Prevention of OHSS

1. Prevention of OHSS Dr. Hakan Özörnek EUROFERTIL IVF Center

4. OHSS • OHSS is an iatrogeniccomplication of ovulationinduction. • Thesyndrom can result in serious life treateningcomplications • Thesyndromcharecterizedbyleakage of fluidfromtheintravascularcompartment, withaccumulation in theperitonealandpleuralcavities, resulting in hypotensionand a decrease in renalbloodflowandvolume of urine.

5. Classification • Mild OHSS • Grade 1 Abdominaldistentionanddiscomfort • Grade 2 + nausea, vomitingand/ordiarrhoea • Moderate OHSS • Grade 3 + ultrasonicevidence of ascites • Severe OHSS • Grade 4 + clinicalevidence of ascitesand/orhydrothoraxordyspnoea • Grade 5 + haemoconcentration, coagulationabnormalities, diminishedrenalperfusion Golan et al. 1989

6. Prevention of OHSS

7. Risk factorsfor OHSS • PCOS • Highnumber of antralfollicles at day3 (>10/ovary) • Enlargedovarianvolume • LH/FSH > 2 • Hyperandrogenism • Youngage < 35 • Low body weight • Previousocurrence of OHSS

8. Preventionby PCOS • Diet – weightlose • Metformin • Ovariandrilling • Nonstimulated – naturalcycle • IVM • Oral ovulationinduction • Lowdosegonadotropin

9. Metformin Khattab, ReprodBiomed Online, 2006

10. Metformin • In a systematicreviewfor IVF, it wasfoundthatmetforminledtofewercases of OHSS (RR 0.33;95% CI 0.13-0.80) Moll et al. 2007

11. Prevention of OHSS • WithholdinghCG ‘cancelling’ • DelayinghCG ‘coasting’ • Modification of methodstotriggerovulation • Earlyunilateralfollicularaspiration • Progesteroneforlutealphasesupport • Cryopreservation of allembryos • GradualandslowhMGprotocol in PCOS • Albuminadministration at time of retrieval • Glucocorticoidadministration

12. CancelingCycles • hCGtriggersthedevelopment of OHSS • WithholdinghCG is theonlymethodthattotallyavoidsthe risk of OHSS • Serum E2 levelupper limit 4000 pg/ml • AfterstoppingthegonadotrophintreatmenttheGnRHagonistor antagonist should be continiueduntiltheovariesrecoverto normal size

13. Modification of methodstotriggerovulation • Decrease in hCGdose • 10.000 IU vs. 5.000 IU or 3.000 IU no difference • GnRHa • Used in antagonist cycle, as effective as hCG, decreasedinsidence of OHSS • rLH • PRT multicenterhCG vs rLHsignificantlyfewermoderateand severe cases of OHSS • rhCG

14. 5000 vs. 10000 IU uHCG Tsoumpou I, RBM Online, 2009

15. GnRHa • Thequickreversibility of the antagonist inducedpituitarysuppression can be of advantagebyallowingtheuse of GnRHaforthepurpose of ovulationtriggering. • A GnRHagonisttriggereffectivelyprevents OHSS.

16. Folicularaspiration • Folicularaspiration at the time of oocyteretrieval had no protectiveeffect of OHSS • Unilateralfolicularaspirationpriorto HCG alsodoes not reducetheincidence of severe OHSS

17. Glucocorticoidadministration • Because of conflictingreports in theliteraturetherearecurrentlyinsufficient data torecommendglucocorticoidadministration Lainas et al., Fertil Steril, 2002

18. Luthealphasesupport • LuthealphasesupportwithhCGincreasestheincidence of OHSS. • Progesteroneintravaginallyor im should be usedforthepatients at risk of OHSS

19. Antagonists Al-Inany HG, RBM Online, 2007

20. Antagonists • In a Cochranerewievtherelativeodds of hospitaladmissionfor OHSS wasreducedbye 54 % withantagonistscomparedwithagonists. Kolibianakis EM, Hum ReprodUpdate, 2006

21. Coasting • FirstdescribedandappliedbySher et al in 1993 • hCGadministrationpostponeduntilthepatients serum E2 leveldecreasesto a safer zone. • Significantlyhigherpercentage of granulosaluteincellsbecomeapoptoticaftercoasting. E2 levelsusuallytoriserapidly in the 48 h followinginitiation of thecoastingperiod, thenplateauedandbegantofall 96-168 h afterthegonadotropinswerestopped.

