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OHSS FREE CLINIC Prof Dr P Devroey

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OHSS FREE CLINIC. Prof Dr P Devroey. The Era of a OHSS Free Clinic. By understanding biology By using drugs differently By innovative strategic thinking. Definition. Definition of OHSS. Iatrogenic complication (!) of “controlled” (?) ovarian stimulation - PowerPoint PPT Presentation

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Page 1: OHSS  FREE  CLINIC

OHSS FREE CLINIC

Prof Dr P Devroey

Page 2: OHSS  FREE  CLINIC

The Era of a OHSS Free Clinic

By understanding biology

By using drugs differently

By innovative strategic thinking

Definition

Page 3: OHSS  FREE  CLINIC

Definition of OHSS

Iatrogenic complication (!) of

“controlled” (?) ovarian stimulation

Potentially fatal (!)

Risk factor (PCOS)

Triggering mechanism of hCG ( ! )

Intriguing

Page 4: OHSS  FREE  CLINIC

Intriguing

Iatrogenic Who is responsible?

Ovarian stimulation How to stimulate?

HCG is the trigger HCG to be replaced?

OHSS

Page 5: OHSS  FREE  CLINIC

Ovarian hyperstimulation syndrome

01 09 2011

PubMed n : 2 275 citations

Severe OHSS

Page 6: OHSS  FREE  CLINIC

Severe OHSS

IV fluid Respiratory distress (intensive care

admission) Electrolyte imbalance Dopamine to improve diuresis Heparin to prevent thrombosis Vaginal aspiration of ascitis fluid

Aboulghar SRM 2010

Form

Page 7: OHSS  FREE  CLINIC

Form of OHSS

Early onset (early OHSS) up to 9 days after oocyte retrieval related to excessive ovarian response

Late onset (late OHSS) 10 days after oocyte retrieval induced by endogenously produced hCG after implantation

Papanikolaou HR 2005

Incidence

Page 8: OHSS  FREE  CLINIC

Incidence of OHSS (hospitalized)

2 524 IVF/ICSI cycles

53 patients 2.1 % (95 % CI : 1.6 -

2.8)

Early OHSS (n : 31) 1.2 % (95 % CI : 0.9 - 1.8)

Late OHSS (n : 22) 0.0 % (95 % CI : 0.5 - 1.31)

Papanikolaou FS 2006

Fatal

Page 9: OHSS  FREE  CLINIC

Fatal OHSS

25 years old Japanese lady

Bilateral chest pain - dyspnoea

Pleural effusion

Fatal after respiratory insufficiency

Autopsy massive pulmonary edema

Semba Patol Int 2000

Fatal

Page 10: OHSS  FREE  CLINIC

Fatality due to OHSS

31 years old woman

Ovarian stimulation (Gonal F)

Fatal adult respiratory distress

syndrome

Fineschi Int J Legal Med 2006

Maternal death

Page 11: OHSS  FREE  CLINIC

Maternal deathIn IVF in the Netherlands (1984 – 2008)

Death to OHSS : 3 / 100 000 IVF cycles

Respiratory distress (n : 2)

Cerebrovascular thrombosis (n : 1)

Braat HR 2010

Does it mean 30 / 1 000 000 ?

Page 12: OHSS  FREE  CLINIC

At random citations

OHSS is difficult to predict, but multiple preventive strategies and protocols are being developed that may limit it

Patchava Minerva Ginecol 2009

Ovarian stimulation carries a marked risk for … ovarian hyperstimulation syndrome

Kallen Best Pract Res Clin Obstet Gynaecol 2008

Page 13: OHSS  FREE  CLINIC

At random citations (continued)

Low dose hCG at the end of the

follicular phase Nargund RBO 2007

Preventive administration of IV fluid Youssef Cochrane Database Syst Rev 2011

Continuous vaginal and thoracic fluid

drainage for management of severe

ovarian hyperstimulation syndrome Ceyhan Gynecol Endocrinol 2008

Page 14: OHSS  FREE  CLINIC

At random citations (continued)

