OHSS PREVENTION: YES, WE CAN!
Shahar Kol, IVF Unit Rambam Health Care Campus, and Faculty of
Medicine, Technion, Israel Institute of Technology, February, 2014
Faculty Disclosure
X No, nothing to disclose
Yes, please specify:
Off-Label Product Use
Will you be presenting or referencing off-label or investigational use of a therapeutic product?
No
X Yes, please specify:
The use of GnRH agonists for ovulation triggering in IVF
CONTENT
• OHSS: is it still a problem?
• No OHSS post agonist trigger!
• Mechanism?
• Failures?
• The question of pregnancy rate.
• Agonist trigger: back to physiology.
• Agonist trigger is not the issue, luteal support is.
Meta-analysis should follow.
• A revolution in the making.
OHSS: IS IT STILL A PROBLEM?
“We did not have a single case in years.”
SEVERE OHSS: IS IT STILL A PROBLEM?
“In 2003-2005, 4 deaths (of the 12) were due to OHSS”.
~3 OHSS-related deaths per 100,000 ART cycles.
Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen.
Braat et al, 2010
INCIDENCE OF OHSS
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”
F&S January 2006
HOW TO PREVENT OHSS?
• Agonist trigger is the most effective approach.
PRE-ANTAGONIST ERA
ANTAGONIST ERA
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 .
Itskovitz-Eldor et al. 2000
16 publications
Ovulation
trigger
n
OHSS % (n)
RCT, high risk
Oocyte
source
own
GnRHa
hCG
Engamnn et al 2008
RCT, high risk
own
GnRHa
hCG
Acevedo et al 2006
RCT
donors
GnRHa
hCG
Bodri et al 2009
Retrospective
donors
GnRHa
hCG
Griesinger et al 2010
Observational,
High risk
RCT
own
GnRHa
15
13
33
32
30
30
1046
1031
40
0 (0/13)
31(4/13)
0 (0/33)
31 (10/32)
0 (0/30)
17 (5/30)
0 (0/1046)
1.3 (13/1031)
0 (0/40)
own
GnRHa
hCG
Engmann et al 2006
Retrospective, casecontrolled, high risk
own
GnRHa
hCG
152
150
23
23
0 (0/152)
2 (3/150)
0 (0/23)
4 (1/23)
Manzanares et al 2009
Retrospective casecontrol, high risk
own
GnRHa
hCG - cancelled
42
0 (0/42)
Hernandez et al 2009
Retrospective
donors
GnRHa
hCG
Orvieto et al 2006
Retrospective, high
risk
Retrospective, high
risk: agonist arm only
own
GnRHa
hCG
donors
GnRHa
hCG
254
175
82
69
32
42
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
0 (0/32)
1 (1/42)
Sismanoglu et al 2009
RCT
donors
GnRHa
hCG
Humaidan et al 2009
Observational, high
risk
own
GnRH, luteal rescue
with hCG 1500IU
44
44
12
0 (0/44)
7 (3/44)
8 (1/12)
Galindo et al 2009
RCT
donors
GnRHa
hCG
Melo at al 2009
RCT
donors
GnRHa
hCG
Shahrokh et al 2010
RCT, high risk
own
GnRHa
hCG
106
106
50
50
45
45
0 (0/106)
8 (9/106)
0 (0/50)
16(8/50)
0 (0/45)
15 (33)
Reference
Trial type
Babayof et al 2006
Humaidan et al 2009
Agonist: 2,005 patients,
not a single case of
OHSS!
hCG: 92 cases in 1,810
patients, 5.1%
Shapiro et al 2007
WHAT REALLY WORKS:
● GnRH agonist versus hCG for oocyte triggering in GnRH
antagonist ART cycles
Total events 0 (GnRH)
21 (hCG)
Youssef MA, et al. Human Reprod Update
2010;16:459–466
Mechanism of OHSS prevention?
