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Ovarian hyperstimulation syndrome
REVIEW
Ovarian hyperstimulation syndrome
into the third space, intravascular dehydration, and the sequelae of these processes. The true incidence of OHSS in modern reproductive medicine is unknown because there is no international registry to record this complication, there have been varying classification schemes historically and ascertainment of cases is variable. The literature suggests that the incidence of significant OHSS ranges between 3 and 8% of stimulated IVF cycles. However, these figures are historical and it is likely that recent changes in ovarian stimulation practice (see below) are associated with a lower risk of OHSS and the current incidence may be lower. Despite this, OHSS remains a significant threat to the well-being of women undergoing assisted conception, and the iatrogenic nature of this condition makes it even more important that clinicians keep prevention and safe management of OHSS at the centre of their care.
Akanksha Sood Raj Mathur*
Abstract Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic condition arising from supraphysiological ovarian stimulation for fertility treatment. It is characterized by ovarian enlargement with fluid shift to the third space and intravascular dehydration. Ovarian reserve tests can identify patients at high risk of OHSS, allowing targeted preventative measures. Evidence supports the use of GnRH antagonist regimes in women with a high ovarian reserve. GnRH agonist trigger and elective cryopreservation of all embryos further reduce the risk of OHSS. All women at risk of OHSS should have adequate information and access to 24-hour care. Women presenting with possible OHSS should be assessed and investigated to confirm the diagnosis and classify severity. Mild to moderate cases can be managed on an out-patient basis, whilst more severe cases need admission and monitoring. Principles of management are maintaining intravascular hydration by encouraging “drink to thirst”, close monitoring of fluid balance, prevention of thromboembolic complications, drainage of ascites in selected cases and symptom relief. If conception occurs in OHSS cycle, the recovery is protracted.
Pathophysiology Vascular Endothelial Growth Factor (VEGF) is signaling protein that is central to OHSS. In response to HCG, ovarian granulosa cells produce VEGF which causes increased capillary permeability and arteriolar dilatation. This leads to loss of intravascular fluid into third space and consequent intravascular dehydration. The features of OHSS are due to. a. Ovarian enlargement b. Third space fluid loss resulting in ascites, pleural and pericardial effusions c. Intravascular dehydration, with a risk of pre-renal failure and thrombosis These patients are prone to thromboembolic complications, which can present several weeks after apparent resolution of OHSS. There is a preponderance of arterial system thrombosis and upper body sites unlike other conditions. It has been proposed that arterial thrombosis usually occurs with the clinical manifestation of OHSS, whilst venous thrombosis may occur weeks after apparent resolution of symptoms. In the RCOG classification of OHSS (Table 1), more severe pathophysiology and increasing symptoms are seen as the severity of OHSS increases. OHSS can be classified as early and late, based on the timing of symptoms. Early OHSS is seen within 9 days after exogenous ‘trigger’ (usually HCG) used to achieve follicular maturation prior to egg retrieval. If symptoms begin beyond this period, these are due to endogenous HCG from an early pregnancy. This late OHSS tends to be more severe and is poorly predictable from the preceding ovarian response to stimulation.
Keywords ovarian hyperstimulation syndrome; polycystic ovary syndrome; thromboembolism
Introduction Assisted reproductive techniques such as In vitro fertilization (IVF) are part of mainstream medical practice with approximately 70,000 cycles carried out annually in the UK, and more than 2% of UK births now arise from IVF. The majority of IVF cycles include the use of gonadotropin ovarian stimulation, which increases the number of eggs available for fertilization, and embryos for transfer, relative to natural cycles. The use of ovarian stimulation greatly increases the likelihood of an IVF cycle resulting in a live birth, but also carries a risk of Ovarian Hyperstimulation Syndrome (OHSS). OHSS is best thought of as an iatrogenic condition caused by inflammatory mediators released by hyperstimulated ovaries, with a characteristic pathophysiology that encompasses ovarian enlargement, fluid shift
Risk factors OHSS is an iatrogenic condition. Therefore any woman undergoing ovarian stimulation with gonadotropins can develop OHSS. If the “at risk” women can be identified prior to or during treatment, measures can be taken for prevention. Additional risk factors include the following: a. Polycystic ovaries (PCO): Women with PCO morphology, whether or not they express the PCO syndrome, are at increased risk of OHSS. b. Ovarian reserve: Antral Follicle Count (AFC) and Serum Anti-Mullerian Hormone (AMH) levels are reliable predictors
Akanksha Sood MS, DNB, MRCOG, Senior Clinical Fellow in Reproductive Medicine, Saint Mary’s Hospital, Manchester NHS Foundation Trust, UK. Conflicts of interest: None. Raj Mathur MD, FRCOG, Consultant in Reproductive Medicine, Saint Mary’s Hospital, Manchester NHS Foundation Trust, UK. Conflicts of interest: RM Has a Private Practice in Fertility and Has Received Honoraria to Attend Meetings and Speaker’s Fees from Companies That Manufacture Medications Used in Fertility Treatment. Full Details May Be Found at whopaysthisdoctor.org.
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REVIEW
of OHSS, using ovarian reserve parameters (see above), so that appropriate measures can be targeted to them.
