Centrum voor Reproductieve Geneeskunde Prof. Luc O. Delbeke Centrum voor Reproductieve Geneeskunde Universitair Ziekenhuis Antwerpen Ovarieel Hyperstimulatie Syndroom (OHSS) Antwerpen 23/10/2003 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 emailadres. 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 ldebaene@unicall.be +32.(0)475.465440

Ovarieel Hyperstimulatie Syndroom (OHSS) Postuniversitaire studiedag VVOG 23 oktober 2003 Ovarieel Hyperstimulatie Syndroom (OHSS) Prof. Luc O. Delbeke Centrum voor Reproductieve Geneeskunde Universitair Ziekenhuis Antwerpen 1 1 1

Casus 1 T. Spinder Fertiliteit in de praktijk september 2003 32 j., G0 idiopatische infert. 6 x cc/IUI IVF superovulatie : GnRHa kort + 200 IE rec FSH/d 7 d Ovul. inductie : 10.000 IU hCG bij 12 foll.  18 mm E2 niet bepaald ovum aspirat. : 35 h na hCG : 14 eicellen Fertilisation : 13 x 2PN 2 ER + 6 CRYO Luteale fase : 1500 IE hCG op dag OPU + 5, +7, +9 2 2

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 24.5.103; tromb 227.103 CRP 17 ng/l; hypo-albuminaemie behandeling : open hart chirurgie: resectie trombus linker ventr. pleura- en ascites drainage; fraxiparine; P4 vag. evolutie : oplopend hCG tot dag 29 na OPU, waarna miskraam 3 3

Case 2 (Levy ea, Hum Reprod, 1995) 26 y G1P1 , surgical removal of craniopharyngioma : 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. : 10.000 IU hCG E2 475 pg/ml foll.: 2 > 18; 5 < 15; 10 < 9mm luteal phase : ? 5 5

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 6 6

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 7 7 7

OHSS: signs and symptoms (Golan, 1989) Mild Gr I abd. distension ovaries 5 - 12 cm + Gr II nausea, vomiting, diarrhea + Moderate Gr III U/S ascites / weight ovaries > 12 cm + Severe Gr IV clin. ascites/hydrothorax ovaries > 12 cm + Gr V hypovol., hemoconc., coag. disorders renal perfusion , oliguria shock 10 11

OHSS incidence Non IVF: mild 8.0 -23% moderate 0.005 -7% severe 0.008 -10% IVF : mild 100% moderate 21- 44% severe 1- 10% estimated mortality 1/45.000-1/500.000 estimated morbidity 0.1-0.5% 8 8 8

Predisposing factors for OHSS previous OHSS patients constitution: young (< 30); lean PCO(D): hyperinsulinaemia; high E2 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 9 10 9

Pathogenesis of Severe OHSS hCG (LH) Kidney (JGA) Prorenin ovary 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 E2 27 27 37

Pathogenesis of severe OHSS: ‘Capillary Leakage Syndrome’ Vaso Active Component Capillary permeability in: ovaries uterus peritoneum omentum pleura 12 13 12

Severe OHSS: Acute SHIFT of body fluids Vascular compartiment 3th space hypovolemia ascites hemoconcentration ovarian volume (cysts, edema) albumine loss hydrothorax/hydropericard hydro urether anasarca 11 11 12

electrolyte imbalance SHIFT to 3th space in severe OHSS 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 26 36 26

Vascular fluid loss in severe OHSS hypotension HYPOVOLEMIA HEMOCONC hct tachycardia coag. fact renal perfusion blood viscosity uremia hyperkalemia activation of RAAS oligo / anuria thrombosis sodium reabsortion shock limb amp. death 25 35 25

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 14 15 14

signals in severe and critical OHSS severe critical ovaries >12 cm > 12 cm ascites/hydrothorax massive tense hct >45% >55% WBC >15.000 >25.000 oliguria yes extreme creatinin 1.0 - 1.5 >1.6 creat. clearence >50 ml/min <50 ml/min renal failure not yet yes liver disfunction yes yes complications anasarca thrombo-emb. ARDS

Alarm signals patient at risk abdominal pain and distension nausea, vomiting dyspnoe weight gain > 2 kg low urine production 15 18 15

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

Is OHSS predictable? in patients at risk single factors are not predictable best predictable combination (78.5% in 128 cases): log E2 + slope of log E2 + hMG dose + n oocytes + LH/FSH

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 E2 levels (38% if E2>6000, 25% if E2 < 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 13 14 13

Prevention is the most effective treatment Treatment of OHSS No causal treatment Prevention is the most effective treatment 16 20 16

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

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

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

hCG dose and oocyte recovery rate dose recovery% 2.000 IU 77.0 5.000 IU 95.5 10.000 IU 98.1 Abdalla ea, Fertil Steril, 1987

coasting Definition: stop exogenous gonadotropins and postpone hCG administration until E2 levels are ‘safer’ Meta-analysis: Delvigne e.a. 2002 : 493 pts in 11 studies: conclusions: - to heterogenous studies for comparison - 16% ascites and 2.5 % hospitalisation - impact of decreasing E2 on endometrium?

Coasting duration and outcome duration cycles IR % PR % 1 or 2 100 (48.2%) 41.0 55.7 3 days 49 (23.6%) 18.4 27.9 4 days 58 (28.2%) 10.5 26.7 IR : implantation rate; PR pregnancy rate Ulug e.a. Hum Reprod 2002

Coasting in the prevention of severe OHSS cochrane review Review: R.C.T. : 13 studies identified 1 met inclusion criteria ODDS ratio + 95% CI % of mod./severe OHSS (n = 30) 0.76 (0.18 - 3.24) clinical PR (n = 30) 0.75 (0.17 - 3.33) D’Angelo e.a. Cochrane library 2003

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 severe OHSS : 4/193 (2.1%) 14/185 (7.6%) 0.28(0.11 – 0.73) Aboulghar e.a. Hum. Reprod 2003

GnRH agonists vs GnRH antogonists and OHSS GnRHa (long) cetrorelix P n= 85 n= 188 OHSS 6.5% 1.1% 0.03 PR 26.0 % 22% NS PR pregnancy rate Ludwig e.a. 2001 Gynecol/obstet

Embryo freesing for prevention of OHSS: a cochrane review Review: R.C.T up to juli 2001 : 17 studies identified 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

Does OHSS influence the pregnancy? increased E2 levels and altered P4/E2 ratios may impair endometrial receptivity a higher incidence of trombophilia may induce abortions, pre eclampsia and placental insufficient high levels of LH may induce abortions chronic hypoxia (pleural effusion) may induce abortion

OHSS and obstetric outcome % clinical PR 73.0 miscarriage rate 29.8 multips 57.0 premature delivery 44.0 cesarian section 44.0 (24.1 singleton) low birth weight 62.1 (34.1 singleton) hypertensive disorders 13.2 abruptio placentae 40.4 fetal malformations 1.9 Abramov e.a. hum reprod 1998 : 10 y study

Treatment of severe OHSS 1. IN hospital : bedrest 2. maintain plasma volume with: Crystalloids (NaCL or ringers) (under CVP control) Albumin ( 50-100 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? 18 25 18

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

paracentesis : treatment for severe OHSS paracentesis conventional n = 11 n = 10 age 31.9 29.8 E2 (PG/ml) 6.900 6.400 days in hosp. 4 9 Aboulgar ea, Fertil Steril, 1990

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

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 19 29 19

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. 20 30 20

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. 21 31 21