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Deze dia-presentatie werd door bovenvermelde spreker ter beschikking gesteld van de VVOG-homepagina De auteur behoudt zijn volle auteursrechten op deze.

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Presentatie over: "Deze dia-presentatie werd door bovenvermelde spreker ter beschikking gesteld van de VVOG-homepagina De auteur behoudt zijn volle auteursrechten op deze."— Transcript van de presentatie:

1 Deze dia-presentatie werd door bovenvermelde spreker ter beschikking gesteld van de VVOG-homepagina De auteur behoudt zijn volle auteursrechten op deze mededeling Hij is anderzijds zelf verantwoordelijk voor eventuele schending van de copyright-rechten van derden binnen zijn dia-voorstelling De VVOG zal deze beelden enkel gebruiken op de homepagina en voor de aanmaak van de cdrom die van iedere studiedag gemaakt wordt De VVOG zal deze presentatie zelf niet verder ter beschikking stellen van derden. Deze teksten en/of beelden kunnen onder geen enkel beding gecopieerd worden, ook niet voor persoonlijke doeleinden Als u deze teksten en/of beelden toch wenst te gebruiken, dient u toelating te vragen aan de auteur die u kunt bereiken op bovenstaande telefoon of adres. Het gebruik of dupliceren van deze teksten en/of beelden (voor een voordracht, publicatie, electronische verspreiding, e.a. ) kan alleen als u de bron vermeldt en als u de auteur 'voorafgaandelijk' laat weten waar en wanneer u gebruik zult maken van deze data. Deze teksten en/of beelden kunnen zonder de toestemming van de oorspronkelijke auteur nooit deel uitmaken van een voordracht, publicatie, noch van één of andere commerciële uitgave. Wanneer u de oorspronkelijke auteur niet kunt bereiken, neemt u contact op met de webmaster Dr. Luc De Baene Prof. Luc O. Delbeke Centrum voor Reproductieve Geneeskunde Universitair Ziekenhuis Antwerpen Ovarieel Hyperstimulatie Syndroom (OHSS) Antwerpen 23/10/2003

2 Ovarieel Hyperstimulatie Syndroom (OHSS) Prof. Luc O. Delbeke Centrum voor Reproductieve Geneeskunde Universitair Ziekenhuis Antwerpen Postuniversitaire studiedag VVOG 23 oktober 2003

3 Casus 1 T. Spinder Fertiliteit in de praktijk september j., G 0 idiopatische infert. 6 x cc/IUI IVF IVF superovulatie: GnRHa kort IE rec FSH/d 7 d Ovul. inductie: IU hCG bij 12 foll. 18 mm Ovul. inductie: IU hCG bij 12 foll.  18 mm E 2 niet bepaald E 2 niet bepaald ovum aspirat.: 35 h na hCG : 14 eicellen Fertilisation: 13 x 2PN 2 ER + 6 CRYO 2 ER + 6 CRYO Luteale fase: 1500 IE hCG op dag OPU + 5, +7, +9

4 Casus 1 : follow up OPU + 7: misselijk, braken, geen pijn, nl. diurese OPU + 8: opname via HA : apathie + verward spreken helder bewustzijn, afasie, hemianopsie, facialis parese en mot. uitval rechter hand CT hersenen: vers infarct links temporo-parietaal Echocardio: ruimte innemend proces linker ventrikel labo: Hb: 10.5 nmol/l ; Hct 0.48; WBC ; tromb CRP 17 ng/l; hypo-albuminaemie behandeling: open hart chirurgie: resectie trombus linker ventr. pleura- en ascites drainage; fraxiparine; P 4 vag. evolutie: oplopend hCG tot dag 29 na OPU, waarna miskraam

5 Case 2 (Levy ea, Hum Reprod, 1995) 26 y G1P1, surgical removal of craniopharyngioma : panhypopituarism (Hypogon. Hypogonadism - WHO I) panhypopituarism (Hypogon. Hypogonadism - WHO I) G1 after hMG: severe OHSS pre treatment: PCO -like ovaries; low gonadotrop. and TSH superovulation: FSH 1 amp/d 5d, 2 amp/d 5d, 3amp/d 13d ovul. ind.: IU hCGE2 475 pg/ml foll.: 2 > 18; 5 18; 5 < 15; 10 < 9mm luteal phase: ?