Lower levels of inhibin A and pro-alpha C during
the luteal phase after triggering oocyte
maturation with GnRH agonist versus hCG
Nevo et al. 2003
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
SUMMARY
• The lower levels of luteal steroidal and
nonsteroidal hormones reflect luteolysis, and may
explain the mechanism of OHSS prevention by
GnRH-a.
• Pregnancy post agonist trigger does not rescue
the CL!!!
Nevo et al, 2003
A safe and OHSS-free clinical environment
FAILURES?
OHSS prevention by GnRH agonist triggering of final oocyte maturation in a
GnRH antagonist protocol in combination with freeze-all strategy: a
prospective multicenter study
• Conclusions: “…a single case of a severe early onset OHSS occurred”
– E2 trigger day=47,877 pmol/L
– 13 oocytes
– The patient was hospitalized on day of OPU, with abdominal
distension, drastically enlarged ovaries (right and left ovarian volume
363 cm2 and 261 cm2, respectively), and lower abdominal pain.
• She received low molecular weight heparin, cabergoline (0.5 mg/d),
and IV infusion therapy, including albumin.
Griesinger G, et al. Fertil Steril 2011;95:2029–2033
FAILURES? (CNT’D)
– “drastic decrease of hemoglobin levels to 4.9 mmol/L”
(8 grams/dL) patient received blood transfusion 2 days
post OPU.
– Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post
blood transfusion.
– 3–4 days post trigger 3.9 litres of “blood-stained ascites
which was indicative of a subacute intraperitoneal
hemorrhage”.
PREGNANCY RATE POST AGONIST TRIGGER
• We showed that agonist trigger causes quick and
irreversible luteolysis.
• Therefore, the right luteal support is crucial.
• The evolution of post agonist luteal support.
LUTEAL PHASE – NON-SUPPLEMENTED
• Beckers et al (2003) – very low pregnancy rate.
LUTEAL PHASE – CONVENTIONAL SUPPORT
Not good enough!
LUTEAL PHASE – MODIFIED SUPPORT
Agonist triggering
Study or Subgroup
HCG triggering
Risk Difference
M-H, Fixed, 95% CI
Events
Total
Events
Total Weight
Babayof, 2006
1
15
2
13
5.9%
-0.09 [-0.32, 0.15]
Humaidan, 2006
5
13
8
15
5.9%
-0.15 [-0.51, 0.22]
Pirard, 2006
2
12
1
6
3.4%
0.00 [-0.37, 0.37]
Engmann, 2008
16
33
14
32
13.7%
0.05 [-0.19, 0.29]
Humaidan, 2010
36
152
47
150
63.8%
-0.08 [-0.18, 0.02]
4
18
4
17
7.4%
-0.01 [-0.29, 0.27]
233 100.0%
-0.06 [-0.14, 0.02]
Papanikolaou, 2011
Total (95% CI)
Total events
243
64
Risk Difference
M-H, Fixed, 95% CI
76
Heterogeneity: Chi² = 1.35, df = 5 (P = 0.93); I² = 0%
Test for overall effect: Z = 1.40 (P = 0.16)
We are getting there!
-1
-0.5
0
0.5
1
Favours HCG trig Favours Agonist trig
LUTEAL PHASE: INTENSIVE E+P
OHSS high-risk patients
Engmann et al, 2008
ALL FREEZE ADVANTAGES
• No OHSS
• Better endometrium in thaw cycles.
• Less ectopic pregnancies in thaw cycles.
• Comparable, or even better, clinical outcome in
thaw cycles.
• Better obstetric outcome?
• Fresh transfer post agonist trigger requires daily
IM injections of progesterone in oil.
…AND WHEN OHSS IS NOT THE MAIN ISSUE?...
“… 42% of those who received hCG reported subjective
complaints (mostly abdominal discomfort), whereas this
percentage was 0% in those who received GnRH agonist to
trigger ovulation.
Cerrillo et al, 2009
HCG DOES NOT IMITATE PHYSIOLOGY!
LH surge goes together with FSH surge. Is FSH surge redundant?
Gonen et al 1990
DUAL ROLE OF HCG TRIGGER
• Final oocyte maturation.
• Early luteal phase stimulation.
