ohss prevention: yes, we can!
DESCRIPTION
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. Off-Label Product Use. content. OHSS: is it still a problem? No OHSS post agonist trigger! Mechanism? - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/1.jpg)
OHSS PREVENTION: YES, WE CAN !
Shahar Kol, IVF Unit Rambam Health Care Campus, and Faculty of Medicine, Technion, Israel Institute of Technology, February, 2014
![Page 2: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/2.jpg)
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
![Page 3: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/3.jpg)
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.
![Page 4: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/4.jpg)
OHSS: IS IT STILL A PROBLEM?
“We did not have a single case in years.”
![Page 5: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/5.jpg)
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.
![Page 6: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/6.jpg)
Braat et al, 2010
Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen.
![Page 7: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/7.jpg)
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”
![Page 8: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/8.jpg)
HOW TO PREVENT OHSS?
• Agonist trigger is the most effective approach.
![Page 9: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/9.jpg)
PRE-ANTAGONIST ERA
![Page 10: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/10.jpg)
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
![Page 11: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/11.jpg)
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%
![Page 12: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/12.jpg)
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)
![Page 13: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/13.jpg)
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?
![Page 14: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/14.jpg)
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
![Page 15: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/15.jpg)
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
![Page 16: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/16.jpg)
A safe and OHSS-free clinical environment
![Page 17: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/17.jpg)
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
![Page 18: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/18.jpg)
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”.
![Page 19: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/19.jpg)
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.
![Page 20: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/20.jpg)
LUTEAL PHASE – NON-SUPPLEMENTED
• Beckers et al (2003) – very low pregnancy rate.
![Page 21: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/21.jpg)
LUTEAL PHASE – CONVENTIONAL SUPPORT
Not good enough!
![Page 22: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/22.jpg)
LUTEAL PHASE – MODIFIED SUPPORT
Study or SubgroupBabayof, 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)
Events152
16364
64
Total15131233
15218
243
Events281
14474
76
Total13156
3215017
233
Weight5.9%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!
![Page 23: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/23.jpg)
Engmann et al, 2008
LUTEAL PHASE: INTENSIVE E+POHSS high-risk patients
![Page 24: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/24.jpg)
![Page 25: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/25.jpg)
![Page 26: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/26.jpg)
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.
![Page 27: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/27.jpg)
“… 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?...
![Page 28: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/28.jpg)
HCG DOES NOT IMITATE PHYSIOLOGY!
LH surge goes together with FSH surge. Is FSH surge redundant?
Gonen et al 1990
![Page 29: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/29.jpg)
DUAL ROLE OF HCG TRIGGER
• Final oocyte maturation.• Early luteal phase stimulation.• Same dose for both functions?
hCG
![Page 30: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/30.jpg)
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!
![Page 31: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/31.jpg)
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…
![Page 32: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/32.jpg)
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
![Page 33: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/33.jpg)
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
![Page 34: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/34.jpg)
THE ADVANTAGE FOR THE ‘NORMAL RESPONDER’
Kol S, et al. Human Reprod 2011;26:2874–2877
FSH/hMG
AntagonistAgonist
trigger
36 hours
OPU
1500 IU hCG
4 days
1500 IU hCG
ET
![Page 35: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/35.jpg)
Stimulation characteristics and embryology data
Stimulation (days) 9.3 ±2.0GnRH antagonist (days) 3.8 ±0.9FSH (units) 2443 ±925E2 day of trigger (pmol/L) 3764 ±1227P day of trigger (nmol/L) 2.4 ±1.65LH day of trigger (IU/L) 1.9 ±1.3Oocytes 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 ± 86E2 (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
![Page 36: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/36.jpg)
WHAT DO PRACTITIONERS SAY?
Among the five most downloaded papers
![Page 37: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/37.jpg)
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.”
![Page 38: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/38.jpg)
“Agonist triggering is viewed as one of the major advances in ovarian stimulation, with the potential to eliminate OHSS…”
![Page 39: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/39.jpg)
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
![Page 40: OHSS prevention: Yes, we can!](https://reader035.vdocuments.mx/reader035/viewer/2022062305/56816649550346895dd9c2bd/html5/thumbnails/40.jpg)
Thank you