OHSS FREE CLINIC

1
OHSS FREE CLINIC
Prof Dr P Devroey
2
The Era of a OHSS Free Clinic

• By understanding biology
• By using drugs differently
• By innovative strategic thinking

Definition
3
Definition of OHSS

• Iatrogenic complication (!) of controlled
  (?) ovarian stimulation
• Potentially fatal (!)
• Risk factor (PCOS)
• Triggering mechanism of hCG ( ! )

Intriguing
4
Intriguing

• Iatrogenic Who is responsible?
• Ovarian stimulation How to stimulate?
• HCG is the trigger HCG to be replaced?

OHSS
5
Ovarian hyperstimulation syndrome

• 01 09 2011
• PubMed n 2 275 citations

Severe OHSS
6
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
7
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
8
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
9
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
10
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
11
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 ?

12
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

13
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

14
At random citations (continued)

• Severe ovarian hyperstimulation syndrome an
  intensive care disease
• Humeeus Rev Med Chil 1998
• Coasting no benefit
• DAngelo Cochrane Database Syst Rev 2011
• Dopamine antagonist significant reduction
• Sherwal J Human Reprod Sci 2010

Obstetrical outcome
15
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 ?
16
The question Is iatrogenic OHSS avoidable
and erasable ?

• Understanding different biological mechanisms
  
• using different drugs
• using different treatment strategies

Devroey et al HR 2011
17
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

18
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
19
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

20
Cycle outcome
Brussels 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
21
GnRH agonist triggering in a GnRH
antagonist cycle
Triggering GnRH agonist 0.2 mg Triptorelin hCG 10 000
Vaginal progesterone
Estradiol valerate
Discontinuation - -
Pregnancy rate 5.6 41.7
Kolibianakis HR 2005
22
GnRH agonist triggering in GnRH antagonist
cycles in OHSS risk

• AIM avoiding OHSS
• Patients (n 12)
• gt 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

23
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
24
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
25
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
26
Oocyte donation using egg cryobanking

• 153 eggs
• 117 fertilized
• 47 blastocysts transferred
• 2.3 per ET
• 26 implanted (55 )
• Nagy FS 2009

27
Oocyte banking (vitrification)
RCT 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 results 95 CI 0.7 1.3 Similar results 95 CI 0.7 1.3 Similar results 95 CI 0.7 1.3 Similar results 95 CI 0.7 1.3
Cobo HR 2010
28
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
29
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
30
Endometrial biopsy on the day of ovulation,
natural cycle
No secretory features
31
Endometrial biopsy on the day of oocyte
retrieval, GnRH agonist and gonadotrophin
stimulation cycle
Clear secretory features
32
Endometrium histology at OPU and the
probability of pregnancy
Author Stimulation Endometrial advancement Endometrial advancement Odds ratio 95 CI P
3 days gt 3 days
Clinical pregnancy rate Clinical pregnancy rate Clinical pregnancy rate Clinical pregnancy rate Clinical pregnancy rate Clinical pregnancy rate 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 Ongoing pregnancy rate Ongoing pregnancy rate Ongoing pregnancy rate Ongoing pregnancy rate Ongoing pregnancy rate 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
33
Advanced endometrial maturation - no
pregnancies

• Upregulated genes
• SERPINB6
• FOXO3A
• SOX17
• CDC42
• Van Vaerenbergh I HR 2009

34
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

35
CODA
OHSS FREE CLINIC AFR segmentation strategy

1. Optimization of stimulation
2. Optimization of embryology
3. Optimization of endometrial implantation
   potential

• GnRH antagonist and GnRH agonist to trigger
• Freeze all oocytes/embryos
• Replacement in receptive endometrium
  (spontaneous or artificial)