Ovarian hyperstimulation syndrome warda - an overview


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In this detailed presntation I tried to collect the updated knowledge about a common problem facing all practitioner related to the field of assissted reproduction(OHSS). I have given a greater concern to the prevention. I hope that my colleagues get benifit from this presentation

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Ovarian hyperstimulation syndrome warda - an overview

  1. 1. OVARIAN HYPERSTIMULATION SYNDROME (OHSS) By Osama M Warda , MD Professor of Obstetrics & Gynecology Mansoura University- EGYPT
  2. 2. Background Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation therapy. The OHSS is typically associated with exogenous gonadotropin stimulation & is rarely observed with other agents ( e.g. CC, GnRH). Clinicians who prescribe ovulation-inducing agents must be prepared to recognize & manage OHSS . 2WARDA25 May 2014
  3. 3. Background (contd.,) OHSS is a self-limiting disorder that usually resolves spontaneously within several days, but may persist for longer periods, particularly in conception cycles. The syndrome is a broad spectrum of clinical manifestations from mild illness needing only observation to severe disease requiting hospitalization & intensive care. 3WARDA25 May 2014
  4. 4. Background (contd.,) The syndrome is characterized by ovarian enlargement due to multiple ovarian cysts and an acute fluid shift into the extravascular space. Complications of OHSS include ascites, hemo- concentration, hypovolemia, and electrolyte imbalances. Because the prevalence of therapy employing ART is increasing, all physicians dealing with females in the reproductive age should be familiar with OHSS as it causes multi-organ dysfunction & may be fatal. 4WARDA25 May 2014
  5. 5. Epidemiology “Brinsden et al (1995)” Rates of occurrence have been estimated as follows: Mild ; 8-23% Moderate; 1-7% Severe; 0.25% The frequency of OHSS may increase if: a. Ovary overstimulated (high E2 from multiple follicles) b. Protocols combine GnRH agonists and gonadotropins, as compared with gonadotropin alone to induce ovulation. Only women in childbearing age are affected by OHSS 5WARDA25 May 2014
  6. 6. Pathophysiology The hallmark of OHSS is increase in capillary permeability resulting in fluid shift from the intravascular space to 3rd space compartments . This occurs due to hCG stimulation. Factors implicated in the process include: 1. Increased secretion or exudation of protein-rich fluid from enlarged ovaries or peritoneal surfaces. 2. Increased follicular fluid levels of pro-renin & renin 3. Angiotensin-mediated changes in the capillary permeability 6WARDA25 May 2014
  7. 7. Pathophysiology Vascular endothelial growth factor (VEGF) is the major mediator due to the following evidences : VEGF serum levels increase with hCG & correlate with the severity of OHSS. The expression of VEGF & VEGF receptor 2 (VEGFR-2) mRNA increases significantly in response to hCG, and peak levels coincide with maximum vascular permeability Recombinant VEGF produces effects similar to OHSS that can be reversed with specific antiserum. Prostaglandins, inhibin, the renin-angiotensin-aldosterone system & inflammatory mediators have all been implicated in the etiology of OHSS. 7WARDA25 May 2014
  8. 8. Pathogenesis of OHSS adopted from Soares et al (2008) 8WARDA25 May 2014
  9. 9. Pathogenesis of OHSS adopted from Humaidan P et al (2010) WARDA 925 May 2014
  10. 10. RISK FACTORS [Adopted from Humaidan P et al (feritl. steril 2010)*]; “modified” Risk factor Threshold of risk (A). Primary risk factors (patient-related): 1. High basal AMH 2. Young age 3. Previous OHSS 1. PCO-like ovaries (B). Secondary risk factors ( ovarian response related); On day of h C G trigger: 1. High number of medium/large follicles - >3.36 ng/ml (independent predictor). - < 33 years - Moderate & severe cases / hospitalization - > 24 antral follicles in both ovaries combined. - ≥13follicles ≥ 11mm in diameter or > 11 follicles≥10 mm diameter According to Martin et al (1994)**, if the pre-hCG treatment E2 is >6000mcg and /or if >30 follicles are present, the rate of severe OHSS approaches 80% 10WARDA25 May 2014
