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

Text of Ovarian hyperstimulation syndrome warda - an overview

  • OVARIAN HYPERSTIMULATION SYNDROME (OHSS) By Osama M Warda , MD Professor of Obstetrics & Gynecology Mansoura University- EGYPT
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Pathogenesis of OHSS adopted from Soares et al (2008) 8WARDA25 May 2014
  • Pathogenesis of OHSS adopted from Humaidan P et al (2010) WARDA 925 May 2014
  • 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 follicles10 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
  • 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/or18 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
  • 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
  • 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 Cl1.6mg/dl To be continued 13WARDA25 May 2014
  • 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+ 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
  • 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
  • PREVENTION OF OHSS Introduction 16WARDA Complete prevention of OHSS is still not possible. Prevention strategies can be divided into two typesprimary 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
  • 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
  • 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
  • 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
  • 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