RCOG classification of OHSS (5) OHSS Grade
Features
Mild OHSS
Abdominal bloating Mild abdominal pain Ovarian size usually <8 cma Moderate abdominal pain Nauseavomiting Ultrasound evidence of ascites Ovarian size usually 8e12 cma Clinical ascites ( hydrothorax) Oliguria (<300 ml/day or <30 ml/hour) Haematocrit> 0.45 Hyponatraemia (sodium <135 mmol/l) Hypo-osmolality (osmolality <282 mOsm/kg) Hyperkalaemia (potassium >5 mmol/l) Hypoproteinaemia (serum albumin <35 g/l) Ovarian size usually >12 cma Tense ascites/large hydrothorax Haematocrit >0.55 White cell count >25,000/ml Oliguria/anuria Thromboembolism Acute respiratory distress syndrome
Moderate OHSS
Severe OHSS
Critical OHSS
a. Treatment protocol - Prevention of an endogenous LH surge is critical during ovarian stimulation, and can be achieved using Gonadotropin-Releasing Hormone (GnRH) antagonist or GnRH agonist. The GnRH antagonist protocol significantly reduces OHSS risk without reducing likelihood of achieving live birth. A Cochrane review in 2016 concluded GnRH antagonist is associated with lower incidence of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n ¼ 7944, I2 ¼ 31%, moderate quality evidence). b. Choice of trigger e In women receiving GnRH antagonist, the pituitary remains sensitive to the effect of GnRH. Hence, if a woman on GnRH antagonist is administered GnRH agonist, her pituitary responds with a ‘flare’ of FSH and LH. This is sufficient in the majority of cases for inducing final maturation of the oocyte. Hence, GnRH agonist offers an alternative to HCG which is the generally-used ‘trigger’ for final oocyte maturation. Endogenous LH causes shorter and less severe stimulation of granulosa cells as compared with HCG, and hence carries a lower risk of inducing OHSS compared to HCG. Triggering with GnRH agonist instead of HCG in fresh autologous GnRH antagonist IVF/ ICSI treatment cycles prevents OHSS. In women undergoing fresh IVF cycles, GnRH agonists were associated with a lower incidence of mild, moderate or severe OHSS than was HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I2 ¼ 42%, moderate-quality evidence). This suggests that for a woman with a 5% risk of mild, moderate or severe OHSS with the use of HCG, the risk of OHSS with the use of a GnRH agonist would be between 0 and 2%. A disadvantage of GnRH agonist trigger is that the induced LH surge is of a shorter duration than a ‘natural’ LH surge, and although it is adequate for the oocyte to complete its maturation, corpus luteum development is impaired. This is reflected in low pregnancy rates if a fresh embryo is transferred. This problem can be resolved in one of two ways e either by freezing all embryos and opting for an elective frozen embryo transfer, or by modified luteal support regimes which may include a small dose of HCG and estradiol in addition to progesterone. Both alternatives have been shown to yield good results. However it should be remembered that any HCG exposure is likely to increase the risk of OHSS. Newer compounds like Kisspeptin have been evaluated as a means of inducing an endogenous LH surge, and have shown initial promising results in prevention of OHSS.
It is important to note that OHSS is dynamic and level of severity can change during the course of illness. a Ovarian size may not correlate with severity of OHSS in cases of assisted reproduction because of the effect of follicular aspiration. Women demonstrating any feature of severe or critical OHSS should be classified in that category.
Table 1
of ovarian response to stimulation and high levels of both parameters have been correlated with OHSS. There is no clear cut off defined in literature, but AMH >35 pmol/l and AFC >25 are commonly used in clinical practice. c. Previous history of OHSS. d. Ovarian Response: The ovarian response to exogenous stimulation may indicate an increased risk of OHSS, but is not as sensitive or specific as ovarian reserve in predicting the risk of OHSS. Features of concern include a large number of follicles, high serum estradiol concentration and a high number of oocytes collected. There is no agreement on what levels should be used as threshold values to determine ‘highrisk’ cycles. The following are commonly used in clinical practice: oestradiol >15,000 pmol/l or >19 medium/large follicles at the end of stimulation and >20 oocytes collected. e. Pregnancy occurring in a treatment cycle increases the risk of late OHSS due to the effect of HCG. Eliminating the chance of pregnancy by elective cryopreservation of all embryos is associated with the elimination of late OHSS, though the early form can still occur.
c. Elective cryopreservation of oocytes/embryos - Avoidance of embryo transfer following HCG trigger may not prevent early OHSS, but will prevent late OHSS. This strategy is often applied in women with a high ovarian reserve who are at risk of OHSS. In these patients elective cryopreservation followed by delayed transfer of frozen-warmed embryos may have the additional benefit of improving the likelihood of successful outcome. A recent systematic review and meta-analysis showed a higher live birth rate in elective frozen embryo transfer cycles than fresh cycles in hyper-responders (RR ¼ 1.16, 95% CI 1.05e1.28). The same meta-analysis showed that the risk of moderate/severe OHSS was significantly lower with eFET than fresh transfer (RR
Prevention of OHSS A number of preventative measures are available to reduce the risk of OHSS. A key challenge is to identify women at a high risk
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REVIEW
symptoms include abdominal distension, discomfort and nausea. Vomiting, decreased urine output, difficulty in breathing and chest pain are indicators of increased severity. Patients must be provided written and verbal information about OHSS, in addition to contact numbers for access to advice and assessment, including out-of-hours.
0.42, 95% CI 0.19e0.96). This supports the concept that OHSS prevention can be accomplished without reducing the overall chance of having a baby, by judicious use of GnRH antagonist, followed by agonist trigger and elective freeze-all. d. Mild stimulation/individualised FSH dose - In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose was found to reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS.
