nThe two most serious complications of excessive ovarian stimulation are a high incidence of multiple gestation and ovarian hyperstimulation syndrome (OHSS):
- Multiple gestation is a concern because these pregnancies are associated with increased rates of perinatal mortality and morbidity.
- OHSS refers to a combination of ovarian enlargement due to multiple ovarian cysts and an acute fluid shift out of the intravascular space. It is a potentially life-threatening complication of ovulation induction.
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.
- Exogenous gonadotropins
- Endogenous LH surge
- FSH receptor mutations
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:
- The number of intermediate follicles present at the beginning of the LH surge
- The duration and intensity of the LH surge
- Other factors, such as inhibin, insulin-like growth factor(IGF-1), and its binding proteins
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.
- An analysis of several large series encompassing 11,342 treatment cycles showed that the incidence of moderate and severe OHSS was 3.4 and 0.8 percent, respectively .
- Knowledge of the risk factors for OHSS is useful for preventing the occurrence, or at least reducing the incidence of severe hyperstimulation. Factors which should be considered include:- Young age- High serum estradiol concentrations immediately prior to human chorionic gonadotropin (hCG) administration- Transvaginal ultrasound examination findings (women with polycystic ovary morphology tend to have the most exuberant response to exogenous gonadotropins)
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.
- All women undergoing ovarian stimulation with exogenous gonadotropins should be monitored with both serum estradiol measurements and transvaginal ultrasonography. Both are performed on the fifth day of treatment and every two to three days thereafter until hCG administration.
- hCG may be given with a low risk of OHSS to women with estradiol levels less than 1500 pg/mL in the presence of no more than two follicles above 17 mm and less than four smaller follicles. The regimen may be altered in the following settings:
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
- Transforming to an IVF cycle
- Replacing hCG with a GnRH agonist
- Replacing hCG with recombinant LH
- Performing follicular reduction
- Dopamine agonist cabergoline
- Intravenous albumin
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
- To test if Cb2 reduces VP and prevents OHSS in humans. Prospective, randomized and double blind study on oocyte donors at risk of developing OHSS (>20 follicles >12 mm developed, and >20 oocytes retrieved). Cb2 0.5 mg/day (n=37) or a placebo (n=32) was administered from the day of hCG (day 0) until day 8.. Results: Hematocrit (p<0.01), hemoglobin (p=0.003) and ascites (p=0.005) were significantly lower on days 4 and 6 after treatment with Cb2 as compared to placebo. The incidence of moderate OHSS was 20.0% and 43.8%, respectively (p=0.04).
- Conclusions: Given that Cb2 is a well established and safe medication, this study provides proof of concept for the use of Dp agonists in the prevention of OHSS in women undergoing assisted reproduction.
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.
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.
- OHSS is a self-limiting disease; thus, treatment should be symptomatic and conservative. Medical therapy suffices for most patients, with laparotomy reserved for catastrophic complications, such as ovarian torsion or rupture and internal haemorrhage. Women with severe symptoms often require intensive medical care. Vaginal intercourse is restricted in all grades of OHSS because of the risk of cyst rupture. Patients should also avoid impact-type activities or strenuous exertion.
- The best treatment of OHSS is primary prevention. Preventing ovulation by withholding human chorionic gonadotropin (hCG) is an effective method of avoiding hyperstimulation in overstimulated ovaries. Alternatively, aspiration of follicles 36 hours after administration of the ovulatory dose of hCG may lower the risk of developing clinical hyperstimulation by reducing the mass of luteinized granulosa cells.
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 moderate hyperstimulation consists of observation, bed rest, provision of an adequate fluids, and sonographic monitoring of cyst size. Serum electrolytes, hematocrit, and creatinine should also be evaluated. Some physicians have outpatients keep track of their fluid intake and output; intake or output less than 1000 mL/day or a discrepancy in fluid balance greater than 1000 mL/day would be a cause for concern.
- Initiation of resolution is apparent when the cysts become smaller on two consecutive ultrasound examinations and clinical symptoms recede. In contrast, early detection of progression to the severe form of the syndrome is marked by continuous weight gain (two pounds or more a day), increase in severity of existing symptoms, or the appearance of new symptoms, such as vomiting, diarrhea, and dyspnea
Treatment of Grade III hyperstimulation
- Medical treatment of severe hyperstimulation is directed toward:
-Maintaining blood volume while correcting the disturbed fluid and electrolyte balance
– Relieving secondary complications of ascites and hydrothorax
– Preventing thromboembolic phenomena
- Laboratory tests & frequent monitoring of vital signs and intake/output, weight and abdominal girth should be checked daily.
Laboratory monitoring in women with grade 3 OHSS
- Daily :
-Hemoglobin and hematocrit
- Once, repeat as indicated :
-Liver function tests
-Prothrombin and partial thromboplastin time
-Chest radiograph (if respiratory symptoms are present)
- Fluid balance should be carefully monitored by net fluid flow (intake/output record), weight and girth measurements, and hematocrit examinations. A central venous pressure catheter may be required in women who are hemodynamically unstable. In general, one to two liters of isotonic fluid is given to such women in the first hour to rapidly restore tissue perfusion. Further fluids optimally should be given while monitoring the central venous or pulmonary capillary wedge pressure. Fluid repletion should continue at the initial rapid rate as long as the cardiac filling pressures and the systemic blood pressure remain low.
- Plasma expanders such as hemacell, dextran, human albumin (200 mL of 25 percent albumin over 4 hours), and plasma (500 to 1000 mL over 24 hours) supplemented with appropriate electrolytes should be administered early and repeated as needed. The effect of this treatment may be enhanced by the addition of oral indomethacin, which blocks prostaglandin synthesis and reduces capillary permeability. Hematocrit should be monitored every four hours; plasma expanders can be stopped when the hematocrit is less than 38 percent.
- Diuretic agents are not recommended since fluid in the third space is not affected by these drugs. Furthermore, most diuretics act at the distal tubule with minimal effect on the proximal tubule . Thus, the artificially induced diuresis may further diminish the intravascular volume, but may be unable to relieve ascites or hydrothorax. Renal failure may respond to a dopamine drip (0.18 mg/kg per hour) . Oral docarpamine administration could be one of the options in the management of patients with OHSS requiring dopamine therapy
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
- The degree of ascites is reflected by the woman’s weight gain: an initial gain of more than 3 kg following hCG administration should be considered a warning sign of developing OHSS and warrants close observation. Women with severe OHSS can gain as much as 15 to 20 kg over five to 10 days.
- Transvaginal sonographically guided aspiration of ascites and intravenous fluid infusion . This treatment relieved symptoms, reduced the hematocrit, improved renal clearance and urine output, and shortened the duration of hospital stay. Other authors have reinfused the withdrawn ascitic fluid (after microfiltration) and reported relief of symptoms and improvement of renal function
- Women with severe OHSS involving the lungs display an extraparenchymal restrictive type of pulmonary dysfunction due to intraabdominal or pleural fluid accumulation, which limits descent of the diaphragm and expansion of the lungs . This causes uncoordinated lung ventilation and atelectasis leading to ventilation-perfusion mismatch and hypoxemia. Pulmonary infection, thromboembolism, or adult respiratory distress syndrome (ARDS) may further complicate the clinical picture.
- Clinical manifestations included dyspnea, tachypnea, moderate hypoxemia, increased alveolar-arterial oxygen difference, hypocarbia, respiratory alkalosis, and metabolic compensation.
- Pleural effusions should be drained to relieve dyspnea. Paracentesis may also be useful in alleviating breathing difficulties in patients with ascites and hydrothorax
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.
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.
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.