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Prevention of OHSS Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012.

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Presentation on theme: "Prevention of OHSS Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012."— Presentation transcript:

1 Prevention of OHSS Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012

2 Content ●Scope of the problem ●Preventive strategies ●What really works ●Physiology of the agonist trigger ●Side benefits

3 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 Year Deaths 95% CI Number of treatment cycles NumberRate 1997– – , – – , – – ,080 * Source Human Fertilisation and Embryology Authority Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005

4 Three OHSS-related deaths (3:100,000), all had their embryos frozen Braat DDM, et al. Hum Reprod 2010;25:1782–1786

5 Incidence and prediction of OHSS in women undergoing GnRH antagonist IVF cycles ●2524 antagonist-based cycles (1801 patients) ●53 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 ” Papanikolaou EG, et al. Fertil Steril 2006;85:112–120

6 Preventive strategies: coasting ●There was no evidence to suggest any benefit of withholding gonadotrophins (coasting) after ovulation in IVF for the prevention of OHSS D’angelo A, et al. Cochrane Database Syst Rev 2011;(6):CD

7 ●There is not enough evidence to show whether using frozen embryos …can reduce OHSS in women who are at high risk D’angelo A and Amso N. Cochrane Database Syst Rev 2007;(3):CD Preventive strategies: cryopreservation

8 ●Intravenous (iv) colloid fluids … at the time of oocyte retrieval may be beneficial for women with a high risk of developing OHSS ●Borderline evidence of benefit with the routine use of human albumin in the prevention of OHSS (1660 patients) ●Good evidence to support the use of hydroxyethyl starch in the prevention of OHSS (487 patients) Youssef MA, et al. Cochrane Database Syst Rev 2011; (2): CD Preventive strategies: intravenous albumin

9 ●1199 patients ●IV albumin does not appear to reduce the occurrence of severe OHSS Venetis CA, et al. Fertil Steril 2011; 95:188–196,196.e1–3 IV albumin for the prevention of severe OHSS: a systemic review and meta-analysis

10 Preventive strategies: recombinant LH European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618

11 ●15, ,000 IU gave 20% live birth rate but with a 12% OHSS rate Treatment arm5000 IU15,000 IU30,000 IU15, ,000 IU p (linearity) Parameters examined rhLH (n=39) u-hCG (n=34) rhLH (n=39) u-hCG (n=41) rhLH (n=26) u-hCG (n=22) rhLH (n=25) u-hCG (n=24) No. of follicles >10 mm14.03 ± ± ± ± ± ± 4.90 aa No. of oocytes retrieved10.23 ± ± ± ± ± ± 5.70 aa Oocytes in metaphase II85.5%77.8% 90.8%88.6%57.6%84.5% aa No. of oocytes inseminated9.82 ± ± ± ± ± ± 5.74 aa No. of embryos5.42 ± ± ± ± ± ± 5.19 aa No. of embryos transferred2.39 ± ± ± ± ± ± 0.73 aa Implantation rate6.0 ± 0.16%15.0 ± 0.31% 6.0 ± 0.19%9.0 ± 0.24%11.0 ± 0.26%3.0 ± 0.09%19.0 ± 0.33%17.0 ± 0.33% Pregnancy (total)15.4% (n=6)26.5% (n=9) 10.3% (n=4)24.4% (n=10)23.1% (n=6)13.6% (n=3)32.0% (n=8)37.5% (n=9) Clinical pregnancy10.3% (n=4)23.5% (n=8) 7.7% (n=3)14.6% (n=6)15.4% (n=4)13.6% (n=3)28.0% (n=7)25.0% (n=6) Live birth5.1% (n=2)17.6% (n=6)7.7% (n=3)12.2% (n=5)15.4% (n=4)4.5% (n=1)20.0% (n=5)16.7% (n=4) Cryopreserved embryos 4.42 ± ± ± ± ± ± ± ± Cryopreserved embryos transferred 3.42 ± ± ± ± ± ± ± ± Pregnancy from cryopreserved embryos (total) 16.7% (n=2/12) 0.0% (n=0/9) 50.0% (n=5/10) 27.3% (n=3/11) 62.5% (n=5/8) 33.3% (n=2/6) 0.0% (n=0/2) 0.0% (n=0/8) b Clinical pregnancy from cryopreserved embryos 8.3% (n=1/12) 0.0% (n=0/9) 40.0% (n=4/10) 27.3% (n=3/11) 50.0% (n=4/8) 16.7% (n=1/6) 0.0% (n=0/2) 0.0% (n=0/8) b Live birth from cryopreserved embryos 8.3% (n=1/12) 0.0% (n=0/9) 30.0% (n=3/10) 18.2% (n=2/11) 12.5% (n=1/8) 0.0% (n=0/6) 0.0% (n=0/2) 0.0% (n=0/8) b a The IVF data of days u-hCG/rhLH 0–4 of patients from group 15, ,000 IU were pooled with those from group 15,000 IU b Because the numbers were small, no statistical comparison was performed on these data European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618

12 Preventive strategies: lowering hCG dose ●Reducing the dose of hCG does not eliminate the risk of OHSS in a high-risk group Schmidt DW, et al. Fertil Steril 2004;82(4):841–846

13 Youssef MA, et al. Human Reprod Update 2010;16:459–466 Preventive strategies: dopamine agonists OHSS incidence OHSS severity

14 Youssef MA, et al. Human Reprod Update 2010;16:459–466 What really works: ●GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles

15 16 publications Agonist: 2005 patients, not a single case of OHSS! hCG: 92 cases in 1810 patients, 5.1%

16 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” –E 2 trigger day=47,877 pmol/L –13 oocytes –“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” Griesinger G, et al. Fertil Steril 2011;95:2029–2033 Failures?