Treatment Women reporting symptoms of OHSS should be assessed to establish a diagnosis and confirm the severity of the condition. The urgency of assessment depends on the severity of initial presentation. Women with minor abdominal distension and discomfort should be seen within 24 hours, while those reporting significant pain, persistent vomiting or shortness of breath should be seen as an emergency. This may require them to access their local Accident and Emergency or Gynaecology unit, rather than the clinic responsible for their fertility treatment. Fertility clinics should therefore establish close relations with acute care providers in their catchment area, to ensure safe and effective care. A specialist in reproductive medicine should be involved at an early stage in the management of women with OHSS. Initial assessment includes a history, examination and tests required to confirm the diagnosis and establish the severity of OHSS (Table 2). Severe abdominal pain is not a typical symptom of OHSS, and should alert the clinician to a differential diagnosis like ovarian torsion, ectopic pregnancy, bleeding post-egg collection, pelvic infection and other causes of acute abdomen. OHSS is a self-limiting condition that requires supportive treatment until it resolves. If embryo transfer is not done, or if pregnancy does not result, the symptoms resolve with the next menstrual period. If the woman conceives after fresh embryo transfer, the symptoms often worsen and can continue for several weeks. Management is hence aimed at symptom relief, monitoring and prevention of complications. Most women with mild and moderate OHSS can be managed as outpatients, with hospital care reserved for those with severe OHSS and those with social issues that may prevent them from attending for regular follow-up. OUTPATIENT MANAGEMENT- OHSS is mild to moderate in the majority of those affected. These patients can be managed as outpatients with proper monitoring and patient information regarding warning symptoms. In particular the patient should be asked to report for urgent clinical review if there is significant pain, inability to maintain her oral fluid intake (e.g. severe nausea/vomiting), subjective feeling of reduced urine output, increasing shortness of breath or symptoms suggesting a deep venous thrombosis (such as leg pain). Patients should be instructed to maintain hydration and drink to thirst. She should also be advised to avoid intercourse as this may increase pain and the chances of cyst rupture. Patients should be reassured that OHSS has no adverse effect on fetal development and pregnancy. Paracetamol (1 gm every 6 hours) can be safely taken for pain relief, but if pain does not subside then clinical review is warranted. INPATIENT MANAGEMENT- The patient should be admitted to hospital if she shows signs of severe OHSS, if there is diagnostic uncertainty with a serious differential diagnosis, she is unable to cope at home or has the following specific features:
e. Co-treatment with Metformin - Metformin is an insulin sensitising drug, commonly used to treat type 2 diabetes and also PCOS. Meta-analysis of randomised trials indicates that Metformin use is associated with a reduced risk of OHSS in women with PCOS undergoing IVF (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798 women, I2 ¼ 11%, moderate-quality evidence). Some studies have suggested that Metformin does not decrease OHSS risk in non-obese PCOS patients or those with PCO morphology only. f. Dopamine antagonist - Cabergoline reduces VEGF production and may reduce the risk of OHSS. A Cochrane review in 2017 concluded, when compared with placebo or no intervention, dopamine agonists seemed effective in the prevention of moderate or severe OHSS (OR 0.27, 95% CI 0.19 to 0.39; 1022 participants; 8 studies; I2 ¼ 0%; moderate quality evidence). There was no evidence of a difference in live birth rate, clinical pregnancy rate, multiple pregnancy rate or miscarriage rate (very low to moderate quality evidence). g. Coasting - this refers to withholding the FSH stimulation while continuing pituitary suppression in cycles where the ovarian response is thought to be excessive. This allows smaller follicles (which are FSH dependent) to become apoptotic while the larger (FSH independent) follicles continue to grow. As a result of this granulosa cell activity decreases and estradiol levels fall. Coasting if continued for longer than 4 days can significantly decrease the live birth rates and in that event, the cycle is preferably cancelled. There is low-quality evidence to suggest that coasting reduces rates of moderate or severe OHSS compared to no coasting. h. Cycle cancellation - This refers to stopping ovarian stimulation and not administering the trigger injection in cycles with an excessive ovarian response. Avoiding the trigger eliminates the risk of OHSS (early and late), but there is understandable reluctance among patients and clinicians to ‘waste’ a treatment cycle. In modern practice, the use of cycle cancellation has been superseded by GnRH agonist trigger and elective cryopreservation, but it remains the only preventative measure with guaranteed effectiveness.