6 Case 2 follow up day hCG + 11: abdominal pain, swelling nausea, vomiting admission on admission: distended abdomen, ovaries palpaple above the umbilicus no edema nor pleural effusion on U/S multip. ovarian cysts (8-10 cm) treatment: paracentesis (3 l) colloid and crytalloid iv infusions evolution: hCG < 5IU/L full recovery, no further complications

7 OHSS Definition A SERIOUS IATROGENIC COMPLICATION of ovulation induction with a severe impact on the patients health (morbidity and mortality). OHSS rarely occurs spontaneous during pregnancy

8 OHSS: signs and symptoms (Golan, 1989) Mild Gr I abd. distension ovaries cm + ovaries cm + Gr II nausea, vomiting, diarrhea diarrhea + Moderate Gr III U/S ascites / weight ovaries > 12 cm + ovaries > 12 cm + Severe Gr IV clin. ascites/hydrothorax ovaries > 12 cm + ovaries > 12 cm + Gr V hypovol., hemoconc., coag. disorders coag. disorders renal perfusion, oliguria renal perfusion, oliguria shock shock

9 OHSS incidence Non IVF:mild % moderate % severe % IVF:mild 100% moderate21- 44% severe 1- 10% estimated mortality 1/ / estimated morbidity %

10 Predisposing factors for OHSS previous OHSS patients constitution: young (< 30); lean PCO(D): hyperinsulinaemia; high E 2 and rapid increase; multiple immature follicles stimulation protocol: GnRHa + gonadotropins hCG: ovulation trigger, luteal support, pregnancy high number of oocytes retrieved genetical or familial: mutated FSH-receptor

11 Pathogenesis of Severe OHSS Kidney (JGA) Proreninovary renin ace PG Angiotensin II A-tensin I A- tensinogen histamin (liver) inflam. cytokines (IL-1,IL-6,TNF) ANGIOGENESIS VEGF(ovary) IL-2 (FF) Capillary permeability fluid shift hCG (LH) E2E2

12 Pathogenesis of severe OHSS: ‘Capillary Leakage Syndrome’ Vaso Active Component Capillary permeability in: ovaries uterus peritoneum omentum pleura

13 Severe OHSS: Acute SHIFT of body fluids Vascular compartiment3th space hypovolemia ascites hemoconcentration ovarian volume (cysts, edema) albumine loss hydrothorax/hydropericard hydro urether anasarca

14 weight general edema albumine loss electrolyte imbalance SHIFT to 3th space in severe OHSS thorax Ascites ovarian vol.hydro (cysts+stroma edema) pericard abdominal dystension abdominal pain dyspnea nausea, vomiting ovarian torsion diarrhaea cyst rupture/bleeding venous return PG’s

15 Vascular fluid loss in severe OHSS hypotension HYPOVOLEMIA HEMOCONC hct tachycardia coag. fact renal perfusion blood viscosity uremia hyperkalemia activation of RAAS oligo / anuriathrombosis sodium reabsortion shocklimb amp. death

16 Diagnosis of severe OHSS clinic:distended abdomen, nausea, vomiting, diarrhea dyspnea, weight gain, hypotension, tachycardia U/S: enlarged ovaries (>12 cm) + ascites X-ray: pleural effusion lab:Hct > 45% total proteins/albumine trombocytes ureum/creatinine ; creat.clear. electrolyte imbalance ( K, acidosis) liver enzyms  -hCG

