OHSS

OHSS

Clinical Gynecologic Endocrinology and Infertility, 8th edition Fogsi Focus, OHSS Date: 29th March 2015 1 OHSS, Dr. PrashantPujara.

DEFINITION - OHSS is an iatrogenic complication of the luteal phase and/or early pregnancy after ovulation induction or of ovarian stimulation (in the context of IUI/IVF).

ESSENTIAL CHARACTERSTICS - Marked ovarian enlargement.

- High serum estradiol.

- Extra vascular exudate accumulation secondary to ↑ed vascular permeability and shift of proteins & fluid from vascular tree into the peritoneal cavity.

- Depletion of intra vascular volume (haemoconcentration, diminished organ perfusion & propensity for thromboembolism).

- Ovarian neo-angiogenesis.

CAUSES - Exaggerated response to ovulation induction.  Gonadotropins (urinary HMG, pure FSH)  GnRH  CC (rare)  Letrozole - Rarely in pregnancies with supraphysiological concentration of hCG (multiple gestations, molar pregnancy).

- Cases of recurrent OHSS in singleton pregnancies in individuals and families (familial OHSS) are linked to germ line mutations in the FSH receptor resulting in the loss of ligand specificity that permits activation by hCG. INCIDENCE

- Incidence 5-10%  Mild 20-33% of IVF cycle  Moderate 3-8%  Severe 0.1-0.5% ETIOPATHOGENESIS Hyper-stimulated ovaries ↓ Release of vasoactive mediator (prostaglandins, cytokines, VEGF, renin, angiotensin, endothelin) ↓ Endothelial injury, vasodilation&↑sed angiogenesis ↓ ↑ed capillary permeability ↓ 3rd space fluid accumulation (tense ascites)

Hypovolemia

Oliguria

Haemoconcentration Thrombosis End organ failure

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Electrolyte imbalance

Azotemia

Hypovolemic shock

CLASSIFICATION Early Onset(3-9 days after hCG) Reflects excessive ovarian response and the effect of exogenous hCG.

Mild Grade 1 - Abdominal distension and discomfort.

Late Onset(12-17 days after hCG) Related to pregnancy and the number of gestational sacs and reflects endogenous hCG production by implanting embryo.

Golan et al Moderate Grade 3 - Grade 2 + USG evidence of ascites.

Grade 2 - Grade 1 + nausea, vomiting and/or diarrhoea, enlarged ovaries 5-12 cm.

Severe Grade 4 - Grade 3 + clinical e/o ascites and/or hydrothorax and breathing difficulties.

Grade 5 - Grade 4 + haemoconcentration, increased viscosity, coagulation abnormality and diminished renal perfusion.

Daniel Navot et al, 1992 Severe OHSS Critical OHSS Clinical ascites Âą hydrothorax Tense ascites Âą large hydrothorax Haemoconcentration - PCV > 45% Worsening haemoconcentration - PCV > 55% TC > 15000/ml TC > 25000/ml Oliguria with normal serum creatinine (1-1.5), Oliguria/anuria with elevated serum creatinine > 1.6, creatinine clearance >50ml/min creatinine clearance < 50ml/min, renal failure Liver dysfunction, hypo-protienemia, anasarca ARDS, thromboembolic phenomena variably enlarged ovaries variably enlarged ovaries RISK FACTORS - Young age (<30 years), - Low body weight, - PCOS, - Higher doses of exogenous gonadotropins, - Large number of oocytes retrieved, - Large number of small and intermediate sized ovarian follicles, - High absolute or rapidly rising serum E2 levels (>2500 pg/ml), - hCG after ovulation for luteal phase support, - Pregnancy, - Previous OHSS, - H/O of atopy or allergy.

SIGNS AND SYMPTOMS - Distension of lower abdomen, - Ovaries enlarged up to > 12cm, - Nausea and vomiting, - Dyspnoea and respiratory distress, - Diarrhoea, - Rapid weight gain, - Pleural effusion (more frequently on the right side) & pericardial effusion, - Ascites is an exudate (hypo-protienemia&hypo-albuminaemia), - ARDS, - Hypotension, - Oliguria and anuria.

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COMPLICATIONS - Electrolyte imbalance-hyponatraemia with hyperkalaemic acidosis, - Increased thrombogenesis (0.7-10%)-haemo-concentration and immobility. Arterial, venous and intra-cerebral thrombosis occurs. Thrombosis in upper extremities and arterial thrombosis are common, - Cardio-respiratory failure-effusions, ascites and ARDS, - Ovarian torsion, rupture/bleeding into ovarian cyst, - Pre-renal failure & multiple organ failure-death (1/500,000 cycle).

INVESTIGATIONS - Complete Blood Count, - Serum Electrolytes, - Serum total proteins, - Chest X-Ray, - Pelvic ultrasound with Doppler studies, - Blood urea and Serum Creatinine, - Liver function test, - ECG and ECHO.

