Conclusions

1
Prevention of OHSS
S. Kol, May 2006
2
OHSS scope of the problem

• Severe form 0.2-1 of stimulation cycles.
• Mortality 145,00 to 150,000 per infertile
  women receiving gonadotropins.

WHO 2001
3
OHSS 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

4
FS January 2006
Objective to determine OHSS incidence in 2,524
antagonist-based cycles (1801 patients). Results
fifty three patients (2) were hospitalized
because of OHSS. Conclusions 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
5
Morbidity

• 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
6
Past predictions of the future

• We dont 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 142687,
1999. absolute prevention will not be possible
García-Velasco et al FS, March 2006.
7
Accepted preventive strategies

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

8
Coasting

• 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 trialsthere is
  insufficient evidence to determine if coasting is
  an effective strategy for preventing OHSS.

9
IV 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.
10
Cryopreservation

• 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

11
Recombinant LH

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

12
Low 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

13
Severe OHSS will remain a complication of IVF
cycles despite all attempts of prevention. R.G.
Forman, Human Reproduction 142687, 1999.
Total OHSS prevention can only be achieved by
ovulation triggering with a GnRH agonist.
14
The GnRHa-induced LH/FSH surge

• LH and FSH levels rise 4 and 12 hours post
  trigger, respectively.
• LH surge lasts for 24 hours.
• Surge amplitude comparable to physiology.
• A single agonist dose reliably triggers ovulation.

Itskovitz et al 1991
15
Luteal phase

• Normal early follicular-luteal shift in ovarian
  steroidogenesis.
• Short luteal phase early luteolysis.

16
Case-control study(Lewit et al Hum Reprod
111399, 1996)

• 16 patients who developed severe OHSS when hCG
  was given as trigger (group A).
• Each patient underwent at least 1 cycle during
  which GnRH agonist was given as trigger
  (triptorelin 0.2 mg, group B).
• In group B no OHSS!!!

17
Stimulation variables
No. hMG amp No. oocytes E2 max (pmol/l) Group
246 2811 16,9698,948 hCG
214 3614 20,8169,568 GnRH-a
Lewit et al
18
Oocyte quality
Total PB NVS GV Atretic FZ Group
214 180 (84) 10(5) 10(5) 8(4) 6(3) hCG
257 205(80) 7(3) 19(7) 15(6) 11(4) GnRH-a
Lewit et al
19
Limitations

• Prospective study ethical dilemma?
• Not applicable in agonist-based cycles
  unresponsive pituitary.

Use antagonists???
20
Efficacy GnRHa vs hCG for triggering of final
oocyte maturation
Fauser et al, JCEM Feb. 2002, 87709

• 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

21
Protocol
Fauser et al, 2002
22
Clinical outcome (meanSD)
Triptorelin (n17) Leuprorelin (n15) hCG (n15)
Number of oocytes/subject 9.8 5.4 8.7 4.5 8.3 3.3
Proportion of metaphase II oocyte 72 18 85 17 86 17
Fertilization 61 30 62 23 56 18
No. of embryos obtained per subject, grades 1 and 2 pooled 2.7 34 3.2 2.6 3.3 2.0
Implantation rate 15 34 18 37 7 14
Ongoing pregnancy rate 18 20 13
Fauser et al, 2002
23
Serum concentrations of LH (hCG), FSH, E2 and P
Fauser et al, 2002
24
Can this approach prevent OHSS?
25
Human Reproduction, September 2000
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
26
Treatment scheme for high responders
Day 2-3 menses
Day 6 rFSH
High responder - triptorelin 0.2mg
Rec FSH
OPU
ET
ganirelix
Progesterone
27
Stimulation characteristics of 8 women with
increased risk for developing OHSS and who
received 0.2 mg triptorelin for triggering
ovulation Sub. rFSH (IU) Foll?11mm E2
pg/ml Oocytes 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 !!!
a Empty follicle syndrome
28
Results

• Mean no. of folliclesgt11mm25.14.5
• Median E2 (pg/ml)3675 (range 29807670)
• Mean number of oocytes23.4 (15.4), 83 MII
• Mean number of embryos15.46.6
• 7 ETs from fresh embryos 1 pregnancy
• 17 ETs from frozen-thawed embryos 4 pregnancies

Itskovitz et al, 2000
29
Median values of serum LH and E2 after injection
of triptorelin 0.2mg
Time after injection (n8) Serum LH (IU/l) Serum estradiol (pg/ml)
Pre-dose 2.4 4775
0.5 h 12.7 4630
1 h 14.3 4505
2 h 73.7 5080
4 h 219 5540
10-12 h 71.0 6000
Day of OPU 7.9 2375
Day of ET 0.8 963
First week post-ET 1.0 145
Itskovitz et al, 2000
30
Lower levels of inhibin A and pro-alpha C during
the luteal phase after triggering oocyte
maturation with GnRH agonist versus hCG
Mechanism
What is the mechanism of OHSS prevention?

• Nevo et al, Fertil Steril 791123, 2003

31
Clinical characteristics
Nevo et al, 2003
32
Luteal phase
Natural cycle day 7-9 75 pg/ml vs. 18
Natural cycle day 7-9 750 pg/ml vs. 184
Nevo et al, 2003
33
(No Transcript)
34
Evidence-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.

35
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
Connecticut ASRM October, 2005
36
Study Design

• lt 40years, FSH lt 10 with
• PCOS or PCO Morphology
• Or Previous High Response

Randomization
N13
N12
Dual suppression OCPs luprolide HCG trigger
OCPs Ganirelix luprolide trigger
LUTEAL SUPPORT E2 patches 0.1 mg X 3, qod P4 in
oil, 50 mg/day MONITOR E2P4 LEVELS!
37
Engmann et al
38
Incidence of OHSS (April 2006 update)
N27
Plt0.001
N25

Engmann et al
39
Outcome(April 2006 update)
65.4
60
56
60.7
51.9
48.1
37.2

31.7
Engmann et al
40
Agonist n15 hCG n13
oocytes 19.82.5 19.51.9
Mature oocytes 17.72.9 16.42.2
Fertilization rate 57 51
E2 trigger day (pmol/l) 9595996 8081711
Clinical pregnancy 3/15 4/13
Ovarian volume (day of ET, cm3) 421100 846164
OHSS 0/15 4/13
plt0.05
Babayof et al HR May 2006
41
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.

42
The importance of luteal support?
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) 9.8 8.7 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 patches Progesterone 50 IM until 7 W
43
IVF Haifa retrospective data analysis

• 107 high responders, 2004-5
• E2 max (pmol/l)17,2686305
• No. oocytes 307.3
• No. embryos 15.26.5

Fresh ET Thaw ET
n 103 160
Positive ßhCG 25 (24) 75 (47)
Ongoing/delivery 12 (48) 45 (60)
miscarriage 4 (16) 13 (17)
biochemical 9 (36) 17 (23)
44
Endometrial effect of high E2 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

45
Summary

• 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.

46
Thank you
skol_at_rambam.health.gov.il