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Prevention of OHSS. S. Kol, May 2006. OHSS – scope of the problem. Severe form: 0.2-1% of stimulation cycles. Mortality: 1:45,00 to 1:50,000 per infertile women receiving gonadotropins. WHO 2001. OHSS: incidence, recent data. - PowerPoint PPT Presentation
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S. Kol, May 2006 Prevention of OHSS Prevention of OHSS
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Page 1: S. Kol, May 2006

S. Kol, May 2006

Prevention of OHSSPrevention of OHSS

                              

Page 2: S. Kol, May 2006

OHSS – scope of the problemOHSS – scope of the problem• Severe form: 0.2-1% of stimulation cycles.• Mortality: 1:45,00 to 1:50,000 per infertile

women receiving gonadotropins.

WHO 2001

Page 3: S. Kol, May 2006

OHSS: incidence, recent dataOHSS: incidence, recent data

• Two large trials, 1458 patients, agonist-based protocol, comparing Menopur and Gonal F (Arce and Sorensen, ASRM 2005)

• Patients at high risk for OHSS - “drop-outs”.

• Moderate – severe OHSS: 2%

Page 4: S. Kol, May 2006

F&S January 2006

ObjectiveObjective: to determine OHSS incidence in 2,524 antagonist-based cycles (1801 patients).ResultsResults: fifty three patients (2%2%) were hospitalized because of OHSS.ConclusionsConclusions: clinically significant OHSS is a limitation even in antagonist cycles.

“There is more than ever an urgent need for alternative final oocyte maturation – triggering medication”

Page 5: S. Kol, May 2006

MorbidityMorbidity• An autopsy case of ovarian hyperstimulation syndrome with massive pulmonary edema and pleural

effusion.

• Case report: delirium associated with ovarian hyperstimulation syndrome.

• Cortical vein thrombosis misinterpreted as intracranial haemorrhage in severe ovarian hyperstimulation syndrome: case report.

• Subclavian deep vein thrombosis associated with the use of recombinant follicle-stimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome.

• A severe case of ovarian hyperstimulation syndrome: 65 liters of ascites aspirated in an on-going IVF-ET twin pregnancy.

• Central retinal artery occlusion associated with severe ovarian hyperstimulation syndrome.

• A case of forearm amputation after ovarian stimulation for in vitro fertilization-embryo transfer.

• Stroke in ovarian hyperstimulation syndrome in early pregnancy treated with intra-arterial rt-PA.

• Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome despite mini-dose heparin prophylaxis.

and more and more…

Page 6: S. Kol, May 2006

Past predictions of the futurePast predictions of the future

• “We don’t like their sound, and guitar music is on the way out” Decca Recordings Co. rejecting the Beatles, 1962.

• “Stocks have reached what looks like a permanently high plateau”. Irving Fisher, Professor of Economics. Yale University, 1929.

• “$100 million is way too much to pay for Microsoft” IBM 1982.

• “Who the hell wants to hear actors talks?” H.M. Warner, Warner Brothers, 1927.

“Severe OHSS will remain a complication of IVF cycles despite all attempts of prevention.” R.G. Forman, Human Reproduction 14:2687, 1999.“…absolute prevention will not be possible” García-Velasco et al F&S, March 2006.

Page 7: S. Kol, May 2006

Accepted preventive strategiesAccepted preventive strategies

• Canceling the cycle• Coasting• Albumin IV• Cryopreservation• Recombinant LH• Low hCG dose

Page 8: S. Kol, May 2006

CoastingCoasting

• Most popular choice.• Open questions: for whom? how many days? Safe value to

give hCG? Magnitude of E2 drop?• Cochrane database: D'Angelo A, Amso N. Coasting for

preventing ovarian hyperstimulation syndrome. The Cochrane Database 2002 “There is a lack of randomised controlled trials…there is insufficient evidence to determine if coasting is an effective strategy for preventing OHSS.”

Page 9: S. Kol, May 2006

IV albuminIV albumin• Conflicting results.• Cochrane database: Aboulghar M, Evers JH, Al-Inany H.

Intra-venous albumin for preventing severe ovarian hyperstimulation syndrome. The Cochrane Database of Systematic Reviews 2002: “Clear benefit from administration of intra-venous albumin at the time of oocyte retrieval in prevention of severe OHSS in high-risk cases”.

Intravenous albumin does not prevent moderate-severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study. Bellver at al 2003

The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial. Ben-Chetrit et al 2001

Personal communication with Professor Aboulghar: review amendment: albumin is ineffective.