17 signals in severe and critical OHSS severe critical ovaries >12 cm > 12 cm ascites/hydrothorax massive tense hct >45% >55% WBC > > oliguria yes extreme creatinin >1.6 creat. clearence >50 ml/min <50 ml/min renal failure not yet yes liver disfunctionyes yes complications anasarca thrombo-emb. ARDS

18 Alarm signals patient at risk abdominal pain and distension nausea, vomiting dyspnoe weight gain > 2 kg low urine production

19 complications of severe OHSS n n Thrombo embolism u u limb amputation u u Aorto-subclavian embolism u u CVA n n ARDS n n ovarian torsion (dd ectopic) n n acute hydrothorax n n death

20 Is OHSS predictable? n n in patients at risk n n single factors are not predictable n n best predictable combination (78.5% in 128 cases) : log E 2 + slope of log E 2 + hMG dose + n oocytes + LH/FSH

21 Severe OHSS: high risk groups young lean patients (<30y) previous OHSS PCO-like ovarian architecture and endocrinology hMG stimulation, specifically after GnRHa high number of small follicles high E 2 levels (38% if E 2 >6000, 25% if E 2 < 2500pg/ml) n immature/ n mature follicles high number of oocytes (23% if >30) high E2 levels plus high number of oocytes (80%) hCG trigger (ovulation, luteal phase, pregnancy) serum or urine detection of VEGF? Genetical/familial: FSH receptor mutant

22 Treatment of OHSS No causal treatment Prevention is the most effective treatment

23 Prevention of OHSS before stimulation n identify patients at risk: u previous OHSS, familial, genetic u PCO, young, lean n avoid GnRHa in patients at risk: use GnRH antgonists or no down regulation n Ovarian drilling (PCO patients )

24 Prevention of OHSS during stimulation n identify patients at risk: u high E2 levels and increase u high ratio small follicles/mature follicles n low dose gonadotropins, slow increase or COASTING n Close monitoring by E2 and U/S n avoid hCG in risk patients ( E2 > 3500 pg/ml; > foll.) u as ovulation trigger (sp. LH, GnRHa, hCG dose, rec LH or hCG) u during luteal phase n avoid pregnancy: cancel cycle; cryopreservation of all embryos n Early unilateral follicle aspiration (EUFA) +/- IVM n Albumin or 6% hydroxyethyl starch (HAES)at OPU n glucocorticosteroids

25 Withholding hCG for prevention of OHSS n n in PCO patients n n OHSS in previous cycle n n E2 > 3500 pg/ml n n rapid E2 increase (slope) n n presence of >25 small follicles Risk ea, Hum Reprod, 1991

26 hCG dose and oocyte recovery rate doserecovery% IU IU IU 98.1 Abdalla ea, Fertil Steril, 1987

27 coasting Definition: stop exogenous gonadotropins and postpone hCG administration until E 2 levels are ‘safer’ Meta-analysis: Delvigne e.a : 493 pts in 11 studies: conclusions: - to heterogenous studies for comparison - 16% ascites and 2.5 % hospitalisation - 16% ascites and 2.5 % hospitalisation - impact of decreasing E 2 on endometrium?

28 Coasting duration and outcome duration duration cycles IR % PR % 1 or 2100 (48.2%) days 49 (23.6%) days 58 (28.2%) IR : implantation rate; PR pregnancy rate Ulug e.a. Hum Reprod 2002

29 Coasting in the prevention of severe OHSS cochrane review Review:R.C.T. : 13 studies identified 1 met inclusion criteria ODDS ratio + 95% CI ODDS ratio + 95% CI % of mod./severe OHSS (n = 30) 0.76 ( ) clinical PR (n = 30) 0.75 ( ) D’Angelo e.a. Cochrane library 2003

30 Albumin vs placebo (at OPU) in severe OHSS prevention: a Cochrane review Review:R.C.T. : 7 studies identified 5 met the inclusion criteria (378 pts) Conclusion: clear benefit of IV Albumin in OHSS prevention albumin placebo OR + 95 % CI albumin placebo OR + 95 % CI severe OHSS : 4/193 (2.1%) 14/185 (7.6%) 0.28(0.11 – 0.73) Aboulghar e.a. Hum. Reprod 2003

