Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a complication from some forms of fertility medication, particularly those of ovarian hyperstimulation. Most cases are mild, but a small proportion are severe.

Causative medications

Ovarian hyperstimulation syndrome is particularly associated with injection of a hormone called human chorionic gonadotropin (hCG) which is used for inducing final oocyte maturation and/or triggering oocyte release. The risk is further increased by multiple doses of hCG after ovulation and if the procedure results in pregnancy.^[1]

Using a GnRH agonist instead of hCG for inducing final oocyte maturation and/or release results in an elimination of the risk of ovarian hyperstimulation syndrome, but a slight decrease of the delivery rate of approximately 6%.^[2]

Symptoms

Symptoms are set into 3 categories: mild, moderate, and severe. Mild symptoms include abdominal bloating and feeling of fullness, nausea, diarrhea, and slight weight gain. Moderate symptoms include excessive weight gain (weight gain of greater than 2 pounds per day), increased abdominal girth, vomiting, diarrhea, darker urine and less in amount, excessive thirst, and skin and/or hair feeling dry (in addition to mild symptoms). Severe symptoms are fullness/bloating above the waist, shortness of breath,pleural effusion, urination significantly darker or has ceased, calf and chest pains, marked abdominal bloating or distention, and lower abdominal pains (in addition to mild and moderate symptoms).

Classification

In mild forms of OHSS the ovaries are enlarged (5–12 cm)^[3] and there may be additional accumulation of ascites with mild abdominal distension, abdominal pain,^[3] nausea,^[3] and diarrhea.^[3] In severe forms of OHSS there may be hemoconcentration, thrombosis and distension, oliguria (decreased urine production), pleural effusion, and respiratory distress. Early OHSS develops before pregnancy testing and late OHSS is seen in early pregnancy.

Criteria for severe OHSS include enlarged ovary, ascites, hematocrit > 45%, WBC > 15,000, oliguria, creatinine 1.0-1.5 mg/dl, creatinine clearance > 50 ml/min, liver dysfunction, anasarca.^[3] Critical OHSS includes enlarged ovary, tense ascites with hydrothorax and pericardial effusion, hematocrit > 55%, WBC > 25,000, oligoanuria, creatinine > 1.6 mg/dl, creatinine clearance < 50 ml/min, renal failure, thromboembolic phenomena, ARDS.^[3]

Complications

OHSS may be complicated with ovarian torsion, ovarian rupture, thrombophlebitis and renal insufficiency. Symptoms generally resolve in 1 to 2 weeks, but will be more severe and persist longer if pregnancy occurs. This is due to human chorionic gonadotropin (hCG) from the pregnancy acting on the corpus luteum in the ovaries in sustaining the pregnancy before the placenta has fully developed. Typically, even in severe OHSS with a developing pregnancy, the duration does not exceed the first trimester.

Pathophysiology

OHSS has been characterized by the presence of multiple luteinized cysts within the ovaries leading to ovarian enlargement and secondary complications, but that definition includes almost all patients undergoing ovarian stimulation. The central feature of clinically significant OHSS is the development of vascular hyperpermeability and the resulting shift of fluids into the third space.

As hCG causes the ovary to undergo extensive luteinization, large amounts of estrogens, progesterone, and local cytokines are released. It is almost certain that vascular endothelial growth factor (VEGF) is a key substance that induces vascular hyperpermeability, making local capillaries "leaky", leading to a shift of fluids from the intravascular system to the abdominal and pleural cavity. Supraphysiologic production of VEGF from many follicles under the prolonged effect of hCG appears to be the specific key process underlying OHSS. Thus, while the patient accumulates fluid in the third space, primarily in the form of ascites, she actually becomes hypovolemic and is at risk for respiratory, circulatory (such as arterial thromboembolism since blood is now thicker), and renal problems. Patients who are pregnant sustain the ovarian luteinization process through the production of hCG.