Page 10: S. Kol, May 2006

CryopreservationCryopreservation• OHSS can be severe until menses.

• Cochrane database: D'Angelo A, Amso N. Embryo freezing for preventing ovarian hyperstimulation syndrome. The Cochrane Database of Systematic Reviews 2002, “insufficient evidence to support routine cryopreservation and insufficient evidence for the relative merits of intra-venous albumin versus cryopreservation“

Page 11: S. Kol, May 2006

Recombinant LHRecombinant LH

• Not available as trigger.• No data on OHSS prevention.• In theory, will not prevent late, pregnancy-

associated, OHSS.

Page 12: S. Kol, May 2006

Low hCG doseLow hCG dose

• Questionable, unreliable.• “Reducing the dose of hCG does not

eliminate the risk of OHSS in a high risk group” Schmidt el al, Fertility Sterility October 2004

Page 13: S. Kol, May 2006

Total OHSS prevention can only be achievedby ovulation triggering with a GnRH agonist.

“Severe OHSS will remain a complication of IVF cycles despite all attempts of prevention.” R.G. Forman, Human Reproduction 14:2687, 1999.

Page 14: S. Kol, May 2006

The GnRHa-induced LH/FSH surgeThe GnRHa-induced LH/FSH surge

• LH and FSH levels rise 4 and 12 hours post LH and FSH levels rise 4 and 12 hours post trigger, respectively.trigger, respectively.

• LH surge lasts for 24 hours.LH surge lasts for 24 hours.• Surge amplitude comparable to physiology.Surge amplitude comparable to physiology.• A single agonist dose reliably triggers A single agonist dose reliably triggers

ovulation.ovulation.

Itskovitz et al 1991

Page 15: S. Kol, May 2006

Luteal phaseLuteal phase

• Normal early follicular-luteal shift in Normal early follicular-luteal shift in ovarian steroidogenesis.ovarian steroidogenesis.

• Short luteal phase: early luteolysis.Short luteal phase: early luteolysis.

Page 16: S. Kol, May 2006

Case-control studyCase-control study(Lewit et al Hum Reprod 11:1399, 1996)(Lewit et al Hum Reprod 11:1399, 1996)

• 1616 patients who developed severe OHSS patients who developed severe OHSS when hCG was given as trigger (group A).when hCG was given as trigger (group A).

• Each patient underwent at least 1 cycle Each patient underwent at least 1 cycle during which GnRH agonist was given as during which GnRH agonist was given as trigger (triptorelin 0.2 mg, group B).trigger (triptorelin 0.2 mg, group B).

• In group B – no OHSS!!!In group B – no OHSS!!!

Page 17: S. Kol, May 2006

Stimulation variables Stimulation variables

Group E2 max (pmol/l) No. oocytes No. hMG amphCG 16,969±8,948 28±11 24±6GnRH-a 20,816±9,568 36±14 21±4

Lewit et alLewit et al

Page 18: S. Kol, May 2006

Oocyte qualityOocyte quality

Group FZ Atretic GV NVS PB Total

hCG 6(3%) 8(4%) 10(5%) 10(5%) 180 (84%) 214

GnRH-a 11(4%) 15(6%) 19(7%) 7(3%) 205(80%) 257

Lewit et alLewit et al

Page 19: S. Kol, May 2006

LimitationsLimitations• Prospective study – ethical dilemma? Prospective study – ethical dilemma? • Not applicable in agonist-based cycles: Not applicable in agonist-based cycles:

unresponsive pituitary.unresponsive pituitary.

Use antagonists???

Page 20: S. Kol, May 2006

Efficacy GnRHa vs hCG for triggering of final Efficacy GnRHa vs hCG for triggering of final oocyte maturationoocyte maturation

• Objective: Can agonists trigger ovulation as effective as hCG?

• Randomized prospective multi-center study.• Antagonist-based cycles, normal responders.• Outcome measures: number of metaphase II

oocytes

Fauser et al, JCEM Feb. 2002, 87:709

Page 21: S. Kol, May 2006

Fauser et al, 2002

ProtocolProtocol

Page 22: S. Kol, May 2006

Clinical outcome (mean±SD)Triptorelin

(n=17)Leuprorelin

(n=15)hCG

(n=15)Number of oocytes/subject 9.8 ± 5.4 8.7 ± 4.5 8.3 ± 3.3Proportion of metaphase II oocyte

72 ± 18% 85 ± 17% 86 ± 17%

Fertilization 61 ± 30% 62 ± 23% 56 ± 18%

No. of embryos obtained persubject, grades 1 and 2 pooled 2.7 ± 34% 3.2 ± 2.6 3.3 ± 2.0Implantation rate 15 ± 34% 18 ± 37% 7 ± 14%Ongoing pregnancy rate 18% 20% 13%

Fauser et al, 2002

Page 23: S. Kol, May 2006

Serum concentrations of LH (hCG), FSH, E2 and P

Fauser et al, 2002

Page 24: S. Kol, May 2006

CCan this approach an this approach prevent OHSSprevent OHSS??