  11. 11. RISK FACTORS [Adopted from Humaidan P et al (feritl. steril 2010)]” modified” Risk factor Threshold of risk 2. High or rapidly rising E2 levels & high number of follicles 3. Number of oocyte retrieved 4. VEGF levels 5. Elevated inhibin- B levels 6. hCG administration for luteal phase supp. 7. Pregnancy (increase in endogenous hCG) • E2 5,000 pg/ml and/or≥18 follicles predictive of severe OHSS • > 11predicts OHSS • Not applicable • Elevated levels on day 5 of gonadotropin stimulation, at oocyte retrieval and 3 days before • Not applicable • Not applicable 11WARDA25 May 2014
  12. 12. CLINICAL PRESENTATION & CLASSIFICATION According to time of onset, 2 main clinical forms of OHSS early & late; 1- Early OHSS: It occurs within 9 days after oocyte retrieval . It is correlated to ovarian response to exogenous hCG stimulation. 2- Late OHSS: It occurs after 10 days of ovum pickup, and correlated to endogenous hCG produced by implanting embryo. WARDA 1225 May 2014
  13. 13. CLASSIFICATION OF OHSS Adopted from Navot et al fertil steril (1992)* with modification OHSS stage Clinical features Lab. features Mild : 1. Abdominal distension/discomfort 2. Mild nausea/vomiting 3. Diarrhea 4. Ovarian enlargement 5-12cm No important alterations Moderate : 1. Mild features + 2. Ultrasound evidence of ascites 1. Hematocrit>41% 2. WBC >15,000 3. Hypoalbuminemia Severe 1. Moderate features+ 2. Clinical ascites, and/ or 3. hydrothorax, Severe dyspnea, 4. Oliguria/anuria To be continued 1. Hct >55% 2. WBC>25,000 3. Cr Cl<50ml/min 4. Cr >1.6mg/dl To be continued 13WARDA25 May 2014
  14. 14. CLASSIFICATION OF OHSS Adopted from Navot et al fertil steril (1992) OHSS stage Clinical features Lab. features Severe OHSS (continued) 5. Intractable vomiting 6. Tense ascites 7. Low blood/central venous pressure 8. Rapid weight gain(>1kg/24hrs) 9. Syncope severe abdominal pain 10. Venous thrombosis 5. Na+ <135mEq/L 6. K+ > 5mEq/L 7. Elevated liver enzymes Critical OHSS 1- Anuria/ acute renal failure 2- Arrhythmia 3- Thromboembolism 4-Pericardial effusion 5- Massive hydrothorax 6-Arterial embolism 7- Adult RDS 8- Sepsis Worsening of the previous finding 14WARDA25 May 2014
  15. 15. Prognosis (Lucidi,2013) Mild and moderate cases = excellent prognosis Severe cases = morbidity is clinically significant, and fatalities do occur. However, the prognosis is optimistic if adequate treatment is given. Death from OHSS is largely due to: 1. hypovolemic shock 2. Electrolyte imbalance 3. Hemorrhage 4. Thromboembolism Estimated fatality rates are 1per 400,000 – 500,000 stimulated cycles 15WARDA25 May 2014
  16. 16. PREVENTION OF OHSS Introduction 16WARDA • Complete prevention of OHSS is still not possible. • Prevention strategies can be divided into two types—primary and secondary. • Primary prevention methods ; the stimulation protocol is individualized (iCOS) after assessment of primary risk factors to classify patients as poor, normal, or high responders. • Secondary prevention methods: are used in the presence of risk factors arising from an excessive response to ovarian stimulation 25 May 2014
  17. 17. PREVENTION OF OHSS Primary Prevention 1- Reducing exposure to gonadotropins 2-Using combined oral contraceptives 3- GnRH antagonists protocols 4- Avoidance of hCG in LPS 5- In vitro oocyte maturation (IVM) 6- Insulin- Sensitizing agents WARDA 1725 May 2014
  18. 18. PREVENTION OF OHSS Primary Prevention 18WARDA 1. Reducing Exposure to Gonadotrpins: (a) Reducing the dose – IUI cycles: e.g. PCOS patients; use chronic * low-dose step-up protocols are associated with lower OHSS & multiple pregnancy. (b) Reducing Duration of FSH Exposure- IVF/ICSI cycles: - Use of “mild stimulation protocols**” . - Once E2 reach 250-300pg/ml + several follicles 11-12mm, we begin to reduce gonadotropin dose in step-down fashion (more physiologic) 25 May 2014
