OVARIAN HYPER STIMULATION SYNDROME (OHSS) TREATMENT AND PREVENTION

Ovarian hyper stimulation syndrome (OHSS) is an exaggerated response to ovulation induction. The OHSS is typically associated with exogenous gonodotrophin stimulation and is rarely observed with oral ovulation induction agents.

OHSS is usually a self-limiting disorder. Milder forms resolves spontaneously within few days, but may persist for longer periods and progress to severe disease especially if conception occurs.

More over there is a significant increase in pregnancy related complications among OHSS affected pregnancies. There fore it is the responsibility of the treating physician to well aware of this iatrogenic disease, prevention and management of its complications.

Rates of occurrence • Mild : 8-23% • Moderate : 1-7% • Severe : 0.25% • Mortality • 3/100,000 cycles

AETIOLOGY

Over response

HCG

Over stimulation pregnancy,

PATHOGENISIS

Vascular endothelial growth factor (VGEF)is the main mediator of these exaggerated response. Secondary mediators include renin – angiotensin system and platelet‐derived factors.Associated increased capillary permeability leads to ASCITES, Pleural /Pericardial effusions. Ovarian enlargement may lead to torsion or cyst rupture.

CLASSIFICATION

According to the time of onset classified into

  • Early OHSS: Occurs within 9 days of oocyte retrieval due to exogenous hCG trigger.
  • Late OHSS: Occurs after 10 days of ovum pickup due to endogenous hCG produced by implanting embryo. It is more likely to be severe and lasts longer. (mathur et al Fertil Steril 2000)

CLASSIFICATION (Golan et al 1989)

Grade 1: abdominal distension and discomfort.

Grade 2: grade 1 + nausea,vomiting and/or Diarrhoea, enlarged ovaries (5-12 cm).

Grade 3: grade 2 + ultrasound evidence of ascites

Grade 4: grade 3 + clinical evidence of ascites and/or hydrothorax and breathing difficulties

Grade 5: grade 4 + haemoconcentration, increase blood viscosity, coagulation abnormality and diminished renal perfusion

Modification of Navot et al (1992) CRITICAL OHSS

Variable enlarged ovary Tense ascites Hydrothorax Hct >55% WBC >25 000 Oliguria Creatinine >1.6 Creatinine clearance <50ml/min Renal failure; Thromboembolic phenomena; ARDS

MANAGEMENT

PREDICTION

Young patients

Lean women

Polycystic Ovarian syndrome

Previous OHSS

Increased antral follicular count (> 10 per ovary)

Increased anti mullerian hormone levels (>3.3 ng/ml)

High or rapidly rising E2 levels (> E2 5,000 pg/ml)

High number of follicles (≥18)

PRIMARY PREVENTION

Insulin- Sensitizing agents

Reducing dose of gonadotropins

GnRH antagonists protocols

Low dose of hCG /r hcg/r LH

Alternative agents to hcg

Avoiding hCG for Luteal support

In vitro oocyte maturation (IVM)

INSULIN SENSITIZERS

Metformin suppresses insulin levels & decreases ovarian androgen production with improved ovulatory rates.

Metformin treatment before or during ART cycles decreased the risk of OHSS in PCOS women. (Cochrane Database of Systematic Reviews 2014)

REDUCED GONADOTROPHIN

Chronic low dose step up protocol results in better pregnancy rates with reduced incidence of OHSS compared to high dose regimens in IUI cycles.

Minimal stimulation / natural cycle IVF.

Using r FSH instead of urinary FSH have no effect in reducing the incidence of OHSS.

ANTAGONIST PROTOCOL

The use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS and there was no evidence of a difference in live-birth rates.

The added advantage being possibility of using agonist instead of hcg to trigger final oocyte maturation. (Cochrane Database of Systematic Reviews 2011)

LOW DOSE HCG / R- LH

The trigger of oocyte maturation with low dose of hCG in high-risk patients reduces the risk of OHSS. (kolibianakis et al 2007,ying et al 2013).

No evidence of difference between rhCG or rhLH and uhCG in achieving final follicular maturation with equivalent pregnancy rates and OHSS incidence. (Cochrane Database of Systematic Reviews 2011)

GNRH AGONIST TRIGGER

Use of GnRH agonists instead of HCG for trigger results in a lower incidence of OHSS but extremely high early pregnancy loss due to luteolysis.