Patient information Women should be informed of the potential risk of developing OHSS prior to starting treatment. When receiving ovarian stimulation women must be made aware of the symptoms of OHSS and advised to report them to the treating unit. Relevant
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REVIEW
volume. Effective control of nausea and pain are helpful in allowing patients to achieve this. If the patient is tolerating oral fluids, there is no need for i.v. fluids. However if there is severe dehydration (haematocrit >0.45; haemoglobin >14 g/dL) then initial rehydration with intravenous crystalloid may be necessary with an aim to sustain satisfactory urine output. Careful attention to electrolyte balance is essential and usually requires 0.9% saline, rather than Hartmann’s solution (Ringer’s lactate) as patients tend to be hyperkalaemic. Persistent haemoconcentration is managed by colloidal agents such as human albumin 20% (100 ml every 4 hours), in addition to thirst-guided oral intake or intravenous maintenance crystalloid. Diuretics should be avoided as they deplete intravascular volume further, although they may have a role with careful haemodynamic monitoring in cases where oliguria persists despite adequate intravascular volume expansion and a normal intra-abdominal pressure. Complex fluid management issues should be managed with the advice of physicians. 2.Thromboprophylaxis - Low molecular weight heparin in prophylactic doses should be started for all cases of severe OHSS and admitted patients, in addition to anti-embolic stockings. Any suspicion of venous thromboembolism must be thoroughly investigated and if present the dose increased to therapeutic levels. Prophylactic doses are advised to continue as a minimum until the next menstrual period (if not pregnant) or and until the end of first trimester if pregnant. Thereafter, the patient should be reviewed by a specialist and an individualised decision made about continuation of prophylactic LMWH. 3.Pain relief- Paracetamol and codeine can be used safely. Non-steroidal anti-inflammatory agents are avoided as these can aggravate renal dysfunction. 4.ParacentesiseThere is evidence that early drainage of ascites may shorten the course of severe OHSS, but this is not standard practice in the UK. Most clinicians agree that paracentesis is indicated in women with tense ascites causing pain or breathing difficulty, and in women with a persistent low urine output despite adequate rehydration with colloids. Paracentesis should be guided by ultrasound and may be performed through the abdominal or vaginal route, with the abdominal route being more popular in the UK. It is essential to replace the protein lost in the form of albumin infusion (20% human albumin every 4 hours). Thoracentesis is rarely indicated but may be necessary if the patient develops a symptomatic pleural effusion that does not resolve following paracentesis. 5.Surgery has no role in the management of OHSS unless the patient has an additional complication requiring treatment such as suspected ovarian torsion or ectopic pregnancy. Hyperstimulated ovaries are very friable and vascular and surgery should be carried out by an appropriately experienced surgeon. 6. Critical care: Women with critical OHSS with persistent oliguria and haemoconcentration despite initial colloid volume expansion may need invasive monitoring. Multi-disciplinary input with the involvement of an intensivist, renal physician and reproductive medicine specialist should be sought. A
Examination and Investigations of women with suspected OHSS (5) Examination General: assess for dehydration, oedema (pedal, vulval and sacral); record heart rate, respiratory rate, blood pressure, body weight Abdominal: assess for ascites, palpable mass, peritonism; measure girth Respiratory: assess for pleural effusion, pneumonia, pulmonary oedema Investigations Full blood count Haematocrit (haemoconcentration) C-reactive protein (severity) Urea and electrolytes (hyponatraemia and hyperkalaemia) Serum osmolality (hypo-osmolality) Liver function tests (elevated enzymes and reduced albumin) Coagulation profile (elevated fibrinogen and reduced antithrombin) hCG (to determine outcome of treatment cycle) if appropriate Ultrasound scan: ovarian size, pelvic and abdominal free fluid. Consider ovarian Doppler if torsion suspected Additional investigations (based on individual presentation) Arterial blood gases D-dimer Electrocardiogram (ECG)/echocardiogram Chest X-ray Computed tomography pulmonary angiogram (CTPA) or ventilation/ perfusion (V/Q) scan Table 2
severe abdominal pain vomiting that prevents fluid intake oliguria/anuria tense ascites dyspnoea/tachypnoea hypotension electrolyte imbalance haemoconcentration The most important aspect of in-patient management is monitoring symptoms and signs and providing supportive treatment. A baseline and daily record of patient’s weight and abdominal girth must be maintained. Strict fluid intake and output charting is required, along with observations of vital signs every 4 hours as a minimum, depending on severity. Investigations should be undertaken as per Table 2 and repeated daily. Investigations and assessments may need carried out more frequently depending on the clinical situation. Principles of management 1.Maintenance of intravascular volume (to prevent thrombosis and renal failure) - Symptomatic OHSS is a state of hypovolaemic hyponatraemia. Patients should be encouraged to drink to thirst, as this is the most physiological way of replacing
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REVIEW
assisted reproductive technology. Cochrane Database Syst Rev 2016; 4: CD001750. https://doi.org/10.1002/14651858.CD001750. pub4. Tan B, Mathur R. Management of ovarian hyperstimulation syndrome. Produced on behalf of the BFS Policy and Practice Committee Human Fertility 2013; 16: 151e9. Youssef MAFM, Van der Veen F, Al-Inany HG, et al. Gonadotropinreleasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev 2014; 10: CD008046. https://doi.org/10.1002/14651858. CD008046.pub4. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2e14. https://doi.org/10.1093/ humupd/dmy033. The Management of Ovarian Hyperstimulation Syndrome. 9 (RCOG Green-top Guideline) [Internet][cited 17 January 2020]. 2020; 1e22. Available from:, https://www.rcog.org.uk/globalassets/ documents/guidelines/green-top-guidelines/gtg_5_ohss.pdf.
Practice points C
C
C
C C
Risk factors for developing OHSS are young age, PCOS, PCO morphology, high ovarian reserve, exaggerated ovarian response to stimulation and previous history of OHSS. Risk of OHSS can be lowered by using GnRH antagonist protocol, GnRH agonist trigger, co-treatment with Metformin in cases of PCOS, use of Cabergoline and elective cryopreservation of embryos. All women undergoing ovarian stimulation must be warned about symptoms of OHSS and should have a 24-hour contact for advice. Mild to moderate cases can be managed on out-patient basis Severe cases need admission with careful monitoring of fluid balance, weight, abdominal girth and symptoms. Intravascular hydration must be maintained. Thromboprophylaxis should be provided in all severe cases. Paracentesis may hasten recovery.