Page 25: S. Kol, May 2006

Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: Short communication

J. Itskovitz-Eldor et al

Human Reproduction, Human Reproduction, September 2000

Page 26: S. Kol, May 2006

Treatment scheme for Treatment scheme for high respondershigh responders

Day 2-3 menses

Day 6 rFSH

Rec FSH

ganirelix

High responder -triptorelin 0.2mg

OPUOPU ETETProgesterone

Page 27: S. Kol, May 2006

Stimulation characteristics of 8 women with increased risk for developing OHSS and who received 0.2 mg triptorelin for triggering ovulation Sub.Sub. rFSH (IU)rFSH (IU) FollFoll11mm 11mm EE2 pg/ml2 pg/ml Oocytes %MIIOocytes %MII

7 1350 22 2980 29 100

33 1500 21 3660 14 100

39 1950 24 3350 30 90

108a 1875 22 6410 1 100

109 1275 28 7670 52 54

112 1575 34 4050 30 93

126 2175 22 3690 15 67

158 1575 28 3020 16 56

No OHSS !!!No OHSS !!!a Empty follicle syndrome

Page 28: S. Kol, May 2006

ResultsResults

• Mean no. of follicles>11mm=25.1±4.5• Median E2 (pg/ml)=3675 (range 2980–7670)• Mean number of oocytes=23.4 (±15.4), 83%

MII• Mean number of embryos=15.4±6.6 • 7 ETs from fresh embryos: 1 pregnancy• 17 ETs from frozen-thawed embryos: 4

pregnancies

Itskovitz et al, 2000

Page 29: S. Kol, May 2006

Median values of serum LH and Median values of serum LH and EE22 after injection of triptorelin after injection of triptorelin

0.2mg0.2mgTime after

injection (n=8)Serum LH

(IU/l)Serum estradiol

(pg/ml)Pre-dose 2.4 47750.5 h 12.7 46301 h 14.3 45052 h 73.7 50804 h 219 554010-12 h 71.0 6000Day of OPU 7.9 2375Day of ET 0.8 963First week post-ET

1.0 145Itskovitz et al, 2000

Page 30: S. Kol, May 2006

Lower levels of Lower levels of inhibin Ainhibin A and and pro-alpha Cpro-alpha C during the luteal phase after triggering oocyte during the luteal phase after triggering oocyte maturation with GnRH agonist versus hCGmaturation with GnRH agonist versus hCG

Nevo et al, Fertil Steril 79:1123, 2003Nevo et al, Fertil Steril 79:1123, 2003

MechanismMechanismWhat is the mechanism of OHSS prevention?

Page 31: S. Kol, May 2006

Clinical characteristicsClinical characteristics

Nevo et al, 2003

Page 32: S. Kol, May 2006

Luteal phaseLuteal phase

Nevo et al, 2003

Natural cycle day 7-9=75 pg/ml vs. 18

Natural cycle day 7-9=

750 pg/ml vs. 184

Page 33: S. Kol, May 2006
Page 34: S. Kol, May 2006

Evidence-based medicineEvidence-based medicine

• We need a RCT in the context of OHSS prevention.• Study group: agonist trigger, control group: hCG

trigger.• The ethical problem of exposing high-responders to

the risk of OHSS.

Page 35: S. Kol, May 2006

Prevention of OHSS with the use of GnRH agonist to trigger final oocyte maturation after cotreatment with GnRH antagonist in patients with PCOS or previous high response undergoing IVF treatment - a prospective randomized clinical trial.

L. Engmann, A. DiLuigi, D. Schmidt, J. Nulsen,D. Maier, C. Benadiva

University of ConnecticutASRM October, 2005

Page 36: S. Kol, May 2006

Study Design

Dual suppression OCP’s & luprolide

HCG triggerOCP’s + Ganirelix

luprolide trigger

•< 40years, FSH < 10 with< 40years, FSH < 10 with•PCOS or PCO MorphologyPCOS or PCO Morphology• Or Previous High ResponseOr Previous High Response

RandomizationRandomization

N=13 N=12

LUTEAL LUTEAL SUPPORTSUPPORT: : E2 patches 0.1 mg X 3, E2 patches 0.1 mg X 3, qodqodP4 in oil, 50 mg/day; P4 in oil, 50 mg/day; MONITOR E2+P4 MONITOR E2+P4 LEVELS!LEVELS!

