Ovarian hyperstimulation syndrome is a relatively common complication of ovarian stimulation and can be life-threatening. The pathophysiology of ovarian hyperstimulation syndrome is characterised by increased capillary permeability, leading to leakage of fluid from the vascular compartment, with third space fluid accumulation and intravascular dehydration. The combined use of a gonadotrophin-releasing hormone antagonist protocol with gonadotrophin-releasing hormone agonist triggering and oocyte and embryo freezing has considerable promise in preventing ovarian hyperstimulation syndrome. Women with severe ovarian hyperstimulation syndrome require hospitalisation for more careful monitoring and treatment. Transvaginal paracentesis can be used as an outpatient treatment to prevent the need for hospitalisation. The inhibition of vascular permeability seems to be a novel therapeutic approach to preventing and treating ovarian hyperstimulation syndrome.
Introduction
Ovarian hyperstimulation syndrome (OHSS) is a relatively common complication of ovarian stimulation and can be life-threatening. It is characterised by enlargement of the ovaries, fluid retention, and weight gain. Ovarian hyperstimulation syndrome is self-limiting and will undergo gradual resolution with time. The pathophysiology of OHSS is characterised by increased capillary permeability, leading to leakage of fluid from the vascular compartment, with third-space fluid accumulation and intravascular dehydration. Although the exact cause of OHSS has not been completely elucidated, it seems likely that the release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has emerged as one of the factors most likely involved in the pathophysiology of OHSS.
Presentation and complications
The clinical manifestations of ovarian hyperstimulation syndrome originate from the combination of decreased intravascular space and the accumulation of protein-rich fluid into body cavities and interstitial space. This ‘third spacing’ causes depletion of the intravascular space. Loss of intravascular volume leads to haemodynamic changes manifested as hypotension, severe tachycardia, and decreased renal perfusion as well as haemoconcentration. Loss of intravascular volume combined with decreased renal perfusion results in electrolyte abnormalities (e.g. hyperkalaemia, hyponatraemia), increase in haematocrit and white cell count, and decrease in creatinine clearance. Accumulation of fluid in the peritoneal cavity leads to abdominal distention and discomfort.
Pulmonary function may be compromised as enlarged ovaries and ascites restrict diaphragmatic movement. Pleural effusions are present in 21% of OHSS cases. Although pleural effusion is generally thought to be a consequence of pronounced ascites, associated with a shift of liquid from the peritoneal cavity to the pleura, isolated pleural effusion without concomitant ascites has been reported as the only symptom of OHSS.
Hepatic manifestations are present in about one-quarter of OHSS cases, generally in association with severe OHSS, and disappear with the recovery from OHSS. The presence of liver dysfunction in severe OHSS was associated with a lower clinical pregnancy rate.
Thromboembolic events are serious complications of OHSS. The incidence of venous thromboembolism in relation to in-vitro fertilisation (IVF) has been reported in about 0.1% of treatment cycles. According to data from relatively few cases, the venous thromboembolism risk associated with OHSS is reported to be between 0.8% and 2.4%. Pregnancies with fresh IVF cycles complicated by OHSS were at a 100-fold increased risk of venous thromboembolism in the first trimester, compared with the background population. A hypercoagulable state is most likely caused by haemoconcentration and hypovolaemia resulting from third spacing and fluid shift. It is also related to increased oestrogen levels.
Severe OHSS is associated with a higher likelihood of pregnancy and multiple gestations. The influence of OHSS on the outcome of the pregnancy remains difficult to appreciate. Data on the relation of OHSS and pregnancy complications are insufficient.
Accidents of the hyperstimulated ovary, such as torsion or rupture, are rare but recognised complications. Ovarian hyperstimulation syndrome, particularly if associated with pregnancy, may be by itself a risk factor for ovarian torsion. Life-threatening complications of OHSS include renal failure, hypovolaemic shock, adult respiratory distress syndrome, haemorrhage from ovarian rupture, and thromboembolic episodes.
Classification of ovarian hyperstimulation syndrome
The OHSS has traditionally been classified as mild, moderate, or severe. The most popular classification system for staging OHSS is that of Golan el al. This system incorporated the use of transvaginal sonography for both estimating of ovarian enlargement and detection of ascitic fluid. The detection of ascites establishes the diagnosis of moderate OHSS. Subsequent modifications defined a group of critical or complicated OHSS and added to the severe category of the syndrome.