Luteal rescue is still possible with low dose hcg (1500 IU) with comparable pregnancy rates and minimal risk of OHSS. (humaidan et al 2012)

GnRH agonist could be useful for cryopreservation & and donor/ recipient cycles. (Cochrane Database of Systematic Reviews 2014)

AVOIDING HCG FOR LPS

Progesterone, hCG or GnRH agonists are used for LPS but use of hCG was linked to significantly higher risk of OHSS.

Progesterone seems to be the best option as LPS in high risk patients with out the risk of OHSS. (Cochrane Database of Systematic Reviews 2011)

 IN VITRO MATURATION

It is an attractive strategy to prevent OHSS in PCOS patients. It involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by IVM & ICSI

Though promising data on the IVM technique have been published, unfortunately there is still no evidence from RCTs upon which to base any practice recommendations.

SECONDARY PREVENTION

Cycle cancellation

Coasting

Cryopreservation

Intravenous albumin and HES

Dopamine agonists

Calcium gluconate infusion

Luteal phase antagonist

CANCELLATION

Cycle cancellation before administration of hcg is an effective strategy for the prevention of OHSS.  May be acceptable in an IUI cycle but not in an IVF cycle because of the financial burden and psychological stress to the patient.

COASTING

Coasting involves withholding further gonadotropin stimulation & delaying hCG administration until E2 levels plateau or decrease significantly .There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions. (Cochrane Database of Systematic Reviews 2011)

CRYOPRESERVATION

Cryopreservation involves freezing of all embryos to be thawed & implanted at a later date.  Early OHSS may occur but it almost eliminates the risk of late OHSS.  Though reduced pregnancy rates from frozen- thawed embryos was a concern, the introduction of vitrification technique shows promising results. (CDC Report 2005,Fertil Steril 2008)

IV ALBUMIN vs HES

There is limited evidence of benefit from intra- venous albumin administration at the time of oocyte retrieval in the prevention of severe OHSS.  Where as Hydroxyethyl starch markedly decreases the incidence of severe OHSS and this is a cheaper, potentially safer alternative to albumin. (Cochrane Database of Systematic Reviews 2011)

DOPAMINE AGONIST

Cabergoline appears to reduce the risk of OHSS in high-risk women, especially for moderate OHSS. (0.5 mg daily for 8 days post hcg trigger) . The use of cabergoline does not affect the pregnancy outcome nor is there an increased risk of adverse events. (Cochrane Database of Systematic Reviews 2012)

CA GLUCONATE / ANTAGONIST Calcium infusion (10 ml of 10% IV Ca gluconate in 2oo ml saline for 3 days post OPU) can effectively prevent severe OHSS and decreases OHSS occurrence rates. (Naredi & Karunkaran 2013)  Antagonists 0.25 mg daily from day 5 -8 post OPU with or without embryo transfer causes rapid resolution of early onset severe OHSS. (Lainas et al 2012,2013).

RECOMMENDED

Metformin co‐treatment in PCOS.

Lower starting dose of FSH

GnRH antagonist protocol

GnRH agonist trigger

Avoiding hCG for luteal support

Dopamine agonists

Elective single embryo transfer

Cryopreservation of all embryos (Canadian task force 2014)

NOT RECOMMENDED

Intravenous albumin during OPU

Coasting > 3 days

Using one type of FSH versus another

Lowering dose of hCG for final oocyte maturation

Using rec LH instead of hCG for trigger (Canadian task force 2014)

MANAGEMENT

Out patient management is the norm in mild to moderate OHSS.

Monitor hematological & renal parameters

USG to asses severity of OHSS

Adequate oral hydration to prevent haemoconcentration / oliguria

GNRH antagonist & dopamine agonist to control early OHSS.

CRITICAL OHSS •

Multi disciplinary management in a intensive care unit

Strict fluid & electrolyte management

Crystalloids & HES for hydration

IV albumin if required

Thromboprophylaxsis

Paracentesis/culdocentesis/pleuracentesis relieves abdominal tension & dysnoea. It also promotes diuresis & clinical resolution.

Antagonist protocol with agonist trigger and vitrification of all embryos for subsequent transfer in natural / estrogen administered cycles (segmentation of IVF) seems to be the best available option at present to reduce the incidence and severity of OHSS.

Further research is needed to explore possibilities of fresh embryo transfer to reduce the cost and improve outcome.

Dr. IRA BISWAS

 

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