OHSS Should this be treated or be prevented

OHSS Should this be treated or be prevented? When to cancel a cycle? All cycles should be triggered with Gn. RH agonist and not by h. CG! Shahar Kol, IVF Unit Rambam Health Care Campus and Macabbi Health Services, Haifa, Israel November, 2011

Content How do we routinely trigger ovulation? Is it in agreement with physiology? Do we have other options? The physiology of agonist trigger. Agonist trigger main advantage: OHSS-free clinic. No need to cancel cycles, ever. • The advantage of agonist trigger for the “normal responder”. • • •

How do we routinely trigger ovulation ? • We have only one option: h. CG.

Is it in agreement with physiology? • Adequate final oocyte maturation. • Early luteal phase over-stimulation – main reason for luteal phase defect in IVF. * • No FSH surge. h. CG *Fauser and Devroey, 2003

Do we have other options? JCEM 2001

15, 000+10, 000 IU gave 20% live birth rate but with a 12% OHSS rate.

The physiology of agonist trigger. LH surge Humaidan et al, 2011

The physiology of agonist trigger. FSH surge Gonen et al, 1990

Does it make a difference? (1) • Agonist trigger: more MII oocytes compared with h. CG trigger. Humaidan et al, 2005, 2009 Imoedemhe et al, 1991 Octay et al, 2009

Does it make a difference? (2) The pregnancy rate in completed cycles and the ongoing pregnancy rate per ET were significantly higher in the study group (dual trigger) than in the control group (h. CG only). F&S 2008 Is it possible that in some patients FSH surge is needed?

Does it make a difference? (3) The effect of adding 450 IU of FSH to the h. CG trigger. Lamb et al, 2011

What happens after agonist trigger? Complete luteolysis! Induction of LH surge and oocyte maturation by Gn. RH analogue (Buserelin) in women undergoing ovarian stimulation for IVF “No signs of OHSS were observed in 2 patients who on previous stimulation developed severe OHSS… Gn. RHa offers a new means by which OHSS can be prevented. ” Itskovitz et al, Gynecological Endocrinology 1988, 2: Suppl 1, 165.

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

“agonist trigger provides a safe and OHSS-free clinical environment”

Agonist trigger main advantage: OHSS-free clinic. No need to cancel cycles, ever. “The utilization of Gn. RH agonist for triggering ovulation in antagonist cycles has been a breakthrough in the elimination of OHSS. ”

16 publications Ovulation trigger n OHSS % (n) RCT, high risk Oocyte source own Gn. RHa h. CG Engamnn et al 2008 RCT, high risk own Gn. RHa h. CG Acevedo et al 2006 RCT donors Gn. RHa h. CG Bodri et al 2009 Retrospective donors Gn. RHa h. CG Griesinger et al 2010 Observational, High risk RCT own Gn. RHa 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 Gn. RHa h. CG Engmann et al 2006 Retrospective, casecontrolled, high risk own Gn. RHa h. CG 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 Gn. RHa h. CG - cancelled 42 0 (0/42) Hernandez et al 2009 Retrospective donors Gn. RHa h. CG Orvieto et al 2006 Retrospective, high risk: agonist arm only own Gn. RHa h. CG donors Gn. RHa h. CG 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 Gn. RHa h. CG Humaidan et al 2009 Observational, high risk own Gn. RH, luteal rescue with h. CG 1500 IU 44 44 12 0 (0/44) 7 (3/44) 8 (1/12) Galindo et al 2009 RCT donors Gn. RHa h. CG Melo at al 2009 RCT donors Gn. RHa h. CG Shahrokh et al 2010 RCT, high risk own Gn. RHa h. CG 106 50 50 4 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: 2005 patients, not a single case of OHSS! h. CG: 92 cases in 1810 patients, 5. 1% Shapiro et al 2007

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

Hyper-responder: How to prevent OHSS + good clinical outcome? • Trigger with agonist. • Intensive luteal support.

OHSS high risk patients Randomization N=32 N=34 Dual suppression OCP’s & luprolide OCP’s + Ganirelix HCG trigger luprolide trigger Engmann, et al, 2008 LUTEAL SUPPORT: E 2 patches 0. 1 mg X 3, qod P 4 in oil, 50 mg/day; MONITOR E 2+P 4 LEVELS!

Engmann et al, 2008

How high can we go?

The advantage for the “normal responder” antagonist FSH/h. MG Agonist trigger OPU 36 h 1, 500 IU h. CG ET 4 days 1, 500 IU h. CG

Kol et al 2011

”The granulosa/luteal cells obtained on the day of oocyte retrieval after agonist trigger have the capacity to respond to h. CG by increasing the secretion of steroids. ” Engmann et al, 2011

Crystal ball: where are we heading? In Out Antagonist-based protocols “long agonist” protocols Agonist trigger h. CG trigger LH activity-based luteal support Progesterone-based luteal support Total OHSS elimination ~1% severe OHSS Total OHSS elimination OHSS-related death rate: 3: 100, 000 Patient friendly luteal phase Painful P injections or leaky, messy vaginal P. Thank you