  19. 19. PREVENTION OF OHSS Primary Prevention 19WARDA 2- Using combined oral contraceptives:( OCP-GnRH agonist- dual suppression protocol) : in high risk patients; -OCP for 28 days leuprolide acetate (Lupron) 1mg started on day 21, overlapping OCP for 7days. On D3 of withdrawal bleeding low- dose (150 IU) hMG or rFSH is started & leuprolide dose reduced to 0.5mg/day. Step-down gonadotropin adjustment is usually made. -In some patients start gonadotropin at very low dose (37.5 IU/d) increased in a step-up fashion until follicles = 12 mm then step down. 25 May 2014
  20. 20. PREVENTION OF OHSS Primary Prevention 3. GnRH Antagonist Protocols: - The differential action of GnRH antagonists at both pituitary & ovarian receptors suggests that antagonist- suppressed cycles might result in a lower incidence of OHSS. - Other advantages of GnRH antagonists: lack of flare effect, no accompanying menopausal- like symptoms, no refractory period, reduced risk of ovarian cyst formation, shorter treatment cycle, reduced FSH consumption. - However, clinical pregnancy rate may be less than with agonists WARDA 2025 May 2014
  21. 21. PREVENTION OF OHSS Primary Prevention 4. Avoidance of hCG for LPS: - Luteal phase defect is the result of lowered endogenous LH release as a negative feedback from the supra-physiological levels of E2 & P of ovarian hyper-stimulation. - Based on the currently available evidence, it is recommended that LPS in GnRH analog-suppressed cycles be provided in the form of P with or without supplemental E2, rather than in the form of hCG. - As an alternative to P, it has been suggested that repeated intranasal administration of GnRHa could be used for LPS. (Pirard C et al 2005) WARDA 2125 May 2014
  22. 22. PREVENTION OF OHSS Primary Prevention 5. In Vitro Oocyte Maturation (IVM): - In PCOS, and OHSS- high risk patient. - It is an attractive yet underutilized strategy to prevent OHSS. - IVM can be applied in patients undergoing COS for ICSI, where hCG was given when the leading follicle =12-14mm. - The use of IVM and natural cycle IVF combined has resulted in clinical pregnancy rates comparable to those obtained with conventional IVF. (Buckett et al 2005) WARDA 2225 May 2014
  23. 23. PREVENTION OF OHSS Primary Prevention 6. Insulin-Sensitizing Agents: ’metformin’ - Women with PCOS are at greater risk of developing OHSS. - Metformin suppresses insulin levels & decreases ovarian theca cell androgen production, resulting in improved ovulatory and pregnancy rates ( Barbieri (2000), Attia et al 2001) - Metformin is effective insulin sensitizing agent with a good safety profile used as mono-therapy or in combination with other in IO drugs and as a pretreatment before IUI or IVF/ICSI. - A 2006 meta-analysis of 8 RCT of metformin co-administration during gonadotropin-stimulated IO or IVF in women with PCO found a significant positive effect on the incidence of OHSS ( Costello et al 2006) WARDA 2325 May 2014
  24. 24. PREVENTION OF OHSS Secondary Prevention 1. Coasting 2. Reduced dose of hCG 3. Cryopreservation of all embryos 4. Cycle cancellation 5. Alternative agents for triggering ovulation 6. GnRH antagonist salvage 7. Intravenous albumin and hydroxyethyl starch 8. Dopamine agonists 9. Glucocorticoids 10. Calcium gluconate infusion 11. Non-recommended strategies WARDA 2425 May 2014
  25. 25. PREVENTION OF OHSS Secondary Prevention 1- Coasting : - It means withholding further gonadotropin stimulation & delaying hCG administration until E2 levels plateau or decrease significantly (Sher et al 1993). - Despite its wide and popular use as the 1st line intervention of choice to reduce severity of OHSS, yet the scientific evidence base supporting the use of coasting to prevent OHSS is NOT strog ( Humaidan et al 2010) WARDA 2525 May 2014
  26. 26. PREVENTION OF OHSS Secondary Prevention 2- Reduced Dose of hCG: Compared to the standard 10,000 IU, doses of 5,000 IU have been used successfully to trigger ovulation without impairing clinical outcome (Kolibianakis et al 2007). Cornell low dose protocol, which determines hCG dosage according to serum E2 levels on the day of hCG administration. A sliding scale is used, with between 5,000 and 3,300 IU of hCG administered to women with E2 levels of 2,000–3,000 pg/mL . Women with E2 levels >3,000 pg/mL undergo coasting until E2 falls below 3,000 pg/mL. ( Chen et al 2003) Cycle cancellation is a possible drawback of low dose hCG WARDA 2625 May 2014