The Practice Committee of the American Society for Reproductive Medicine proposed a simplified classification of the syndrome into mild, worsening, and serious. Progression of illness is recognised when symptoms persist, worsen, or include ascites that may be demonstrated by increasing abdominal girth or ultrasound evaluation. Serious illness was defined by the presence of abdominal pain plus one or of the following signs: rapid weight gain, tense ascites, haemodynamic instability, respiratory distress, progressive oliguria, and laboratory abnormalities. Laboratory criteria for women with serious illness include the following: haemoconcentration (haematocrit > 45%), leukocytosis (white blood cell count > 15,000), sodium less than 135 mEq/L, potassium of more that 5.0 mEq/L, elevated liver enzymes, and serum creatinine of more than 1.2 mg/dL. According to the Practice Committee, most people with serious illness require hospitalisation.
It should be remembered that OHSS is a dynamic situation. The clinical symptoms and signs of OHSS are broad in scope and severity, and can defy attempts at specific classification. A person with moderate OHSS may progress within hours or days to a severe case. Therefore, clinicians have to be cautious in monitoring moderate or even mild OHSS.
A division of OHSS into ‘early’ and ‘late’, depending on the time of onset, may be useful in determining the prognosis. Ovarian hyperstimulation syndrome presenting within 9 days after the ovulatory dose of hCG is likely to reflect excessive ovarian response and the precipitating effect of exogenous hCG administered for final follicular maturation. Ovarian hyperstimulation syndrome presenting after this period reflects endogenous hCG stimulation from an early pregnancy. Late OHSS is more likely to be severe and to last longer than early OHSS.
Presentation and complications
The clinical manifestations of ovarian hyperstimulation syndrome originate from the combination of decreased intravascular space and the accumulation of protein-rich fluid into body cavities and interstitial space. This ‘third spacing’ causes depletion of the intravascular space. Loss of intravascular volume leads to haemodynamic changes manifested as hypotension, severe tachycardia, and decreased renal perfusion as well as haemoconcentration. Loss of intravascular volume combined with decreased renal perfusion results in electrolyte abnormalities (e.g. hyperkalaemia, hyponatraemia), increase in haematocrit and white cell count, and decrease in creatinine clearance. Accumulation of fluid in the peritoneal cavity leads to abdominal distention and discomfort.
Pulmonary function may be compromised as enlarged ovaries and ascites restrict diaphragmatic movement. Pleural effusions are present in 21% of OHSS cases. Although pleural effusion is generally thought to be a consequence of pronounced ascites, associated with a shift of liquid from the peritoneal cavity to the pleura, isolated pleural effusion without concomitant ascites has been reported as the only symptom of OHSS.
Hepatic manifestations are present in about one-quarter of OHSS cases, generally in association with severe OHSS, and disappear with the recovery from OHSS. The presence of liver dysfunction in severe OHSS was associated with a lower clinical pregnancy rate.
Thromboembolic events are serious complications of OHSS. The incidence of venous thromboembolism in relation to in-vitro fertilisation (IVF) has been reported in about 0.1% of treatment cycles. According to data from relatively few cases, the venous thromboembolism risk associated with OHSS is reported to be between 0.8% and 2.4%. Pregnancies with fresh IVF cycles complicated by OHSS were at a 100-fold increased risk of venous thromboembolism in the first trimester, compared with the background population. A hypercoagulable state is most likely caused by haemoconcentration and hypovolaemia resulting from third spacing and fluid shift. It is also related to increased oestrogen levels.
Severe OHSS is associated with a higher likelihood of pregnancy and multiple gestations. The influence of OHSS on the outcome of the pregnancy remains difficult to appreciate. Data on the relation of OHSS and pregnancy complications are insufficient.
Accidents of the hyperstimulated ovary, such as torsion or rupture, are rare but recognised complications. Ovarian hyperstimulation syndrome, particularly if associated with pregnancy, may be by itself a risk factor for ovarian torsion. Life-threatening complications of OHSS include renal failure, hypovolaemic shock, adult respiratory distress syndrome, haemorrhage from ovarian rupture, and thromboembolic episodes.
Classification of ovarian hyperstimulation syndrome
The OHSS has traditionally been classified as mild, moderate, or severe. The most popular classification system for staging OHSS is that of Golan el al. This system incorporated the use of transvaginal sonography for both estimating of ovarian enlargement and detection of ascitic fluid. The detection of ascites establishes the diagnosis of moderate OHSS. Subsequent modifications defined a group of critical or complicated OHSS and added to the severe category of the syndrome.
