OHSS FREE CLINICProf 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

Potentially fatal (!)

Risk factor (PCOS)

Triggering mechanism of hCG ( ! )

Intriguing

Intriguing

Iatrogenic Who is responsible?

Ovarian stimulation How to stimulate?

HCG is the trigger HCG to be replaced?

OHSS

Ovarian hyperstimulation syndrome

01 09 2011

PubMed n : 2 275 citations

Severe OHSS

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

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

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) 0.9 % (95 % CI : 0.5 - 1.31)

Papanikolaou FS 2006

Fatal

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

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

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 ?

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

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

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

Obstetrical outcome of IVF pregnancies in OHSS syndromeOccurrence 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 ?

The question : Is iatrogenic OHSS avoidable and erasable ?

Understanding different biological

mechanisms

using different drugs

using different treatment strategies

Devroey et al HR 2011

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

GnRH agonist triggeringGnRH-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

Reflection

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

Cycle outcomeBrussels

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

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

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

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

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

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

Oocyte donation using egg cryobanking

153 eggs 117 fertilized 47 blastocysts transferred 2.3 per ET 26 implanted (55 %)

Nagy FS 2009

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

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

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

Endometrial biopsy on the day of ovulation, natural cycle

No secretory features

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

Clear secretory features

Endometrium histology at OPU and the probability of pregnancyAuthor Stimulation Endometrial

advancementOdds ratio 95% CI P

≤ 3 days > 3 days

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

Advanced endometrial maturation - no pregnancies

Upregulated genes SERPINB6 FOXO3A SOX17 CDC42

Van Vaerenbergh I HR 2009

CONCLUSIONPast 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 %

CODA

o Optimization of stimulation

o Optimization of embryology

o Optimization of endometrial implantation potential

o GnRH antagonist and GnRH agonist to trigger

o Freeze all oocytes/embryos

o Replacement in receptive endometrium (spontaneous or artificial)

OHSS FREE CLINICAFR segmentation strategy