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Prevention of OHSS. Dr. Hakan Özörnek EUROFERTIL IVF Center. OHSS. OHSS is an iatrogenic complication of ovulation induction . The syndrom can result in serious life treatening complications
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Prevention of OHSS Dr. Hakan Özörnek EUROFERTIL IVF Center
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.
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
Risk factorsfor OHSS • PCOS • Highnumber of antralfollicles at day3 (>10/ovary) • Enlargedovarianvolume • LH/FSH > 2 • Hyperandrogenism • Youngage < 35 • Low body weight • Previousocurrence of OHSS
Preventionby PCOS • Diet – weightlose • Metformin • Ovariandrilling • Nonstimulated – naturalcycle • IVM • Oral ovulationinduction • Lowdosegonadotropin
Metformin Khattab, ReprodBiomed Online, 2006
Metformin • In a systematicreviewfor IVF, it wasfoundthatmetforminledtofewercases of OHSS (RR 0.33;95% CI 0.13-0.80) Moll et al. 2007
Prevention of OHSS • WithholdinghCG ‘cancelling’ • DelayinghCG ‘coasting’ • Modification of methodstotriggerovulation • Earlyunilateralfollicularaspiration • Progesteroneforlutealphasesupport • Cryopreservation of allembryos • GradualandslowhMGprotocol in PCOS • Albuminadministration at time of retrieval • Glucocorticoidadministration
CancelingCycles • hCGtriggersthedevelopment of OHSS • WithholdinghCG is theonlymethodthattotallyavoidsthe risk of OHSS • Serum E2 levelupper limit 4000 pg/ml • AfterstoppingthegonadotrophintreatmenttheGnRHagonistor antagonist should be continiueduntiltheovariesrecoverto normal size
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
5000 vs. 10000 IU uHCG Tsoumpou I, RBM Online, 2009
GnRHa • Thequickreversibility of the antagonist inducedpituitarysuppression can be of advantagebyallowingtheuse of GnRHaforthepurpose of ovulationtriggering. • A GnRHagonisttriggereffectivelyprevents OHSS.
Folicularaspiration • Folicularaspiration at the time of oocyteretrieval had no protectiveeffect of OHSS • Unilateralfolicularaspirationpriorto HCG alsodoes not reducetheincidence of severe OHSS
Glucocorticoidadministration • Because of conflictingreports in theliteraturetherearecurrentlyinsufficient data torecommendglucocorticoidadministration Lainas et al., Fertil Steril, 2002
Luthealphasesupport • LuthealphasesupportwithhCGincreasestheincidence of OHSS. • Progesteroneintravaginallyor im should be usedforthepatients at risk of OHSS
Antagonists Al-Inany HG, RBM Online, 2007
Antagonists • In a Cochranerewievtherelativeodds of hospitaladmissionfor OHSS wasreducedbye 54 % withantagonistscomparedwithagonists. Kolibianakis EM, Hum ReprodUpdate, 2006
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.
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
Coastingstudies(Garcia-Velasco, F&S, 2006) 34/1624 0.02%
Coastingduration Mansour, et al., Fertil Steril, 2005
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
Coasting • Coasting is a goodalternativethat can avoidcyclecancellation in highresponders, whohavehigh risk of developing severe OHSS • Evenif OHSS developsaftercoastingbothitsincidenceandseveritywill be diminished
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
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
HES (Hydroxyethylstarchsolution) administration • Syntheticmacromoleculesusedtoprevent OHSS andavoidthepotentialrisksfromusinghumanproductssuch as albumin • HES is effectivevolumeexpander. It is as effective as albumin • It is cheaperand safer
Dopamineagonists • VEGF is directlyinvolved in theclinicalmanifestations of OHSS byincreasingvascularpermeability. • Dopamineagonistshavebeenshowntosignificantlyreducevascularpermeability. • Theadministration of dopamineagonists at dosesthatareroutinelyusedtotreathyperprolactinaemicpatients, can reducevascularpermeabilitydecreasingthe risk andseverity of OHSS
DopamineAgonists • Dopamineagonistshave a positiveeffect on OHSS symptomssuch as ascites, abdominaldistensionanddiscomfort. • Fertilization, implantationandongoingpregnancyratesare not affectedbytheuse of dopamineagonistsduringassistedreproductiontreatments.
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
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.
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
Conclusion • Cryopreservation of oocytes, use of GnRH antagonist andDopaminederivateswereusedsuccessfully. • There is a clearneedforlargerandomisedstudies