  27. 27. PREVENTION OF OHSS Secondary Prevention 3- Cryopreservation of All Embryos: Entails normal progression of IVF/ICSI until OPU, followed by cryopreservation of embryos to be thawed & implanted at a later date when patient’s hormones are not elevated. Although the early OHSS associated with hCG administration may still occur, yet the late OHSS resulting from endogenous hCG from pregnancy is prevented( Wada et al 1992) The major disadvantage was reduced pregnancy rates from frozen/thawed embryos than fresh, however, the introduction of vitrification technique reduced the difference (CDC 2005 Report) WARDA 2725 May 2014
  28. 28. PREVENTION OF OHSS Secondary Prevention 4- Cycle Cancellation: Cycle cancellation & withholding of hCG is the only guaranteed method for prevention of early OHSS (Schenker & Weinstein 1978). Despite the efficacy of this method, most physicians are reluctant to use it in IVF cycles because of the financial burden & psychological distress to the patient. WARDA 2825 May 2014
  29. 29. PREVENTION OF OHSS Secondary Prevention 5- Alternative Agents for Triggering Ovulation: A- GnRH agonist: Used in gonadotropin-only or antagonist- stimulated cycles (i.e. No receptor down-regulation). Administration of a bolus dose of GnRHa results in a surge (flare) of gonadotropins (LH&FSH) mimicking the natural surge (Itskovitz et al 1991). Luteal phase defect is the main drawback of this method resulting in extremely high early pregnancy loss (Kolibianakis et al 2005, ) , hence more LPS needed ( Arslan et al 2005). Luteal phase can be rescued with a small bolus (1,500 IU hCG given 35 hrs after GnRHa triggering dose, after OPU ( Humaidan et al 2009) WARDA 2925 May 2014
  30. 30. PREVENTION OF OHSS Secondary Prevention 5- Alternative Agents for Triggering Ovulation: B- Recombinant LH (rLH) Triggering ovulation via administration of rLH would more closely mimic the natural LH surge than is achieved with hCG administration (Emperaire et al 2004) Despite the safety advantages of r LH in terms of OHSS reduction, however, reduced pregnancy rates and a poor cost/benefit ratio reduce its applicability in the clinical situation ( Humaidan et al 2010) WARDA 3025 May 2014
  31. 31. PREVENTION OF OHSS Secondary Prevention 6- GnRH Antagonist salvage: - Based on the observation that An initial decrease or plateau in serum E2 levels 24–48 hours after the initial administration of a GnRH antagonist in IVF cycles, with no apparent impact on treatment outcome (Shapiro et al 2005). - Thus, it is possible that administration of an antagonist to patients with elevated serum E2 at risk of developing OHSS may provide a means of interrupting the development or progression of the condition while salvaging the current treatment cycle. WARDA 3125 May 2014
  32. 32. PREVENTION OF OHSS Secondary Prevention 7- Intravenous Albumin and Hydroxyethyl Starch: - Albumin may reduce the incidence of OHSS by binding to the vasoactive agents responsible for its development removing them from circulation &/or it increases the plasma osmotic pressure. (Shoham et al 1994). - The evidence supporting its use is not strong, moreover it may cause pulmonary edema in patients with diminished cardiac reserve (McClelland ,1990 ). - Hydroxyethyl starch (HES) is a cheaper, potentially safer alternative to albumin and should be the 1st line treatment WARDA 3225 May 2014
  33. 33. PREVENTION OF OHSS Secondary Prevention 8- Dopamine Agonists: - principle: In PCOS; Cabergoline (Cb2)pretreatment before OI, reduces ovarian response to FSH by controlling LH levels potential primary prevention of OHSS in such cases (Papaleo et al 2001). Moreover, Cb2 act on the VEGF receptors implicated in vascular hyperpermeability during OHSS potential 2ry prevention of OHSS (Gomez et al 2002). - Cabergoline reduces the occurrence of moderate-severe OHSS. It is unlikely to have a clinically relevant negative impact on clinical pregnancy or on the number of retrieved oocytes (Leitao et al 2014). WARDA 3325 May 2014