DIFFERENTIAL DIAGNOSIS - Ovarian cyst torsion/haemorrhage, - Pelvic infection, - Intra-abdominal haemorrhage, - Ectopic pregnancy, - Other acute abdomen.

MANAGEMENT PRIMARY PREVENTION - Life style changes (diet, exercise).

- LODS in PCOS. - Reducing the starting dose of gonadotropin for ovulation induction.

- Use of chronic low dose step up protocols in PCOS. - Oral ovulation induction.

- Identifying the women with thrombophilia and positive for anti-phospholipids antibodies.

- Limited ovarian stimulation, which involves stimulation of follicle only to a size of 12mm.

- Antagonist based protocols (Cochrane review 2009) are short and simple with good clinical outcome and significant reduction in incidence of severe OHSS. - Re-initiation ofGnRH antagonist 3 days after oocyte retrieval, in cases diagnosed with severe OHSS for 1 week.

- Using progesterone (50 mg/d injectable or 100 mg or 8% gel/dsuppositories) rather thanhCG for luteal phase support.

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- In Vitro Maturation - in patient with PCOS, patients at risk of OHSS (not widely used owing to reduced live birth rate compared to conventional IVF).

SECONDARY PREVENTION - Cycle cancellation if ultrasound reveals a large number of developing follicles and/or serum estradiol levels are excessively high.

Withhold the ovulatory trigger (hCG).

In cycles where GnRH agonists have not been used, this may not completely prevent early-onset OHSS as a natural LH surge may still occur.

- Coasting -withholding further gonadotropin stimulation and delaying hCG administration, while continuing GnRH agonist and ultrasound and endocrine monitoring until the estradiol level falls below safe limit (<2500 pg/ml or 9000 pmol/l).

Alternative to cycle cancellation.

Allows FSH levels to drop, thus inhibiting granulose cell proliferation and subsequent availability for luteinisation.

Coasting does not completely avoid severe OHSS but significantly reduces the incidence and severity.

Some oocytes may be lost specially if coasting is more than 4 days; it also affects endometrial maturation status and reduces the chances of pregnancy.

- Compared with the standard dose of 10,000 IU,reduced doses of 5,000 IU hCGreduces the risk of hyperstimulation.

- Use of alternative agents for triggering ovulation like GnRH agonist (leuprolide 0.5-1mg) or recombinant LH, thereby avoiding the longer duration of action and further stimulation of hCG, but are associated with reduced pregnancy rates and have poor cost benefit ratio.

- Use of endogenous LH, instead of exogenous hCG to trigger the final oocyte maturation.

-Cryopreservation of all embryos prevents conception and late onset OHSS if there are excessive numbers of follicles and oocytes recovered. Routine cryopreservation in cases with high risk of OHSS is not recommended.

- Prophylactic IV Albumin - is a volume expander and has direct action on membrane permeability. It is a plasma binding protein that may bind to the vasoactive agents responsible for the development of OHSS and facilitate there removal from the circulation.Optimal timing and dose are unclear, as is its effect on implantation. Other risks include febrile reactions, anaphylactic shock and risk of virus and prion transmission.

- HES solution (6%) can be infused at the time of oocyte collection and repeated after 48 hrs later. It is cheaper, potentially safer alternative to albumin.

- Dopamine agonist (cabergoline 0.5mg/d for 8 days from the day of hCG) acts on the dopamine receptor 2, inhibits VEGFR - 2 dependent vascular permeability and angiogenesis.

OUT PATIENT MANAGEMENT - Mild & moderate OHSS can be managed on an outpatient basis.

- Analgesics (paracetamol,codein phosphate), avoid NSAIDs. - Avoid intercourse (painful and increases the risk of ovarian rupture).

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- Avoid further hCG but continue progesterone support.

- Treatment of worsening OHSS requires antiemetic & more potent analgesic on an outpatient basis and…

• Frequent physical and ultrasound examination (to detect increasing ascites), • Monitoring of daily weight and urinary frequency, • Serial laboratory determination of hematocrit, electrolytes, and serum creatinine, • At least daily communication, if not examination, to ensure that progression to more severe disease is promptly recognized.

Recommendation for the outpatient management of persistent and worsening OHSS includes: 1. Oral fluid intake should be maintained at no less than 1 L per day, any of the commercially available electrolyte supplemented drinks is preferable to other beverages.

2. Avoid strenuous physical activity(increases risk of ovarian torsion). Maintain light physical activity. Strict bed rest increases risk of thromboembolism.

3. Weight should be recorded daily, as well as the frequency and/or volume of urine output. Weight gain of > 2 pounds daily and decreasing urinary frequency are indications for prompt clinical and laboratory re-evaluation.