FURTHER READING Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for
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Ovarian hyperstimulation syndrome
into the third space, intravascular dehydration, and the sequelae of these processes. The true incidence of OHSS in modern reproductive medicine is unknown because there is no international registry to record this complication, there have been varying classification schemes historically and ascertainment of cases is variable. The literature suggests that the incidence of significant OHSS ranges between 3 and 8% of stimulated IVF cycles. However, these figures are historical and it is likely that recent changes in ovarian stimulation practice (see below) are associated with a lower risk of OHSS and the current incidence may be lower. Despite this, OHSS remains a significant threat to the well-being of women undergoing assisted conception, and the iatrogenic nature of this condition makes it even more important that clinicians keep prevention and safe management of OHSS at the centre of their care.
Akanksha Sood Raj Mathur*
Abstract Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic condition arising from supraphysiological ovarian stimulation for fertility treatment. It is characterized by ovarian enlargement with fluid shift to the third space and intravascular dehydration. Ovarian reserve tests can identify patients at high risk of OHSS, allowing targeted preventative measures. Evidence supports the use of GnRH antagonist regimes in women with a high ovarian reserve. GnRH agonist trigger and elective cryopreservation of all embryos further reduce the risk of OHSS. All women at risk of OHSS should have adequate information and access to 24-hour care. Women presenting with possible OHSS should be assessed and investigated to confirm the diagnosis and classify severity. Mild to moderate cases can be managed on an out-patient basis, whilst more severe cases need admission and monitoring. Principles of management are maintaining intravascular hydration by encouraging “drink to thirst”, close monitoring of fluid balance, prevention of thromboembolic complications, drainage of ascites in selected cases and symptom relief. If conception occurs in OHSS cycle, the recovery is protracted.
Pathophysiology Vascular Endothelial Growth Factor (VEGF) is signaling protein that is central to OHSS. In response to HCG, ovarian granulosa cells produce VEGF which causes increased capillary permeability and arteriolar dilatation. This leads to loss of intravascular fluid into third space and consequent intravascular dehydration. The features of OHSS are due to. a. Ovarian enlargement b. Third space fluid loss resulting in ascites, pleural and pericardial effusions c. Intravascular dehydration, with a risk of pre-renal failure and thrombosis These patients are prone to thromboembolic complications, which can present several weeks after apparent resolution of OHSS. There is a preponderance of arterial system thrombosis and upper body sites unlike other conditions. It has been proposed that arterial thrombosis usually occurs with the clinical manifestation of OHSS, whilst venous thrombosis may occur weeks after apparent resolution of symptoms. In the RCOG classification of OHSS (Table 1), more severe pathophysiology and increasing symptoms are seen as the severity of OHSS increases. OHSS can be classified as early and late, based on the timing of symptoms. Early OHSS is seen within 9 days after exogenous ‘trigger’ (usually HCG) used to achieve follicular maturation prior to egg retrieval. If symptoms begin beyond this period, these are due to endogenous HCG from an early pregnancy. This late OHSS tends to be more severe and is poorly predictable from the preceding ovarian response to stimulation.
Keywords ovarian hyperstimulation syndrome; polycystic ovary syndrome; thromboembolism
Introduction Assisted reproductive techniques such as In vitro fertilization (IVF) are part of mainstream medical practice with approximately 70,000 cycles carried out annually in the UK, and more than 2% of UK births now arise from IVF. The majority of IVF cycles include the use of gonadotropin ovarian stimulation, which increases the number of eggs available for fertilization, and embryos for transfer, relative to natural cycles. The use of ovarian stimulation greatly increases the likelihood of an IVF cycle resulting in a live birth, but also carries a risk of Ovarian Hyperstimulation Syndrome (OHSS). OHSS is best thought of as an iatrogenic condition caused by inflammatory mediators released by hyperstimulated ovaries, with a characteristic pathophysiology that encompasses ovarian enlargement, fluid shift
Risk factors OHSS is an iatrogenic condition. Therefore any woman undergoing ovarian stimulation with gonadotropins can develop OHSS. If the “at risk” women can be identified prior to or during treatment, measures can be taken for prevention. Additional risk factors include the following: a. Polycystic ovaries (PCO): Women with PCO morphology, whether or not they express the PCO syndrome, are at increased risk of OHSS. b. Ovarian reserve: Antral Follicle Count (AFC) and Serum Anti-Mullerian Hormone (AMH) levels are reliable predictors
Akanksha Sood MS, DNB, MRCOG, Senior Clinical Fellow in Reproductive Medicine, Saint Mary’s Hospital, Manchester NHS Foundation Trust, UK. Conflicts of interest: None. Raj Mathur MD, FRCOG, Consultant in Reproductive Medicine, Saint Mary’s Hospital, Manchester NHS Foundation Trust, UK. Conflicts of interest: RM Has a Private Practice in Fertility and Has Received Honoraria to Attend Meetings and Speaker’s Fees from Companies That Manufacture Medications Used in Fertility Treatment. Full Details May Be Found at whopaysthisdoctor.org.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE xxx:xxx
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REVIEW
of OHSS, using ovarian reserve parameters (see above), so that appropriate measures can be targeted to them.