The Practice Committee of the American Society for Reproductive Medicine proposed a simplified classification of the syndrome into mild, worsening, and serious. Progression of illness is recognised when symptoms persist, worsen, or include ascites that may be demonstrated by increasing abdominal girth or ultrasound evaluation. Serious illness was defined by the presence of abdominal pain plus one or of the following signs: rapid weight gain, tense ascites, haemodynamic instability, respiratory distress, progressive oliguria, and laboratory abnormalities. Laboratory criteria for women with serious illness include the following: haemoconcentration (haematocrit > 45%), leukocytosis (white blood cell count > 15,000), sodium less than 135 mEq/L, potassium of more that 5.0 mEq/L, elevated liver enzymes, and serum creatinine of more than 1.2 mg/dL. According to the Practice Committee, most people with serious illness require hospitalisation.
It should be remembered that OHSS is a dynamic situation. The clinical symptoms and signs of OHSS are broad in scope and severity, and can defy attempts at specific classification. A person with moderate OHSS may progress within hours or days to a severe case. Therefore, clinicians have to be cautious in monitoring moderate or even mild OHSS.
A division of OHSS into ‘early’ and ‘late’, depending on the time of onset, may be useful in determining the prognosis. Ovarian hyperstimulation syndrome presenting within 9 days after the ovulatory dose of hCG is likely to reflect excessive ovarian response and the precipitating effect of exogenous hCG administered for final follicular maturation. Ovarian hyperstimulation syndrome presenting after this period reflects endogenous hCG stimulation from an early pregnancy. Late OHSS is more likely to be severe and to last longer than early OHSS.
Steps to minimise risk
The prevention of OHSS includes three main strategies: identification of women at risk, using different ovulation-induction strategies before stimulation, and preventive therapy modalities during stimulation ( Table 1 ). The combined use of a gonadotrophin-releasing hormone (GnRH) antagonist protocol with GnRH agonist triggering and oocyte and embryo freezing has considerable promise in preventing OHSS.
| Identification of women at risk | |
|---|---|
| Using different ovulation-induction strategies | Individually tailored gonadotrophin regimen GnRH antagonist protocol In-vitro maturation Metformin |
| Preventive therapy modalities during stimulation | Cycle cancellation Coasting (withholding gonadotrophins) Administration of intravenous albumin and hydroxyethyl starch Triggering ovulation by low-dose of hCG GnRH agonist to trigger final oocyte maturation Avoidance of hCG for luteal support Cryopreservation of all oocytes and embryos Dopamine agonist therapy Low-dose aspirin therapy |
Identification of women at risk
Recognising risk factors of OHSS is the key to prevention. All women undergoing ovarian stimulation should be considered at risk of OHSS. Women at higher risk of developing OHSS include young age, low body weight, polycystic ovary syndrome (PCOS), use of GnRH agonists, higher doses of exogenous gonadotrophins, high absolute or rapidly rising serum oestradiol levels, development of multiple follicles during treatment, exposure to hCG, and previous episodes of OHSS. Pregnancy increases the likelihood, duration, and severity of OHSS symptoms. An earlier study had reported an OHSS rate of 37% in women with PCOS, whereas the rate was 15% in women without PCOS. Ovarian stimulation in women with PCOS needs to be individually tailored and closely monitored.
A systematic review and meta-analysis of the existing literature showed that both anti-Müllerian hormone and antral follicle count are accurate predictors of excessive response to ovarian hyperstimulation. Measurement of basal serum anti-Müllerian hormone and antral follicle count can be used to determine the women who are high risk for OHSS.
Using different ovulation-induction strategies
Individually tailored gonadotrophin regimen
Gonadotrophins can be used for induction of ovulation in anovulatory women or ovarian stimulation for intrauterine insemination or IVF. The differences in the objectives of these three forms of treatment were single follicle for induction of ovulation in anovulatory women, two to three follicles in intrauterine insemination and six to 10 follicles in IVF. Ovarian hyperstimulation syndrome can occur in both induction of ovulation and ovarian stimulation for assisted reproduction. The choice of the gonadotrophin starting dose is an important parameter to prevent the onset of OHSS. It is recognised that reducing the starting dose to 100 IU follicle-stimulating hormone (FSH) or even 75 IU per day in high-risk women could minimise the risk of OHSS. Unfortunately, the syndrome may occur even in women who receive small starting doses.
The basis of the classic chronic, low-dose, step-up protocol is to identify the threshold dose that is necessary to induce follicular maturation, especially in women suffering from PCOS. The protocol normally starts with a dose of 75 IU daily for 14 days, followed by small stepwise increases (37.5 IU or less) for a period of 7 days. The dose can again be increased after this period if there is no response. Chronic low-dose step-up gonadotrophin is more useful for induction of ovulation.