4. Pregnant patient with OHSS must be monitored very closely because risk of progressing to severe disease is particularly high, as continuous stimulation by rapidly rising endogenous concentrations of serum hCG. 5. In ART cycles, it may be necessary to consider cryopreserving all embryos and deferring transfer to subsequent cycle after symptoms have completely resolved. Although pregnancy rates in frozen embryo transfer cycles are generally lower than in fresh cycles, this approach may reduce the risk for developing severe OHSS without a marked decrease in pregnancy rates per cycle.

HOSPITALIZATION - Moderate OHSS if pain/nausea not controlled by oral therapy or if close out-patient monitoring not possible & severe OHSS. - No one symptom or sign is an absolute indication, but hospitalization should be considered when one or more of the following are present…

• • • • • •

Severe abdominal pain or peritoneal signs, Intractable nausea and vomiting, Severe oliguria or anuria, Tense ascites, Dyspnoea or tachypnea, Hypotension (relative to baseline), dizziness, or syncope,

Laboratory findings in women with serious illness resulting from OHSS include…

• • • • •

Hemoconcentration (hematocrit> 45%), Leukocytosis (white blood cell count > 15,000), Electrolyte imbalances (hyponatremia: sodium <135mEq/l; hyperkalemia: potassium>5.0mEq/l), Elevated liver enzymes, Decreased creatinine clearance (serum creatinine >1.2; creatinine clearance <50mL/min).

Recommendations for the evaluation and monitoring of hospitalized patients with OHSS include…

• •

Vital signs (every 2-8 hours), Weight, AG at the naval (daily), 6 OHSS, Dr. PrashantPujara.

• • • • • • • • • •

Complete physical examination [chest, abdomen, lower limbs] (daily, avoid bimanual examination of the ovaries due to risk of ovarianrupture), I/O monitoring (daily or more often ), Ultrasound examination (ascites, ovarian size), repeated as necessary to guide management orParacentesis, CXR & ECG (when pleural or pericardial effusion is suspected), repeated asnecessary, Pulse oximetry (for patients with symptoms of pulmonary compromise), CBC (daily, or more often as needed to guide fluid management), LFT, Coagulation profile, Electrolytes (daily), Serum creatinine or creatinine clearance, urine specific gravity, repeated as necessary.

- Complaints of increasing abdominal pain and distension demand immediate attention, remaining mindful that pain and ascites can mask ovarian rupture and acute intra-abdominal hemorrhage. Serial clinical and laboratory evaluation monitors progression of illness, response to treatment and recognizes evidence of resolution.

Analgesics (avoid NSAIDs)&Antiemetics Fluid management - IV fluid management must restore an effective plasma volume but not contribute to the accumulation of extravascular fluid.

- After initial rehydration, fluids should be administered in the lowest volumes necessary to maintain adequate urine output (30ml/hr) and relieve hemoconcentration; because of the tendency to hyponatremia, saline is preferable to RL. - When saline fails, slow infusions of 25% albumin (50-100g in 200 ml at 50ml/hr over 4 hours) at 4–12 h intervals can effectively expand plasma volume.

- Correction of hypovolemia, hypotension, and oliguria has utmost priority.

-Diuretics (furosemide 20mg IV) may be considered after an adequate intravascular volume has been restored (haematocrit <38%). IV fluid support can be reduced after diuresis begins and oral intake is re-established.

- Hyperkalemia may require specific treatment to move potassium into the intracellular space (insulin/glucose, sodium bicarbonate) or to prevent cardiac dysrhythmias (calcium gluconate).

Paracentesis - Ultrasound (TAS/TVS) guided paracentesis (to avoid inadvertent puncture of vascular ovaries with distended large luteal cysts)is indicated for patients with…

• Ascites (that causes pain), • Compromised pulmonary function, • Oliguria/anuria (that does not improve with fluid management).

- Remove gradually → maximum of 4 litres over 12 hours.

- IV colloid replacement should be considered for women who have large volume of ascitic fluid drained.

Massive fluid shifts may cause cardiovascular collapse.

- Paracentesis will be effective in resolving hydrothorax and thoracocentesis may be reserved for those with bilateral or severe effusion that persist.

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Thomboprophylaxis - Thomboprophylaxis should be provided for all admitted in the hospital with OHSS and continued until discharge and possibly longer depending upon other risk factors (RCOG 2006).

- Full length venous support stockings and prophylactic heparin (5000 IUevery 12 hours) should be considered in severely hemoconcentrated patients. When symptoms prevent ambulation, the use of an intermittent pneumatic compression device reduces the risk of thrombosis.

- Clinical signs and symptoms suggesting thromboembolism, documented thrombophilia and uncorrected haemoconcentration after 48 hours of intravenous treatment demand therapeutic anticoagulation.

Notes - OHSS has no adverse effect on pregnancy.

- ICU admission required in critical cases and TOP may be indicated in exceptional circumstances.

â&#x20AC;Ś..â&#x20AC;Śto be continued.

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