nThe two most serious complications of excessive ovarian stimulation are a high incidence of multiple gestation and ovarian hyperstimulation syndrome (OHSS):

nThe ovarian cysts are the result of multifollicular development. The most severe manifestations of the syndrome include massive ovarian enlargement from multiple cysts and, due to fluid movement out of the intravascular space, hemoconcentration and third-space accumulation of fluid; these changes may be complicated by renal failure, hypovolemic shock, thromboembolic episodes, acute respiratory distress syndrome, and death.

Etiology

Exogenous gonadotropins

Exogenous gonadotropins
Exogenous gonadotropins

nOvarian hyperstimulation occurs after luteinization of a large number of follicles. Such massive follicular luteinization is usually only observed in exogenous gonadotropin cycles following administration of human chorionic gonadotropin (hCG), or after administration of gonadotropin releasing hormone (GnRH) agonist; it rarely occurs in women treated with clomiphene citrate. The clinical symptoms usually appear five to ten days following the first dose of the ovulatory trigger (hCG, GnRH agonist).

Endogenous LH surge

nMild ovarian hyperstimulation also rarely develops following an endogenous LH surge in a setting of spontaneous multifollicular development. This has been described in case reports, particularly in women with polycystic ovarian syndrome or hypothyroidism . The rarity and mildness of OHSS in this situation is due to several factors:

FSH receptor mutations

nSevere, recurrent, spontaneous OHSS during pregnancy has been described in several reports. In these instances, the OHSS was due to a mutation in the serpentine region of the FSH receptor that resulted in a broadening of ligand specificity, thereby allowing stimulation by endogenous hCG . The persistent stimulation of the FSH receptor during pregnancy resulted in excessive follicular recruitment and subsequent ovarian hyperstimulation.

CLASSIFICATION AND CLINICAL MANIFESTATIONS

Ovarian hyperstimulation is classified into three grades based upon the severity of symptoms, signs, and laboratory findings. The cardinal event in the genesis of OHSS is ovarian enlargement, with ascites and hypovolemia resulting from an acute fluid shift out of the intravascular space.

Grade I ovarian hyperstimulation

nGrade I (mild hyperstimulation) is characterized by bilateral ovarian enlargement with multiple follicular and corpus luteum cysts measuring up to 5 by 5 cm. Laboratory findings include a serum estradiol (E2) concentration greater than 1500 pg/mL (6000 pmol/L) and progesterone concentration greater than 30 ng/mL (115 nmol/L) in the early part of the luteal phase.

Grade II ovarian hyperstimulation

nGrade II (moderate hyperstimulation) describes ovaries enlarged up to 12 by 12 cm, accompanied by abdominal discomfort and gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea). A sudden increase in weight of more than 3 kg may be an early sign of moderate hyperstimulation

Grade III ovarian hyperstimulation

Grade III (severe hyperstimulation) is defined by the presence of large ovarian cysts (more than 12 by 12 cm), ascites, and, in some patients, pleural and/or pericardial effusion, electrolyte imbalance (hyponatremia, hyperkalemia), hypovolemia, and hypovolemic shock . Marked hemoconcentration, increased blood viscosity, and thromboembolic phenomena including disseminated intravascular coagulation occur in the most severe cases.

Spontaneous regression occurs over 10 to 14 days, but may take longer if implantation occurs.

RISK FACTORS

RISK FACTORS
RISK FACTORS

PREGNANCY OUTCOME

nA controlled study did not shown increased feto-maternal morbidity during the second and third trimesters of gestation among patients who developed OHSS compared to IVF-treated patients without excessive ovarian stimulation . However, uncontrolled studies suggested these pregnancies had a higher rate of gestational diabetes and pregnancy-associated hypertension .

More data are needed to better understand whether OHSS affects the frequency of late pregnancy complications.

PREVENTIVE STRATEGIES

PREVENTIVE STRATEGIES

nIt has been recommended that hCG be withheld if the serum estradiol concentration is greater than 1500 pg/mL (>6,000 pmol/L) . We generally adhere to this rule. In special cases, however, if there are not too many intermediate or large follicles on ultrasonography, we have given hCG when serum estradiol levels exceeded 1500 pg/mL (>6,000 pmol/L). This approach has usually not resulted in severe hyperstimulation. hCG should be withheld if there are more than two follicles larger than 17 mm and more than four follicles <17 mm. In certain situations, the treatment cycle might be salvaged by inducing an LH surge with GnRH agonists. hCG may be given and follicular reduction considered if the serum estradiol is above 1500 pg/mL (>6,000 pmol/L) in the presence of more than two large follicles but fewer than four smaller follicles

OTHER PREVENTIVE STRATEGIES

Coasting

nCoasting refers to delaying the administration of hCG in high risk cycles until serum estradiol falls into an acceptable range (typically less than 2500 to 3000 pg/mL ). IVF studies suggest coasting for an average of two to six days results in a lower rate of OHSS while maintaining reasonable pregnancy rates

Transforming to an IVF cycle

nAnother option is transforming the ovulation induction cycle into an IVF cycle. The embryos obtained can either be replaced in the same cycle or cryopreserved and replaced in subsequent spontaneous cycles. However, a Cochrane review of embryo cryopreservation concluded that there is inadequate evidence that cryopreservation results in a lower risk of OHSS when compared with fresh embryo transfer.