Avoiding OHSS typically requires interrupting the pathological sequence, such as avoiding the use of hCG. One alternative is to use a GnRH agonist instead of hCG. While this has been repeatedly shown to "virtually eliminate" OHSS risk, there is some controversy regarding the effect on pregnancy rates if a fresh non-donor embryo transfer is attempted, almost certainly due to a luteal phase defect. There is no dispute that the GnRH agonist trigger is effective for oocyte donors and for embryo banking (cryopreservation) cycles.

Epidemiology

Sporadic OHSS is very rare, and may have a genetic component. Clomifene citrate therapy can occasionally lead to OHSS, but the vast majority of cases develop after use of gonadotropin therapy (with administration of FSH), such as Pergonal, and administration of hCG to induce final oocyte maturation and/or trigger oocyte release, often in conjunction with IVF. The frequency varies and depends on patient factors, management, and methods of surveillance. About 5% of treated patients may encounter moderate to severe OHSS. Risk factors include young age, the development of many ovarian follicles under stimulation, extreme elevated serum estradiol concentrations, the use of hCG for final oocyte maturation and/or release, the continued use of hCG for luteal support, and the occurrence of a pregnancy (resulting in hCG production).

Mortality is low, but several fatal cases have been reported.

Prevention

Physicians can reduce the risk of OHSS by monitoring of FSH therapy to use this medication judiciously, and by withholding hCG medication.

Cabergoline confers a significant reduction in the risk of OHSS in high risk women according to a Cochrane review of randomized studies, but the included trials did not report the live birth rates or multiple pregnancy rates.^[4] Cabergoline, as well as other dopamine agonists, might reduce the severity of OHSS by interfering with the VEGF system.^[5] A systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.^[6]

The risk of OHSS is smaller when using GnRH antagonist protocol instead of GnRH agonist protocol for suppression of ovulation during ovarian hyperstimulation.^[7] The underlying mechanism is that, with the GnRH antagonist protocol, initial follicular recruitment and selection is undertaken by endogenous endocrine factors prior to starting the exogenous hyperstimulation, resulting in a smaller number of growing follicles when compared with the standard long GnRH agonist protocol.^[7]

Administration of human albumin or hydroxyethyl starch confers a significant decrease in severe OHSS, with no statistically significant evidence of decreased pregnancy rate.^[4] Routine oocyte cryopreservation does not have evidence of preventing OHSS.^[4] Also, coasting, which is ovarian hyperstimulation without induction of final maturation, does not significantly decrease the risk of OHSS.^[4]

Treatment

Treatment of OHSS depends on the severity of the hyperstimulation. Mild OHSS can be treated conservatively with monitoring of abdominal girth, weight, and discomfort on an outpatient basis until either conception or menstruation occurs. Conception can cause mild OHSS to worsen in severity.

Moderate OHSS is treated with bed rest, fluids, and close monitoring of labs such as electrolytes and blood counts. Ultrasound may be used to monitor the size of ovarian follicles. Depending on the situation, a physician may closely monitor a patient's fluid intake and output on an outpatient basis, looking for increased discrepancy in fluid balance (over 1 liter discrepancy is cause for concern). Resolution of the syndrome is measured by decreasing size of the follicular cysts on 2 consecutive ultrasounds.^[8]

Aspiration of accumulated fluid (ascites) from the abdominal/pleural cavity may be necessary, as well as opioids for the pain. If the OHSS develops within an IVF protocol, it can be prudent to postpone transfer of the pre-embryos since establishment of pregnancy can lengthen the recovery time or contribute to a more severe course. Over time, if carefully monitored, the condition will naturally reverse to normal - so treatment is typically supportive, although patient may need to be treated or hospitalized for pain, paracentesis, and/or intravenous hydration.

References

Further reading

• Delvigne A, Rozenberg S (2002). "Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review" (PDF). Hum Reprod Update 8 (6): 559–77. doi:10.1093/humupd/8.6.559. PMID 12498425. 
• Delvigne A, Rozenberg S (2003). "Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS)" (PDF). Hum Reprod Update 9 (1): 77–96. doi:10.1093/humupd/dmg005. PMID 12638783.