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 DisclosureX No, nothing to disclose

Yes, please specify:

Off-Label Product UseWill 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.

Braat et al, 2010

Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen.

INCIDENCE OF OHSS

F&S 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”

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

OHSS % (n) n Ovulation trigger

Oocyte source

Trial type Reference

0 (0/13)31(4/13)

1513

GnRHahCG

own RCT, high risk Babayof et al 2006

0 (0/33)31 (10/32)

3332

GnRHahCG

own RCT, high risk Engamnn et al 2008

0 (0/30)17 (5/30)

3030

GnRHahCG

donors RCT Acevedo et al 2006

0 (0/1046)1.3 (13/1031)

10461031

GnRHahCG

donors Retrospective Bodri et al 2009

0 (0/40) 40 GnRHa own Observational,High risk

Griesinger et al 2010

0 (0/152)2 (3/150)

152150

GnRHahCG

own RCT Humaidan et al 2009

0 (0/23)4 (1/23)

2323

GnRHahCG

own Retrospective, case-controlled, high risk

Engmann et al 2006

0 (0/42) 42 GnRHahCG - cancelled

own Retrospective case-control, high risk

Manzanares et al 2009

0 (0/254)6 (10/175)

254175

GnRHahCG

donors Retrospective Hernandez et al 2009

0 (0/82)7 (5/69)

8269

GnRHahCG

own Retrospective, high risk

Orvieto et al 2006

0 (0/32)1 (1/42)

3242

GnRHahCG

donors Retrospective, high risk: agonist arm only

Shapiro et al 2007

0 (0/44)7 (3/44)

4444

GnRHahCG

donors RCT Sismanoglu et al 2009

8 (1/12) 12 GnRH, luteal rescue with hCG 1500IU

own Observational, high risk

Humaidan et al 2009

0 (0/106)8 (9/106)

106106

GnRHahCG

donors RCT Galindo et al 2009

0 (0/50)16(8/50)

5050

GnRHahCG

donors RCT Melo at al 2009

0 (0/45)15 (33)

4545

GnRHahCG

own RCT, high risk Shahrokh et al 2010

16 publications

Agonist: 2,005 patients, not a single case of OHSS!

hCG: 92 cases in 1,810 patients, 5.1%

WHAT REALLY WORKS:

Youssef MA, et al. Human Reprod Update 2010;16:459–466

● GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles

Total events 0 (GnRH)21 (hCG)

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

Mechanism of OHSS prevention?

Luteal phase

Nevo et al, 2003

Natural cycle day 7-9=75 pg/ml vs. 18

Natural cycle day 7-9=

750 pg/ml vs. 184

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

Study or Subgroup

Babayof, 2006Humaidan, 2006Pirard, 2006Engmann, 2008Humaidan, 2010Papanikolaou, 2011

Total (95% CI)

Total eventsHeterogeneity: Chi² = 1.35, df = 5 (P = 0.93); I² = 0%Test for overall effect: Z = 1.40 (P = 0.16)

Events

152

16364

64

Total

15131233

15218

243

Events

281

14474

76

Total

13156

3215017

233

Weight

5.9%5.9%3.4%

13.7%63.8%7.4%

100.0%

M-H, Fixed, 95% CI

-0.09 [-0.32, 0.15]-0.15 [-0.51, 0.22]0.00 [-0.37, 0.37]0.05 [-0.19, 0.29]

-0.08 [-0.18, 0.02]-0.01 [-0.29, 0.27]

-0.06 [-0.14, 0.02]

Agonist triggering HCG triggering Risk Difference Risk DifferenceM-H, Fixed, 95% CI

-1 -0.5 0 0.5 1Favours HCG trig Favours Agonist trig

We are getting there!

Engmann et al, 2008

LUTEAL PHASE: INTENSIVE E+P

OHSS high-risk patients

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.

“… 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

…AND WHEN OHSS IS NOT THE MAIN ISSUE?...

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 IVFwe 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. Humaidan P, et al. Reprod Biomed Online 2005;11:679–6842. Humaidan P, et al. Human Reprod 2009;24:2389–23943. Imoedemhe DA, et al. Fertil Steril 1991;55:328–3324. Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5. Eppig JJ. Nature 1979;281:483–4846. Strickland and Beers. J Biol Chem 1976;251:5694–57027. Yding Andersen C. Reprod Biomed Online 2002;5:232–2398. Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–7319. Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

THE ADVANTAGE FOR THE ‘NORMAL RESPONDER’

Kol S, et al. Human Reprod 2011;26:2874–2877

FSH/hMG

Antagonist

Agonist trigger

36 hours

OPU

1500 IU hCG

4 days

1500 IU hCG

ET

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 ± 50Values 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…”

Out In“long agonist” protocols Antagonist-based protocols

hCG trigger Agonist trigger

Progesterone-based luteal support LH activity-based luteal support

~1% severe OHSS Total OHSS elimination

Painful P injections or leaky, messy vaginal P.

Patient friendly luteal phase

Revolution in the making

Thank you