  34. 34. PREVENTION OF OHSS Secondary Prevention 9- Calcium gluconate infusion: - Infusion with 10 ml of 10% calcium gluconate solution in 200 ml physiologic saline within 30 min of ovum pick up and continued thereafter on day 1, day 2 and day 3 proved to be as effective as cabergolin in preventing severe OHSS and decreases OHSS occurrence rates when used for high- risk patients. (Naredi & Karunkaran 2013) WARDA 3425 May 2014
  35. 35. PREVENTION OF OHSS Secondary Prevention 10- Glucocorticoids. Glucocorticoids and their derivatives have an inhibitory effect on the VEGF gene expression in vascular smooth muscle cells (Nauck et al 1998). An additional effect is the non specific prevention of the inflammatory response and edema formation ( Perretti 2000). The optimal protocol & the drawback of the antiangiogenic effect on the endometrium needs more investigation WARDA 3525 May 2014
  37. 37. PREVENTION OF OHSS Non recommended strategies 1. Follicular Aspiration: - Therapeutic principle: Aspiration of granulosa cells from one ovary (before IO) has been proposed as a means of inducing intra-ovarian bleeding and limiting the production of OHSS mediators while allowing continued contralateral ovarian development (Gonen et al 1991). - Drawbacks: include cost, patient discomfort, and increased requirement for invasive procedures under anesthesia. WARDA 3725 May 2014
  38. 38. PREVENTION OF OHSS Non recommended strategies 2. Aromatase Inhibitors. - Therapeutic principle: The aromatase enzyme catalyzes the rate-limiting step in the production of E2 , therefore aromatase inhibitors may help to reduce excessive E2 synthesis during ovarian stimulation and thereby reduce the risk of OHSS. - Drawbacks: aromatase inhibitors cannot yet be recommended in a clinical setting because of lack of large trials to evaluate the impact of aromatase inhibitors on OHSS in women with an-ovulatory infertility associated with PCOS (Humaidan et al 2010) WARDA 3825 May 2014
  39. 39. PREVENTION OF OHSS the guidelines Currently available treatment guidelines for the prevention of OHSS, such as those from the (NICE) and the (ESHRE), were produced several years ago (2004), and the 2006; the (ASRM) guidelines did not proffer additional advice compared with the 2004 publication. Hence, these guidelines do not take into account the latest available evidence from the literature (Humaidan et al 2010) WARDA 3925 May 2014
  40. 40. TREATMENT OF OHSS Patient Assessment: History Taking ; Careful assessment of the patient is needed to classify disease severity. -This should include a review of stimulation and a prediction of underlying risk based on age, onset of presentation, follicle number and size during stimulation, number of eggs retrieved, peak E2 level, and E2 level at trigger. - The history should include an estimation of urine output and weight gain, and should seek to identify symptoms such as abdominal pain, bloating, shortness of breath, and the ability to maintain oral hydration. WARDA 4025 May 2014
  41. 41. TREATMENT OF OHSS Patient Assessment (contd.,): Physical examination : - Should include measurement of vital signs, body weight, abdominal girth at the umbilicus, presence of ascites, pleural effusion, and signs of venous thromboembolic disease, such as unilateral increase in calf diameter. - Caution should be taken with pelvic examinations to minimize the risk of trauma to enlarged ovaries. - Initial laboratory investigations should screen for hemo- concentration with a hematocrit and/or hemoglobin measurement and urine specific gravity. WARDA 4125 May 2014
  42. 42. TREATMENT OF OHSS outpatient or inpatient - Outpatient management is usually possible in women with mild & moderate OHSS. Women with severe disease may be considered for outpatient management if they are able to adhere to treatment and follow clinical instructions (Navot et al 1992). - Inpatient management : Women with OHSS who are unable to maintain adequate oral hydration to minimize hemo-concentration and/or unable to overcome the discomfort of abdominal distension with oral analgesia need to be admitted to hospital for IV hydration and possibly paracentesis (Shmorgun 2011). WARDA 4225 May 2014