Severe ovarian hyperstimulation

syndrome : an intensive care disease Humeeus Rev Med Chil 1998

Coasting no benefit D’Angelo Cochrane Database Syst Rev 2011

Dopamine antagonist significant

reduction Sherwal J Human Reprod Sci 2010

Obstetrical outcome

Page 15: OHSS  FREE  CLINIC

Obstetrical outcome of IVF pregnancies in OHSS syndrome

Occurrence 40/3 504 cycles (1.4 %)

Control (80)

P

Duration of hospitalization 10 Days 0

Early OHSS 22.5 % 0

Late OHSS 75.5 % 0

Thrombo-embolic complications

10.0 % 0

Pregnancy induced hypertension

21.0 % 9 % S

Preterm labor 36.0 % 11 % S

Courbiere FS 2011

Iatrogenic ?

Page 16: OHSS  FREE  CLINIC

The question : Is iatrogenic OHSS avoidable and erasable ?

Understanding different biological

mechanisms

using different drugs

using different treatment strategies

Devroey et al HR 2011

Page 17: OHSS  FREE  CLINIC

Is GnRH agonist triggering an option ?

PubMed 01.03.2011 n : 83 publications

Gonadotrophin-releasing hormone agonist

triggering : the way to eliminate ovarian

hyperstimulation syndrome - a 20 years

experience

Kol Sem Reprod Med 2010

Page 18: OHSS  FREE  CLINIC

GnRH agonist triggering

GnRH-a hCG

n : 84 n : 95

Age (years) 33 34

Eggs (mean) 5.9 5.2

Embryos transferred 2.5 2.3

Pregnancy rates 20 % 19 %

Segal FS 1992

Reflexion

Page 19: OHSS  FREE  CLINIC

Reflexion

It is possible that down regulation

of pituitary receptors and reduced

LH support for the corpus luteum

may occur even after a single

administration of GnRH agonist

Segal FS 1992

Page 20: OHSS  FREE  CLINIC

Cycle outcome

Brussels

Agonist hCG

Stimulation (in patients)

18 24

OPU (n) 18 24

ET (n) 15 20

Ongoing pregnancy rate / started cycle

1/18 (5.6 %) 10/24 (41.7 %)

Odds ratio (95 % CI) 0.11 (0.02 – 0.52)

P level = 0.005

Kolibianakis HR 2005

Page 21: OHSS  FREE  CLINIC

Triggering GnRH agonist 0.2 mg Triptorelin

hCG 10 000

Vaginal progesterone

+ +

Estradiol valerate + +

Discontinuation - -

Pregnancy rate 5.6 % 41.7 %

Kolibianakis HR 2005

GnRH agonist triggering in a GnRH antagonist cycle

Page 22: OHSS  FREE  CLINIC

GnRH agonist triggering in GnRH antagonist cycles in OHSS risk AIM : avoiding OHSS Patients (n : 12) > 25 follicles GnRH agonist triggering and 1 500 hCG

35 hours later COC (n : 20) Ongoing pregnancies 50 % (6/12) No OHSS

Humaidan RBMO 2009

Page 23: OHSS  FREE  CLINIC

GnRH agonist triggering in GnRH antagonist cycles (RCT)

GnRH agonist + 1 500 hCG

hCG 10 000

Patients (n) 152 150

Transfer rate (%) 86 92

Delivery rate / patient 36 / 152 (24 %) 47 / 150 (31 %)

Humaidan FS 2010

Page 24: OHSS  FREE  CLINIC

Oocyte donors (GnRHa donors)

Triggering GnRHa hCG P

Subjects (n) 50 50

Age (y) 25 25

rFSH dose (U) 2 300 2 300

Eggs retrieved (mean)