The aim of the step-down protocol is to rapidly achieve the FSH threshold for stimulating follicle development, and thus step-down regimens normally begin with a dose of 150 IU FSH daily followed by reduction of the dose once the initial response is established. Both low-dose, step-up and step-down protocols have been shown to help reduce the risk of over-response associated with a lower incidence of OHSS.
The use of the gonadotrophin-releasing hormone antagonist protocol
The use of GnRH antagonist protocol resulted in a more physiological approach to ovarian stimulation, leading to fewer side-effects and complications than the long-agonist protocol. Additionally, when using GnRH antagonist protocol, one may induce oocyte maturation with GnRH agonists. This issue will be discussed later. A Cochrane review concluded that the use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS, with no evidence of a difference in live-birth rates. The data, however, are inconclusive from a recent systematic review and meta-analysis, which investigated whether GnRH antagonist protocols reduce the risk of OHSS in women with PCOS undergoing IVF compared with the long agonist protocol. This review included nine randomised-controlled trials (RCTs) with a total of 966 women with PCOS, and showed no significant difference in the incidence of severe OHSS with the antagonist group compared with the long-agonist group. The incidence of moderate and severe OHSS, when combined together, is reduced with the GnRH antagonist protocol compared with the GnRH long agonist protocol.
In-vitro maturation of oocytes
Although the pregnancy and implantation rates of in-vitro maturation (IVM) treatment are not as high as conventional IVF treatment, immature oocyte retrieval followed by IVM is a promising potential treatment option for infertile women with PCOS, because this group of women are extremely sensitive to stimulation with exogenous gonadotrophins and is at increased risk of developing OHSS. It has been shown that priming with FSH or hCG before immature oocyte retrieval improved oocyte maturation and pregnancy rates. Therefore, IVM treatment represents an attractive alternative to cycle cancellation, coasting, or embryo cryopreservation.
Metformin
In women with PCOS, short-term treatment with metformin did not improve the response to stimulation but it did improve the pregnancy outcome and reduced the incidence of OHSS. A meta-analysis of RCTs showed that the administration of metformin significantly reduced the risk of OHSS. These findings were obtained from four RCTs that included 449 participants with PCOS who were scheduled for IVF cycles. A recent large RCT found that metformin effectively reduces the incidence of OHSS in a high-risk population of women with PCOS who are receiving gonadotrophin for IVF. The action of metformin is still unknown.
Preventive therapy modalities during stimulation
Cycle cancellation
When symptoms of OHSS emerge even before administration of hCG, cycle cancellation should be seriously considered. Cycle cancellation and withholding of hCG is the only guaranteed method for preventing early OHSS. At present, it is less widely used because of the development of the more acceptable strategies such as coasting.
Coasting (withholding gonadotrophins)
Withholding further gonadotrophin stimulation and delaying hCG administration until oestradiol levels plateau or decrease significantly can reduce risks of OHSS. Coasting does not eliminate the risk of OHSS but may reduce the incidence and severity of the condition. According to a recent Cochrane review, no evidence suggested a benefit of using coasting to prevent OHSS compared with no coasting or other interventions. The Cochrane review included only four studies. Their conclusions were based on heterogeneous studies, and these results have to be interpreted with caution.
Initiating coasting depends on both oestradiol levels and numbers and size of follicles. It is generally accepted that coasting should be initiated when the oestradiol level is greater than 3000 pg/mL in the setting of numerous immature follicles (<16 mm) with rapidly increasing oestradiol level. Human chorionic gonadotrophin can be given when oestradiol levels drop to a ‘safe’ level (e.g. 3000 pg/mL). Such ‘coasting’ does not adversely affect outcome in IVF cycles unless it is prolonged (more than 3 days). Cycle cancellation should be considered if the duration of coasting exceeds 4 days or if the oestradiol level decreases by more than 30% the day after hCG trigger.
Administration of intravenous albumin and hydroxyethyl starch
Prophylactic intravenous administration of 25% albumin (20–50 g) at time of oocyte retrieval has been suggested as a means of reducing risk of OHSS. The most recent Cochrane meta-analysis of eight RCTs suggested that there is limited evidence of benefit from intravenous albumin administration at the time of oocyte retrieval in the prevention or reduction of the incidence of severe OHSS in high-risk women undergoing IVF or intracytoplasmic sperm injection treatment cycles. Another system review and meta-analysis, however, suggested that intravenous albumin administration in high-risk women does not seem to reduce the occurrence of severe OHSS.