Replacing hCG with a GnRH agonist

nGnRH agonists are used routinely in IVF protocols for pituitary desensitization. Complete desensitization can be achieved much more rapidly with GnRH antagonists . In a Cochrane review of five randomized trials, the risk of severe OHSS was significantly lower with GnRH antagonists compared to agonists (odds ratio 0.36; 95 percent CI 0.16 to 0.80) at a cost of a significant reduction in clinical pregnancies (OR 0.78, 95 percent CI 0.62 to 0.97)

Dopamine agonist cabergoline

Dopamine agonist cabergoline
Dopamine agonist cabergoline

Intravenous albumin

nAdministration of intravenous albumin (at the time of oocyte retrieval and immediately thereafter) has been studied as a possible prevention strategy, mostly in small trials . The treatment regimens varied from 10 to 50 g of albumin given one or two hours before oocyte retrieval to 10 to 20 g of albumin given just after oocyte retrieval.

Corticosteroids

n One retrospective series suggested administration of methylprednisolone (16 mg starting on day 6 of the stimulation cycle and tapered beginning day 13 after embryo transfer) to women at high risk of developing OHSS reduced the prevalence of this disorder (10 versus 44 percent in untreated women) . High risk women were defined as those with more than 20 follicles less than 10 mm in diameter and estradiol concentrations greater than 600 pg/mL on the fifth day of the stimulation protocol. The only other series that evaluated administration of glucocorticoids to high risk patients did not find a reduction in the rate of OHSS (about 42 percent in both treated and control groups) . There is insufficient data to recommend use of corticosteroid prophylaxis at this time.

TREATMENT

Treatment of Grade I hyperstimulation

nTreatment is supportive, as needed. However, mild ovarian hyperstimulation can develop into moderate or severe disease, especially if conception ensues. Therefore, women with mild disease  should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least two weeks or until the appearance of menstrual bleeding.

Treatment of Grade II hyperstimulation

Treatment of Grade III hyperstimulation

Treatment of Grade III hyperstimulation
Treatment of Grade III hyperstimulation

 

-Maintaining blood volume while correcting the disturbed fluid and electrolyte balance

– Relieving secondary complications of ascites and hydrothorax

– Preventing thromboembolic phenomena

Laboratory monitoring in women with grade 3 OHSS

-Leukocyte count

-Hemoglobin and hematocrit

-Electrolytes

-Liver function tests

-Prothrombin and partial thromboplastin time

-Chest radiograph (if respiratory symptoms are present)

Hypovolemia

Ovarian enlargement

nOvarian cysts associated with grade III OHSS are so large and brittle that surgical attempts at a palliative procedure usually result in oophorectomy. Therefore, surgery should be avoided unless there is torsion or cyst rupture with hemorrhage. Torsion is characterized by ovarian enlargement, abdominal pain, nausea, progressive leukocytosis, and anemia . Treatment may require oophorectomy, although in many cases the ovary can be saved by unwinding at laparotomy or laparoscop

Ascites

Hydrothorax

Thromboemboli

Thromboembolic events are the most serious, but rarest, complications of OHSS. Thromboses can occur in either the arterial (25 percent) or venous (75 percent) circulations and may lead to permanent neurologic injury or death . Prophylactic anticoagulation with heparin or low molecular weight heparin, antiembolism stockings, and or intermittent pneumatic compression boots should be considered to minimize the risk of venous thrombosis.

Resolution

Resolution
Resolution

n After a period of several days, third space fluid begins to re-enter the intravascular space, hemoconcentration reverses, and natural diuresis ensues. The patient feels better and her appetite and ability to take oral fluids improve. Intravenous fluids are tapered as oral intake increases. Some physicians limit oral intake to 1000 mL/day at this time to facilitate diuresis and maintain euvolemia . Complete resolution typically takes 10 to 14 days from the onset of initial symptoms.

SUMMARY

nCarefully maintaining blood volume, correcting electrolyte imbalance, and relieving secondary complications of ascites and hydrothorax are generally sufficient for supporting the patient during the severe phase of ovarian hyperstimulation. Anticoagulant therapy is usually unnecessary if these therapies are promptly employed. Blood coagulation may be monitored because of the danger of disseminated intravascular clotting.

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