous pressure/pulmonary capillary wedge pressure.
Renal failure may respond to low dose dopamine therapy but occasionally short term dialysis may even be needed.
Pulmonary care may involve oxygen supplementation and assisted ventilation when conservative treatment measures fail.
Termination of pregnancy could be considered in extremely rare life-threatening OHSS.
Surgical treatment
Surgical management is only considered in rare situations where OHSS is complicated by ectopic pregnancy or ovarian torsion.
Pregnancies complicated by OHSS are at risk of adnexal torsion.
As the hyper stimulated ovaries are extremely vascular the surgery is to be undertaken only by experienced surgeons.
The couple should be offered support and counselling should be available to help alleviate the psychological stress associated with severe OHSS.
Reporting
All licensed fertility centres should report their incidence and any hospitalisations related to severe/critical OHSS to the HFEA.
The verbal communication should happen within 12 working hours and an incident form should be completed by 24 working hours.
It is also the responsibility of the admitting centre to inform the originating clinic or assisted conception unit.
MBBRACE-UK requests reporting any death related to OHSS, even if the women were not pregnant.
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