An alternative to human albumin is hydroxyethyl solution (1000 mL 6% at the time of oocyte retrieval, followed by another 500 mL 48 h later). A recent Cochrane meta-analysis of three RCTs involving 487 randomised women suggested that hydroxyethyl starch markedly decreases the incidence of severe OHSS.
Triggering ovulation by low dose of human chorionic gonadotrophin
Although hCG has been the gold standard for ovulation triggering, it is responsible for an increased incidence of OHSS. To date, consensus is lacking over the optimal dose of hCG for final oocyte maturation. A systematic review of all studies that compared the effect of at least two doses of hCG for final oocyte maturation on IVF outcome and on the incidence of OHSS concluded that the clinical outcome were similar between women receiving 5000 or 10,000 IU hCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of urinary hCG. Owing to the lack of concrete evidence, it is believed that the dose of hCG should be individualised in the same way as the starting dose of gonadotrophins. Good responders need not receive a dose higher than 5000 IU of hCG. A lower dose of hCG may be prudent for women judged to be at high risk for OHSS.
Gonadotrophin-releasing hormone agonist to trigger final oocyte maturation
Gonadotrophin-releasing hormone agonist triggering is now a valid alternative to hCG triggering. Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation. Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg, buserelin 0.5 mg, or leuprolide acetate 1.5 mg. Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone. Luteinising hormone activity could be supplemented in the form of either one bolus of 1500 IU hCG administered on the day of oocyte retrieval, a total of three boluses of hCG (250–500 IU) during the luteal phase, or recombinant luteinising hormone 300 IU administered every second day during the luteal phase until a positive pregnancy test.
A recent meta-analysis showed that the modified luteal support has had a significant positive effect on the reproductive outcome after GnRH agonist triggering without an increase in the OHSS rate. Nevertheless, the most optimal luteal phase support still has to be explored. Until the optimal protocol of luteal supplementation is defined, an alterative option is to freeze all oocytes and embryos (so-call ‘freeze-all’) and transfer in subsequent natural or stimulated cycles. The combination of agonist trigger and ‘freeze all’ gives maximum protection and may even result in better implantation. It results, however, in patient inconvenience and additional expense. GnRH agonist triggering should be used in all oocyte donation cycles, owing to a total elimination of OHSS.
Avoidance of human chorionic gonadotrophin for luteal support
Luteal support with hCG is associated with a higher risk for OHSS and should be avoided. The use of exogenous progesterone (e.g. 50 mg progesterone in oil intramuscular, 100 mg progesterone vaginal suppositories, or 8% progesterone vaginal gel, daily) for luteal phase support rather than supplemental doses of hCG, may further reduce risks of OHSS. When symptoms of OHSS emerge even before administration of hCG, cycle cancellation and less aggressive stimulation in a subsequent cycle should be seriously considered.
Cryopreservation of all oocytes and embryos
Administration of hCG to trigger ovulation followed by oocyte retrieval and elective freezing of all embryos will not avoid early OHSS but will prevent the development of the late form of OHSS. In a recently updated Cochrane review, however, there is insufficient evidence to support routine cryopreservation. The reviewers concluded that these results have to be interpreted with caution because of the small number of women in the individual studies. Many IVF centres continue to use this method as a way of reducing the risk of OHSS. More research is needed to determine whether using elective cryopreservation of embryos can reduce the rate of severe OHSS in IVF. The true value of cryopreservation for the prevention of OHSS during IVF, however, may be as an adjunct intervention in support of other effective rescue techniques rather than as a stand-alone option.
Dopamine agonist therapy
The increase vascular permeability seen in OHSS is primarily caused by ovarian secretion of vascular endothelial growth factor, which activates its receptor (VEGFR-2). Administration of a dopamine or dopamine receptor 2 agonist, inactivates VEGFR-2 and prevents the increase in vascular permeability. Cabergoline 0.5 mg tablet daily starting on the day of hCG injection and continue for 8 days have been shown to reduce the risk of severe OHSS. Recently, a systematic review and meta-analysis of four randomised trials comparing the prophylactic effect of the dopamine agonist, cabergoline, versus no treatment in IVF and intracytoplasmic sperm injection cycles showed that prophylactic treatment with the dopamine agonist, cabergoline, reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.
Low-dose aspirin therapy
Low-dose aspirin therapy for prevention of OHSS is based on the theory that superovulation treatment may induce platelet hyperstimulation, which is associated with OHSS, and that aspirin therapy may inhibit this effect. Recently, the low-dose aspirin treatment (100 mg daily, beginning on the first day of ovarian stimulation) was shown to reduce the risk of severe OHSS in a large randomised clinical trial.
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