• Same dose for both functions?
hCG
Gonadotropin-releasing hormone agonist
versus HCG for oocyte triggering in
antagonist assisted reproductive technology
cycles. 11/2010
 Totally different approaches to luteal support, no common ground
for comparison.
 Agonist triggering is not the issue, individualized luteal support is!
Plain language summary:
“We recommend that GnRH
agonist as a final oocyte maturation
trigger should be not used”.
1985: In view of the poor reproductive outcomes following IVF
we believe there is no indication for further research with IVF for the
treatment of infertile couples…
FURTHER RESEARCH
• Agonist trigger in “empty follicle syndrome”
• Agonist trigger in “egg factor” infertility
• Agonist trigger in repeated IVF failure cases.
• Immature eggs post hCG in face of adequate follicular size on
trigger day.
• hCG-based, P-free luteal support post agonist trigger
NON OHSS-HIGH-RISK PATIENTS: SIDE
BENEFITS
• Agonist trigger: more MII oocytes compared with hCG
trigger1-4
• Potential benefit of FSH surge:5-9
• Promotes LH receptor formation in luteinizing
granulosa cells
• Promotes nuclear maturation (i.e. resumption of
meiosis)
• Promotes cumulus expansion
1.
2.
3.
4.
5.
6.
7.
8.
9.
Humaidan P, et al. Reprod Biomed Online 2005;11:679–684
Humaidan P, et al. Human Reprod 2009;24:2389–2394
Imoedemhe DA, et al. Fertil Steril 1991;55:328–332
Oktay K, et al. Reprod Biomed Online 2010;20:783–788
Eppig JJ. Nature 1979;281:483–484
Strickland and Beers. J Biol Chem 1976;251:5694–5702
Yding Andersen C. Reprod Biomed Online 2002;5:232–239
Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731
Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
THE ADVANTAGE FOR THE ‘NORMAL RESPONDER’
Antagonist
FSH/hMG
Kol S, et al. Human Reprod 2011;26:2874–2877
Agonist
trigger
OPU
36 hours
1500 IU hCG
ET
4 days
1500 IU hCG
Stimulation characteristics and embryology data
Stimulation (days)
9.3 ± 2.0
GnRH antagonist (days)
3.8 ± 0.9
FSH (units)
2443 ± 925
E2 day of trigger (pmol/L)
3764 ± 1227
P day of trigger (nmol/L)
2.4 ± 1.65
LH day of trigger (IU/L)
1.9 ± 1.3
Oocytes retrieved
6.7 ± 2.5
Embryos obtained
3.6 ± 1.7
Embryos transferred
2.9 ± 0.9
Embryos frozen
0.8 ± 1.5
Beta hCG (IU/L)
152 ± 86
E2 (day of pregnancy test, pmol/L)
6607 ± 3789
P (day of pregnancy test, nmol/L)
182 ± 50
Values are mean ± SD
Reproductive outcomes
Positive hCG/cycle, n (%)
11/15 (73)
Clinical ongoing pregnancy, n (%)
7/15 (47)
Early pregnancy loss, n (%)
4/11 (36)
Kol S, et al. Human Reprod 2011;26:2874–2877
WHAT DO PRACTITIONERS SAY?
Among the five most downloaded papers
SURVEY RESULTS:
Triggering of ovulation with GnRH-a in ART:
Worldwide feedback on an emerging new option with great potential
TAKE HOME MESSAGE
“The results of this survey indicate that GnRH trigger is widely used
worldwide and therefore has become part of the standard of care today.
Hence, doctors are entitled to prescribe it just as patients may ask that
this option is considered in their case.”
“Agonist triggering is viewed as one of the major advances in ovarian
stimulation, with the potential to eliminate OHSS…”
Revolution in the making
In
Out
Antagonist-based protocols
“long agonist” protocols
Agonist trigger
hCG trigger
LH activity-based luteal support
Progesterone-based luteal support
Total OHSS elimination
~1% severe OHSS
Patient friendly luteal phase
Painful P injections or leaky, messy
vaginal P.
Thank you