22. Coasting • Cochranereviewidentified 13 studies of whichonlyonetrial met theinclusioncriteria. • Therewas no difference in theincidence of moderateand severe OHSS and in theclinicalpregnancy rate betweenthegroups. D’Angelo et al., CochraneLibrary, 2002

23. Coastingstudies(Garcia-Velasco, F&S, 2006) 34/1624 0.02%

24. Coastingduration Mansour, et al., Fertil Steril, 2005

25. Coasting(Practicalguidelines) • Start at • Serum E2>4500 pg/ml • > 15 and < 30 maturefollicles • Measure E2 on a dailybasis, do not skipanydaytoavoidsuddenunexpecteddrops • GivehCGwhen E2 levelfallsto < 3500 pg/ml • Abandone if • E2 levelrisesto >6500 pg/ml • > 30 maturefollicles • Coastingtakes > 4 days

26. Coasting • Coasting is a goodalternativethat can avoidcyclecancellation in highresponders, whohavehigh risk of developing severe OHSS • Evenif OHSS developsaftercoastingbothitsincidenceandseveritywill be diminished

27. Cryopreservation of allembryos • Insted of cancelingthecycleaftertheadministration of hCGretrievetheoocytesandthancryopreserveallembryos • Cochranereviewidentified 17 studies, two of which met theinclusioncriteria. • Whenelectivecryopreservationwascomparedwithfreshembryo transfer no differencewasfoundbetweenthetwogroups in theincidence of OHSS. • There is insufficientevidencetosupportroutinecryopreservation. D’Angelo et al., CochraneLibrary, 2002

28. Albuminadministration • Albumin is preventthedevelopment of OHSS byincreasingplasmaoncoticpressureandbinding of OHSS mediators of ovarianorigin • Thecochranereviewshows a clearbenefitfromadministration of iv albumin at te time of oocyteretrieval in prevention of severe OHSS in high risk cases. • Forevery 18 women at risk of severe OHSS albumininfusionwillsaveonemorecase • Albumin is a humanproduct! D’Angelo et al., CochraneLibrary, 2002

29. HES (Hydroxyethylstarchsolution) administration • Syntheticmacromoleculesusedtoprevent OHSS andavoidthepotentialrisksfromusinghumanproductssuch as albumin • HES is effectivevolumeexpander. It is as effective as albumin • It is cheaperand safer

30. Dopamineagonists • VEGF is directlyinvolved in theclinicalmanifestations of OHSS byincreasingvascularpermeability. • Dopamineagonistshavebeenshowntosignificantlyreducevascularpermeability. • Theadministration of dopamineagonists at dosesthatareroutinelyusedtotreathyperprolactinaemicpatients, can reducevascularpermeabilitydecreasingthe risk andseverity of OHSS

31. DopamineAgonists • Dopamineagonistshave a positiveeffect on OHSS symptomssuch as ascites, abdominaldistensionanddiscomfort. • Fertilization, implantationandongoingpregnancyratesare not affectedbytheuse of dopamineagonistsduringassistedreproductiontreatments.

32. Cabergoline • First RCT showedthatcabergolinesignificantlyloweredhaematocrit, haemoglobinandascites on day 4 andday 6 aftertreatment, as comparedwithplacebo. • 35 high risk OHSS patients • 0.5 mg Cabergolin start on HCG dayadministerfor 8 days • No OHSS, pregnancy rate 41% Alvarez et al, 2007

33. Conclusion • OHSS is a seriouscomplication of ovarianstimulation • Theidentification of high risk patientsand in particular PCOS patientsandtheuse of lowdoseprotocols of ovarianstimulationhave an important role in theprevention of OHSS • Todate no methodsareavailabletocompletlypreventthiscomplicationexceptforwithholdinghCG.

34. Conclusion • Coastingfor at least as long as 3 days can be successfullyused in theprevention of OHSS • Itappearsthat iv albuminadministered at the time of oocyteretrievalmayhelptheprevention of OHSS • Theeffect of combiningmethodswhichact at twodifferentlevels (eq. coastingand HES administration) helpsfor a betterprevention

35. Conclusion • Cryopreservation of oocytes, use of GnRH antagonist andDopaminederivateswereusedsuccessfully. • There is a clearneedforlargerandomisedstudies