RCOG classification of OHSS (5) OHSS Grade
Features
Mild OHSS
Abdominal bloating Mild abdominal pain Ovarian size usually <8 cma Moderate abdominal pain Nauseavomiting Ultrasound evidence of ascites Ovarian size usually 8e12 cma Clinical ascites ( hydrothorax) Oliguria (<300 ml/day or <30 ml/hour) Haematocrit> 0.45 Hyponatraemia (sodium <135 mmol/l) Hypo-osmolality (osmolality <282 mOsm/kg) Hyperkalaemia (potassium >5 mmol/l) Hypoproteinaemia (serum albumin <35 g/l) Ovarian size usually >12 cma Tense ascites/large hydrothorax Haematocrit >0.55 White cell count >25,000/ml Oliguria/anuria Thromboembolism Acute respiratory distress syndrome
Moderate OHSS
Severe OHSS
Critical OHSS
a. Treatment protocol - Prevention of an endogenous LH surge is critical during ovarian stimulation, and can be achieved using Gonadotropin-Releasing Hormone (GnRH) antagonist or GnRH agonist. The GnRH antagonist protocol significantly reduces OHSS risk without reducing likelihood of achieving live birth. A Cochrane review in 2016 concluded GnRH antagonist is associated with lower incidence of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n ¼ 7944, I2 ¼ 31%, moderate quality evidence). b. Choice of trigger e In women receiving GnRH antagonist, the pituitary remains sensitive to the effect of GnRH. Hence, if a woman on GnRH antagonist is administered GnRH agonist, her pituitary responds with a ‘flare’ of FSH and LH. This is sufficient in the majority of cases for inducing final maturation of the oocyte. Hence, GnRH agonist offers an alternative to HCG which is the generally-used ‘trigger’ for final oocyte maturation. Endogenous LH causes shorter and less severe stimulation of granulosa cells as compared with HCG, and hence carries a lower risk of inducing OHSS compared to HCG. Triggering with GnRH agonist instead of HCG in fresh autologous GnRH antagonist IVF/ ICSI treatment cycles prevents OHSS. In women undergoing fresh IVF cycles, GnRH agonists were associated with a lower incidence of mild, moderate or severe OHSS than was HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I2 ¼ 42%, moderate-quality evidence). This suggests that for a woman with a 5% risk of mild, moderate or severe OHSS with the use of HCG, the risk of OHSS with the use of a GnRH agonist would be between 0 and 2%. A disadvantage of GnRH agonist trigger is that the induced LH surge is of a shorter duration than a ‘natural’ LH surge, and although it is adequate for the oocyte to complete its maturation, corpus luteum development is impaired. This is reflected in low pregnancy rates if a fresh embryo is transferred. This problem can be resolved in one of two ways e either by freezing all embryos and opting for an elective frozen embryo transfer, or by modified luteal support regimes which may include a small dose of HCG and estradiol in addition to progesterone. Both alternatives have been shown to yield good results. However it should be remembered that any HCG exposure is likely to increase the risk of OHSS. Newer compounds like Kisspeptin have been evaluated as a means of inducing an endogenous LH surge, and have shown initial promising results in prevention of OHSS.
It is important to note that OHSS is dynamic and level of severity can change during the course of illness. a Ovarian size may not correlate with severity of OHSS in cases of assisted reproduction because of the effect of follicular aspiration. Women demonstrating any feature of severe or critical OHSS should be classified in that category.
Table 1
of ovarian response to stimulation and high levels of both parameters have been correlated with OHSS. There is no clear cut off defined in literature, but AMH >35 pmol/l and AFC >25 are commonly used in clinical practice. c. Previous history of OHSS. d. Ovarian Response: The ovarian response to exogenous stimulation may indicate an increased risk of OHSS, but is not as sensitive or specific as ovarian reserve in predicting the risk of OHSS. Features of concern include a large number of follicles, high serum estradiol concentration and a high number of oocytes collected. There is no agreement on what levels should be used as threshold values to determine ‘highrisk’ cycles. The following are commonly used in clinical practice: oestradiol >15,000 pmol/l or >19 medium/large follicles at the end of stimulation and >20 oocytes collected. e. Pregnancy occurring in a treatment cycle increases the risk of late OHSS due to the effect of HCG. Eliminating the chance of pregnancy by elective cryopreservation of all embryos is associated with the elimination of late OHSS, though the early form can still occur.
c. Elective cryopreservation of oocytes/embryos - Avoidance of embryo transfer following HCG trigger may not prevent early OHSS, but will prevent late OHSS. This strategy is often applied in women with a high ovarian reserve who are at risk of OHSS. In these patients elective cryopreservation followed by delayed transfer of frozen-warmed embryos may have the additional benefit of improving the likelihood of successful outcome. A recent systematic review and meta-analysis showed a higher live birth rate in elective frozen embryo transfer cycles than fresh cycles in hyper-responders (RR ¼ 1.16, 95% CI 1.05e1.28). The same meta-analysis showed that the risk of moderate/severe OHSS was significantly lower with eFET than fresh transfer (RR
Prevention of OHSS A number of preventative measures are available to reduce the risk of OHSS. A key challenge is to identify women at a high risk
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symptoms include abdominal distension, discomfort and nausea. Vomiting, decreased urine output, difficulty in breathing and chest pain are indicators of increased severity. Patients must be provided written and verbal information about OHSS, in addition to contact numbers for access to advice and assessment, including out-of-hours.
0.42, 95% CI 0.19e0.96). This supports the concept that OHSS prevention can be accomplished without reducing the overall chance of having a baby, by judicious use of GnRH antagonist, followed by agonist trigger and elective freeze-all. d. Mild stimulation/individualised FSH dose - In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose was found to reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS.