Page 37: S. Kol, May 2006

Engmann et al

Page 38: S. Kol, May 2006

Incidence of OHSS Incidence of OHSS (April 2006 update)(April 2006 update)

05

101520253035404550

OHSS Mild OHSS ModerateOHSS

Severe OHSS

ControlTreatment

%

P<0.00P<0.0011

N=27N=27N=25N=25

Engmann et al

Page 39: S. Kol, May 2006

OutcomeOutcome(April 2006 update)(April 2006 update)

0

10

20

30

40

50

60

70

80

Positive B-HCG

Implantationrate

ClinicalPregnancy rate

OngoingPregnancy rate

ControlTreatment

%

48.1%

56%60.7%65.4%

31.7%37.2%

51.9%60%

Engmann et al

Page 40: S. Kol, May 2006

Agonist n=15 hCG n=13

oocytes 19.8±2.5 19.5±1.9

Mature oocytes 17.7±2.9 16.4±2.2

Fertilization rate 57% 51%

E2 trigger day (pmol/l) 9595±996 8081±711

Clinical pregnancy 3/15 4/13

Ovarian volume (day of ET, cm3) 421±100** 846±164

OHSS 0/15** 4/13

*p<0.05

Babayof et al HR May 2006

Page 41: S. Kol, May 2006

Agonist trigger in normal responders?Agonist trigger in normal responders?

Since there are no ethical problems, we can trigger with agonist, although there is no reason to look for a substitute to hCG:

• GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. HR Humaidan et al, May 2005.

• A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. HR Kolibianakis et al, October 2005.

• GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. HR Update Griesinger et al, March 2006.

Page 42: S. Kol, May 2006

reference E2 trigger day (pmol/l)

oocytes

Clinical pregnancy

Ongoing pregnancy

Luteal support

Humaidan et al

7100 8.4 6% Vag gel prog. 8%, p.o. estradiol 4 mg, for 12 days

Kolibianakis et al

7067 10.2 5.6% (Brussels)2.9% (Lübeck)

Vag tab prog 600 mg, p.o. estradiol 4 mg. untill 7 W

Fauser et al

4070 (trip)2590 (leu)

9.88.7

18%20%

50 mg progesterone IM for 2 weeks

Babayof et al 9595 19.8 20% Progesterone 50mg IM, p.o. estradiol 4 mg

Engmann et al

8410 16 60% 56% 0.1mg E2 patchesProgesterone 50 IM until 7 W

The importance of luteal support?The importance of luteal support?

Page 43: S. Kol, May 2006

IVF Haifa: retrospective data analysisIVF Haifa: retrospective data analysis

• 107 high responders, 2004-5• E2 max (pmol/l)=17,268±6305• No. oocytes: 30±7.3• No. embryos: 15.2±6.5

Fresh ET Thaw ET

n 103 160

Positive βhCG 25 (24%) 75 (47%)

Ongoing/delivery 12 (48%) 45 (60%)

miscarriage 4 (16%) 13 (17%)

biochemical 9 (36%) 17 (23%)

Page 44: S. Kol, May 2006

Endometrial effect of high EEndometrial effect of high E22 levels levels

• High serum estradiol concentrations on the day of HCG injection are detrimental to uterine receptivity without affecting embryo quality. Simon et al, HR, 1995.

• Implantation rate was significantly higher in normal (18.5%) as compared with high (0%) responders. Pellicer et al FS, 1996

Page 45: S. Kol, May 2006

SummarySummary• Agonist trigger is an effective alternative to hCG. Its use is associated

with dramatic and irreversible luteolysis. • This remarkable phenomenon can be utilized to completely and reliably

prevent OHSS, even in extreme ovarian response. • Aggressive luteal support is necessary. • Agonist trigger in high responders is associated with low fresh cycle

pregnancy rate, probably due to the extremely high E2 levels. • Thaw cycles with embryos obtained after agonist trigger yield good

pregnancy rate. • Agonist trigger offers no advantage in normal responders.• Agonist trigger is the perfect patient-tailored safe-gate if a patient hyper-

responds.

Page 46: S. Kol, May 2006

Thank [email protected]


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