31 GnRH agonists vs GnRH antogonists and OHSS GnRHa (long) cetrorelix P n= 85 n= 188 OHSS6.5% 1.1% 0.03 PR 26.0 % 22% NS PR pregnancy rate Ludwig e.a Gynecol/obstet

32 Embryo freesing for prevention of OHSS: a cochrane review Review: R.C.T up to juli 2001 : 17 studies identified 2 met the criteria 2 met the criteria Interventions compared: 1. cryopreservation of all embryos vs IV albumin 2. freesing all embryos vs fresh embryo transfer Conclusions: 1. insuff. evidence to support routine cryopreservation 2. insuff. evidence to determine the relative merits of albumin vs cryo

33 Does OHSS influence the pregnancy? n n increased E 2 levels and altered P 4 /E 2 ratios may impair endometrial receptivity n n a higher incidence of trombophilia may induce abortions, pre eclampsia and placental insufficient n n high levels of LH may induce abortions n n chronic hypoxia (pleural effusion) may induce abortion

34 OHSS and obstetric outcome % clinical PR73.0 miscarriage rate29.8 multips 57.0 premature delivery44.0 cesarian section44.0 (24.1 singleton) low birth weight62.1 (34.1 singleton) hypertensive disorders13.2 abruptio placentae40.4 fetal malformations1.9 Abramov e.a. hum reprod 1998 : 10 y study

35 Treatment of severe OHSS 1. IN hospital : bedrest with: 2. maintain plasma volume with:Crystalloids (NaCL or ringers) (under CVP control)Albumin ( ml/2-12 h) 3. maintain renal perfusion:NO diuretics (unless hemodilution) Dopamin (4 mg/kg/day) 4. reduce capillary permeability:indomethacin?, ACE-inhibitors (captopril) ?, anti histaminic drugs ?,anti- VEGF Antibodies? 5. paracentesis of ascites (  reinfusion) /pleural effusions 6. Heparin : as prevention or treatment (only if thromboembolic problems) 7. surgery: only with ovarian tumor, rupture or ectopic 8. pregnancy interruption?

36 paracentesis in severe OHSS: indications n n need for symptomatic pain relief n n tense ascites n n oliguria with impaired renal function n n hemoconcentration unresponsive to medical treatment

37 paracentesis : treatment for severe OHSS paracentesisconventional n = 11 n = 10 age E2 (PG/ml) days in hosp. 4 9 Aboulgar ea, Fertil Steril, 1990

38 severe OHSS : treatment hemoconcentration/ascites crystalloids albumin relative hemodilution tense ascites hct 45% crystalloids albumin WBC>25000 albumin lasix paracentesis diuresis impaired renal function crystalloids albumin recovery paracentesis I.C.U. /dopamin renal failureARDS Thromb. heparin termination

39 Conclusions 1 severe OHSS is a serious, iatrogenic complication of ovulation induction with high morbidity and sometimes mortality, mostly in young healthy patients The incidence is related to the stimulation protocol, the underlying fertility problem (PCO-like), the use of hCG and the occurence of pregnancy

40 Conclusions 2 The underlying pathology is an acute shift of body fluids from the vascular compartiment to the 3th space. Vaso active components ( ovarian renine-angiotensine system, histamine, PG’s, PRL, inflammatory cytokines, VEGF ) will stimulate angiogenesis under influence of LH (hCG) and E2, and thus increase capillary permeability.

41 Conclusions 3 Prevention is the best treatment. Absolute prevention: no hCG or cycle cancellation Relative prevention: coasting, albumin or HAES, cryopreservation of all embryos, ovulation trigger by lower hCG dose or GnRHa or rec-LH or rec-hCG. The pilars of treatment are :bedrest, maintaining plasma volume, reducing capillary permeability and draining of ascites while surgery is only indicated in case of torsion or ectopic.


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