Treatment Women reporting symptoms of OHSS should be assessed to establish a diagnosis and confirm the severity of the condition. The urgency of assessment depends on the severity of initial presentation. Women with minor abdominal distension and discomfort should be seen within 24 hours, while those reporting significant pain, persistent vomiting or shortness of breath should be seen as an emergency. This may require them to access their local Accident and Emergency or Gynaecology unit, rather than the clinic responsible for their fertility treatment. Fertility clinics should therefore establish close relations with acute care providers in their catchment area, to ensure safe and effective care. A specialist in reproductive medicine should be involved at an early stage in the management of women with OHSS. Initial assessment includes a history, examination and tests required to confirm the diagnosis and establish the severity of OHSS (Table 2). Severe abdominal pain is not a typical symptom of OHSS, and should alert the clinician to a differential diagnosis like ovarian torsion, ectopic pregnancy, bleeding post-egg collection, pelvic infection and other causes of acute abdomen. OHSS is a self-limiting condition that requires supportive treatment until it resolves. If embryo transfer is not done, or if pregnancy does not result, the symptoms resolve with the next menstrual period. If the woman conceives after fresh embryo transfer, the symptoms often worsen and can continue for several weeks. Management is hence aimed at symptom relief, monitoring and prevention of complications. Most women with mild and moderate OHSS can be managed as outpatients, with hospital care reserved for those with severe OHSS and those with social issues that may prevent them from attending for regular follow-up. OUTPATIENT MANAGEMENT- OHSS is mild to moderate in the majority of those affected. These patients can be managed as outpatients with proper monitoring and patient information regarding warning symptoms. In particular the patient should be asked to report for urgent clinical review if there is significant pain, inability to maintain her oral fluid intake (e.g. severe nausea/vomiting), subjective feeling of reduced urine output, increasing shortness of breath or symptoms suggesting a deep venous thrombosis (such as leg pain). Patients should be instructed to maintain hydration and drink to thirst. She should also be advised to avoid intercourse as this may increase pain and the chances of cyst rupture. Patients should be reassured that OHSS has no adverse effect on fetal development and pregnancy. Paracetamol (1 gm every 6 hours) can be safely taken for pain relief, but if pain does not subside then clinical review is warranted. INPATIENT MANAGEMENT- The patient should be admitted to hospital if she shows signs of severe OHSS, if there is diagnostic uncertainty with a serious differential diagnosis, she is unable to cope at home or has the following specific features:
e. Co-treatment with Metformin - Metformin is an insulin sensitising drug, commonly used to treat type 2 diabetes and also PCOS. Meta-analysis of randomised trials indicates that Metformin use is associated with a reduced risk of OHSS in women with PCOS undergoing IVF (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798 women, I2 ¼ 11%, moderate-quality evidence). Some studies have suggested that Metformin does not decrease OHSS risk in non-obese PCOS patients or those with PCO morphology only. f. Dopamine antagonist - Cabergoline reduces VEGF production and may reduce the risk of OHSS. A Cochrane review in 2017 concluded, when compared with placebo or no intervention, dopamine agonists seemed effective in the prevention of moderate or severe OHSS (OR 0.27, 95% CI 0.19 to 0.39; 1022 participants; 8 studies; I2 ¼ 0%; moderate quality evidence). There was no evidence of a difference in live birth rate, clinical pregnancy rate, multiple pregnancy rate or miscarriage rate (very low to moderate quality evidence). g. Coasting - this refers to withholding the FSH stimulation while continuing pituitary suppression in cycles where the ovarian response is thought to be excessive. This allows smaller follicles (which are FSH dependent) to become apoptotic while the larger (FSH independent) follicles continue to grow. As a result of this granulosa cell activity decreases and estradiol levels fall. Coasting if continued for longer than 4 days can significantly decrease the live birth rates and in that event, the cycle is preferably cancelled. There is low-quality evidence to suggest that coasting reduces rates of moderate or severe OHSS compared to no coasting. h. Cycle cancellation - This refers to stopping ovarian stimulation and not administering the trigger injection in cycles with an excessive ovarian response. Avoiding the trigger eliminates the risk of OHSS (early and late), but there is understandable reluctance among patients and clinicians to ‘waste’ a treatment cycle. In modern practice, the use of cycle cancellation has been superseded by GnRH agonist trigger and elective cryopreservation, but it remains the only preventative measure with guaranteed effectiveness.