17 19

OHSS rate 0 / 50 8 / 50 0.03

Melo RBMO 2009

Page 25: OHSS  FREE  CLINIC

Elective vitrification of all zygotes after GnRH agonist triggering

Days of stimulation (mean) 10

FSH (U) 1 900

COC (mean) 16

Ongoing pregnancy / patient 7 / 19 (37 %)

Griesinger HR 2007

Page 26: OHSS  FREE  CLINIC

Oocyte donation using egg cryobanking

153 eggs

117 fertilized

47 blastocysts transferred

2.3 per ET

26 implanted (55 %)

Nagy FS 2009

Page 27: OHSS  FREE  CLINIC

Oocyte banking (vitrification)

RCT P

Frozen Fresh

Ongoing pregnancy rate / ET

43.7 % 41.7 % NS

Clinical pregnancy rate / ET

55.0 % 56.0 % NS

Implantation rate 40.0 % 41.0 % NS

Similar results95 % CI : 0.7 – 1.3

Cobo HR 2010

Page 28: OHSS  FREE  CLINIC

Oocyte vitrification : closed carrier

Patients N : 20

Survival rate 111 / 123 (90 %)

Fertilization rate 86 / 111 (75.5 %)

Cleavage rate (day 3) 80 / 86 (93 %)

Clinical pregnancy rate per patient 10 / 20

Ongoing pregnancy rate 9 / 20

Frozen embryo replacement 1 / 3

Cumulative Ongoing pregnancy rate per patient Implantation per warmed oocyte

10 / 20 (50 %) 14 / 123 (11.4 %)

Personal communication

Page 29: OHSS  FREE  CLINIC

Oocyte vitrification after GnRH agonist triggering versus coasting

Observational study

Oocyte vitrification after GnRH agonist

triggering (n : 152)

Classical coasting (n : 96)

Egg vitrification (pregnancy rate 50 %)

Clinical coasting (pregnancy rate 30 %)

Herrero FS 2010

Page 30: OHSS  FREE  CLINIC

Endometrial biopsy on the day of ovulation, natural cycle

No secretory features

Page 31: OHSS  FREE  CLINIC

Endometrial biopsy on the day of oocyte retrieval, GnRH agonist and gonadotrophin stimulation cycle

Clear secretory features

Page 32: OHSS  FREE  CLINIC

Endometrium histology at OPU and the probability of pregnancy

Author Stimulation Endometrial advancement

Odds ratio 95% CI P

≤ 3 days > 3 days

Clinical pregnancy rate

Ubaldi (1997) hMG/agonist 10/32 0/7

Kolibianakis (2002)

Rec-FSH/antagonist

11/49 0/6

21/81 0/13 0.22 0.06-0.89 0.03

Ongoing pregnancy rate

Ubaldi (1997) hMG/agonist 10/32 0/7

Kolibianakis (2002)

Rec-FSH/antagonist

8/49 0/6

18/81 0/13 0.23 0.05-0.98 0.05

Kolibianakis FS 2002

Page 33: OHSS  FREE  CLINIC

Advanced endometrial maturation - no pregnancies

Upregulated genes

SERPINB6

FOXO3A

SOX17

CDC42

Van Vaerenbergh I HR 2009

Page 34: OHSS  FREE  CLINIC

CONCLUSION

Past

Down regulation with GnRH agonist

HCG for final egg maturation

OHSS ≈ 2 %

Today

For first cycle always GnRH antagonist

GnRH agonist triggering if at risk for OHSS Freeze all

ET of fresh embryo

adding low dose hCG in

luteal phase

OHSS 0 %

Page 35: OHSS  FREE  CLINIC

CODA

(A) Optimization of

stimulation

(B) Optimization of

embryology

(C) Optimization of

endometrial

implantation potential

(A) GnRH antagonist and

GnRH agonist to trigger

(F) Freeze all

oocytes/embryos

(R) Replacement in receptive

endometrium

(spontaneous or artificial)

OHSS FREE CLINICAFR segmentation strategy