17 The physiology of agonist trigger 1.Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print); 2.Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922 LH surge 1 FSH surge 2

18 What happens after agonist trigger? Complete luteolysis! Luteal phase Natural cycle Day 7–9 = 75 pg/mL vs 18 Natural cycle Day 7–9 = 750 pg/mL vs 84 Nevo O, et al. Fertil Steril 2003;79:1123–1128

19 How to secure good clinical outcome post agonist trigger? ●High risk fresh transfer: intensive E 2 +P luteal support ●High risk: ‘freeze-all’ ●Low risk: luteal rescue based on LH activity

20 Luteal phase: intensive E+P OHSS high-risk patients Study groupControl groupOdds ratio (95%CI)p value Primary end points OHSS (ITT) Total, n (%)0/33 (0)10/32 (31.3)0 (0–0.26) a <0.01 Moderate/severe, n (%)0/33 (0)5/32 (15.6)0 (0–0.74) a 0.02 OHSS (PP) Total, n (%)0/30 (0)10/2 (34.5)0 (0–0.26) a <0.01 Moderate/severe, n (%)0/30 (0)5/29 (17.2)0 (0–0.73) a 0.02 Secondary end point (PP) Implantation rate, n (%)22/61 (36)20/64 (31)1.18 (0.52–2.65)0.69 Other end points (PP) Positive pregnancy, n (%)19/30 (63.3)18/29 (62.1)1.06 (0.37–3.0)0.92 Clinical pregnancy rate, n (%)17/30 (56.7)15/29 (51.7)1.22 (0.4–3.4)0.45 Ongoing pregnancy rate, n (%)16/30 (53.3)14/29 (48.3)1.22 (0.4–3.4)0.45 a The estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat; PP=per protocol Engmann L, et al. Fertil Steril 2008;89:84–91

21 Modified luteal support post agonist trigger 1500 IU hCG administered at oocyte retrieval rescues the luteal phase when GnRH agonist is used for ovulation induction: a prospective, randomized, controlled study ●305 patients ●No significant differences were seen regarding: –Positive hCG/ET rate (48 and 48%) –Ongoing pregnancy rate (26 and 33%) –Delivery rate (24 and 31%) –Rate of early pregnancy loss (21 and 17%) –Between the GnRHa and 10,000 intrauterine hCG groups, respectively Humaidan P, et al. Fertil Steril 2010;93:847–854

22 Tailored luteal phase support GnRHa/hCG hCG Patients, n Rate of transfer, n (%)110/125 (88)116/141 (82) Embryos transferred, mean1.3 IR49/158 (36)43/145 (30) Pos hCG per ET, n (%)47/110 (43)41/116 (35) Clinical pregnancy per patient, n (%)43/125 (34)40/141 (28) Ongoing pregnancy per patient, n (%)37/125 (30)36/141 (26) Humaidan P, et al. personal communication Patients with ≤14 follicles ≥12 mm on day of trigger GnRHa IU hCG x 2, versus 5000 IU hCG, both groups E 2 +P luteal support.

23 Side benefits ●Agonist trigger: more MII oocytes compared with hCG trigger 1-4 ●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;11:679–684 2.Humaidan P, et al. Human Reprod 2009;24:2389– Imoedemhe DA, et al. Fertil Steril 1991;55:328–332 4.Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5.Eppig JJ. Nature 1979;281:483–484 6.Strickland and Beers. J Biol Chem 1976;251:5694– Yding Andersen C. Reprod Biomed Online 2002;5:232–239 8.Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731 9.Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

24 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

25 Stimulation characteristics and embryology data Stimulation (days)9.3 ± 2.0 GnRH antagonist (days)3.8 ± 0.9 FSH (units)2443 ± 925 E 2 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 retrieved6.7 ± 2.5 Embryos obtained3.6 ± 1.7 Embryos transferred2.9 ± 0.9 Embryos frozen0.8 ± 1.5 Beta hCG (IU/L)152 ± 86 E 2 (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

26 “The concept of an OHSS-Free Clinic has become a reality. This approach should include pituitary down-regulation using a GnRH antagonist, ovulation triggering with a GnRH agonist and vitrification of oocytes or embryos” “…luteal phase supplementation with low-dose hCG has to be fine tuned.” Devroey P, et al. Human Reprod 2011; 26: 2593–2597

27 Crystal ball: where are we heading? Thank you OutIn ‘Long agonist’ protocolsAntagonist-based protocols hCG triggerAgonist trigger Progesterone-based luteal supportLH activity-based luteal support 1–2% severe OHSSTotal OHSS elimination OHSS-related death rate: 3:100,000Total OHSS elimination Painful P injections or leaky, messy vaginal P Patient-friendly luteal phase


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