Patient information Women should be informed of the potential risk of developing OHSS prior to starting treatment. When receiving ovarian stimulation women must be made aware of the symptoms of OHSS and advised to report them to the treating unit. Relevant
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volume. Effective control of nausea and pain are helpful in allowing patients to achieve this. If the patient is tolerating oral fluids, there is no need for i.v. fluids. However if there is severe dehydration (haematocrit >0.45; haemoglobin >14 g/dL) then initial rehydration with intravenous crystalloid may be necessary with an aim to sustain satisfactory urine output. Careful attention to electrolyte balance is essential and usually requires 0.9% saline, rather than Hartmann’s solution (Ringer’s lactate) as patients tend to be hyperkalaemic. Persistent haemoconcentration is managed by colloidal agents such as human albumin 20% (100 ml every 4 hours), in addition to thirst-guided oral intake or intravenous maintenance crystalloid. Diuretics should be avoided as they deplete intravascular volume further, although they may have a role with careful haemodynamic monitoring in cases where oliguria persists despite adequate intravascular volume expansion and a normal intra-abdominal pressure. Complex fluid management issues should be managed with the advice of physicians. 2.Thromboprophylaxis - Low molecular weight heparin in prophylactic doses should be started for all cases of severe OHSS and admitted patients, in addition to anti-embolic stockings. Any suspicion of venous thromboembolism must be thoroughly investigated and if present the dose increased to therapeutic levels. Prophylactic doses are advised to continue as a minimum until the next menstrual period (if not pregnant) or and until the end of first trimester if pregnant. Thereafter, the patient should be reviewed by a specialist and an individualised decision made about continuation of prophylactic LMWH. 3.Pain relief- Paracetamol and codeine can be used safely. Non-steroidal anti-inflammatory agents are avoided as these can aggravate renal dysfunction. 4.ParacentesiseThere is evidence that early drainage of ascites may shorten the course of severe OHSS, but this is not standard practice in the UK. Most clinicians agree that paracentesis is indicated in women with tense ascites causing pain or breathing difficulty, and in women with a persistent low urine output despite adequate rehydration with colloids. Paracentesis should be guided by ultrasound and may be performed through the abdominal or vaginal route, with the abdominal route being more popular in the UK. It is essential to replace the protein lost in the form of albumin infusion (20% human albumin every 4 hours). Thoracentesis is rarely indicated but may be necessary if the patient develops a symptomatic pleural effusion that does not resolve following paracentesis. 5.Surgery has no role in the management of OHSS unless the patient has an additional complication requiring treatment such as suspected ovarian torsion or ectopic pregnancy. Hyperstimulated ovaries are very friable and vascular and surgery should be carried out by an appropriately experienced surgeon. 6. Critical care: Women with critical OHSS with persistent oliguria and haemoconcentration despite initial colloid volume expansion may need invasive monitoring. Multi-disciplinary input with the involvement of an intensivist, renal physician and reproductive medicine specialist should be sought. A
Examination and Investigations of women with suspected OHSS (5) Examination General: assess for dehydration, oedema (pedal, vulval and sacral); record heart rate, respiratory rate, blood pressure, body weight Abdominal: assess for ascites, palpable mass, peritonism; measure girth Respiratory: assess for pleural effusion, pneumonia, pulmonary oedema Investigations Full blood count Haematocrit (haemoconcentration) C-reactive protein (severity) Urea and electrolytes (hyponatraemia and hyperkalaemia) Serum osmolality (hypo-osmolality) Liver function tests (elevated enzymes and reduced albumin) Coagulation profile (elevated fibrinogen and reduced antithrombin) hCG (to determine outcome of treatment cycle) if appropriate Ultrasound scan: ovarian size, pelvic and abdominal free fluid. Consider ovarian Doppler if torsion suspected Additional investigations (based on individual presentation) Arterial blood gases D-dimer Electrocardiogram (ECG)/echocardiogram Chest X-ray Computed tomography pulmonary angiogram (CTPA) or ventilation/ perfusion (V/Q) scan Table 2
severe abdominal pain vomiting that prevents fluid intake oliguria/anuria tense ascites dyspnoea/tachypnoea hypotension electrolyte imbalance haemoconcentration The most important aspect of in-patient management is monitoring symptoms and signs and providing supportive treatment. A baseline and daily record of patient’s weight and abdominal girth must be maintained. Strict fluid intake and output charting is required, along with observations of vital signs every 4 hours as a minimum, depending on severity. Investigations should be undertaken as per Table 2 and repeated daily. Investigations and assessments may need carried out more frequently depending on the clinical situation. Principles of management 1.Maintenance of intravascular volume (to prevent thrombosis and renal failure) - Symptomatic OHSS is a state of hypovolaemic hyponatraemia. Patients should be encouraged to drink to thirst, as this is the most physiological way of replacing
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assisted reproductive technology. Cochrane Database Syst Rev 2016; 4: CD001750. https://doi.org/10.1002/14651858.CD001750. pub4. Tan B, Mathur R. Management of ovarian hyperstimulation syndrome. Produced on behalf of the BFS Policy and Practice Committee Human Fertility 2013; 16: 151e9. Youssef MAFM, Van der Veen F, Al-Inany HG, et al. Gonadotropinreleasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev 2014; 10: CD008046. https://doi.org/10.1002/14651858. CD008046.pub4. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2e14. https://doi.org/10.1093/ humupd/dmy033. The Management of Ovarian Hyperstimulation Syndrome. 9 (RCOG Green-top Guideline) [Internet][cited 17 January 2020]. 2020; 1e22. Available from:, https://www.rcog.org.uk/globalassets/ documents/guidelines/green-top-guidelines/gtg_5_ohss.pdf.
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Risk factors for developing OHSS are young age, PCOS, PCO morphology, high ovarian reserve, exaggerated ovarian response to stimulation and previous history of OHSS. Risk of OHSS can be lowered by using GnRH antagonist protocol, GnRH agonist trigger, co-treatment with Metformin in cases of PCOS, use of Cabergoline and elective cryopreservation of embryos. All women undergoing ovarian stimulation must be warned about symptoms of OHSS and should have a 24-hour contact for advice. Mild to moderate cases can be managed on out-patient basis Severe cases need admission with careful monitoring of fluid balance, weight, abdominal girth and symptoms. Intravascular hydration must be maintained. Thromboprophylaxis should be provided in all severe cases. Paracentesis may hasten recovery.
FURTHER READING Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for
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