  43. 43. TREATMENT OF OHSS 1- Paracentesis - patient with tense ascites . - It will relieve pain, respiratory discomfort & improve oliguria - Insertion of an indwelling pigtail catheter under ultrasound guidance circumvents the need for multiple attempts at drainage and limits potential infectious complication (Whelan 2000). - Clinical resolution is achieved when paracentesis output starts to decrease as urine output increases. When ascites output is < 50 mL/ day the catheter can be removed (Rahami et al 1997). WARDA 4325 May 2014
  44. 44. TREATMENT OF OHSS 2- Culdocentesis - Paracentesis by trans-vaginal ultrasound guidance can be done through the outpatient clinic (Abramov etal 1999). - Culdocentesis can be offered in an attempt to prevent disease progression from moderate to severe OHSS and keep the woman out of hospital (Fluker et al 2000). - In addition to alleviating discomfort, culdocentesis may precipitate diuresis in women who are oliguric, and it helps resolution of severe OHSS. ( Borenstein et al 1989) - WARDA 4425 May 2014
  45. 45. TREATMENT OF OHSS 3- Pleuracentesis: Drainage of ascites usually resolves a pleural effusion. Symptomatic pleural effusions that persist despite paracentesis can also be drained. WARDA 4525 May 2014
  46. 46. TREATMENT OF OHSS 4- Fluids and electrolytes: - Women should drink according to their thirst. - In addition, IV hydration with a crystalloid solution (100 to 150 mL/hr) should be instituted until diuresis occurs. - If clinical and laboratory findings indicate persistent intra-vascular volume depletion despite aggressive IV fluid hydration, IV albumin (15 to20 mL/hr of 25% albumin over 4 hours) should be initiated and repeated until hydration status improves ( Fluker et al 2000) - Diuretics should not be used as they can further deplete intravascular volume. WARDA 4625 May 2014
  47. 47. TREATMENT OF OHSS 5- Pain relief: - Symptomatic relief of abdominal pain can be achieved with acetaminophen and if necessary oral or parenteral opiates. - Non-steroidal anti-inflammatory agents with antiplatelet properties should not be used because they may interfere with implantation and may also compromise renal function in women with severe OHSS (Navot et al 1992). WARDA 4725 May 2014
  48. 48. TREATMENT OF OHSS 6- Nausea and/or vomiting Antiemetic agents considered to be safe in early pregnancy should be used to alleviate nausea and/or vomiting. WARDA 4825 May 2014
  49. 49. TREATMENT OF OHSS 7- Thromboprophylaxis: - Hospitalized patients should be considered at risk of thrombosis secondary to hemo-concentration and immobilization. - Daily prophylactic doses of low-molecular weight heparin (e.g., dalteparin sodium 5000 IU/day) and use of thromboembolic deterrent stockings should be considered on admission and continued until discharge. - However, there have been several reports of thrombo- embolism in women with OHSS treated with thromboprophylaxis ( Hignett et al 1995, Hortskamp et al1994, Cil et al 2000) WARDA 4925 May 2014
  50. 50. TREATMENT OF OHSS Monitoring the patient (Whelan et al 2000) - Admitted patients should be assessed by a physician at least once daily, with more frequent assessment in cases of critical OHSS. - Weight and urine specific gravity should be recorded daily. - Vital signs, urine output, and fluid balance should also be recorded. Urine output should be maintained at a minimum of 30 mL/hour. - Physical examination should assess hydration, cardiorespiratory status, degree of ascites, and signs of thromboembolism. - Daily monitoring of hemoglobin, hematocrit, creatinine, electrolytes, and albumin is useful to document disease progress. - A weekly measurement of liver enzymes may also be useful.50WARDA25 May 2014
  51. 51. TREATMENT OF OHSS Management of Complications - Renal failure, thromboembolism, pericardial effusion, and adult respiratory distress syndrome are potential life-threatening complications of OHSS. - These conditions should be diagnosed early and managed by a multidisciplinary team possibly in an ICU setting. WARDA 5125 May 2014
  52. 52. WARDA 52 THANK YOU 25 May 2014