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
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) 0.0 % (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 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 ?
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 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
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
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
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 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
Advanced endometrial maturation - no pregnancies
Upregulated genes
SERPINB6
FOXO3A
SOX17
CDC42
Van Vaerenbergh I HR 2009
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 %
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