1. Mild stimulation Filippo Maria Ubaldi Filippo Maria Ubaldi M.D. M.Sc. CLINICA VALLE GIULIA, Rome www.generaroma.it 3° Congress of Society of Reproductive Medicine Antalya 5-9 October 2011

2. Introduction www.generaroma.it About 50% of patients who initiate IVF, will not conceive partially due to the high drop-out rates: 25% of patients who fail first IVF cycle will refrain from further cycles. (Osmanagaoglu, 1999; Stolwijk 2000) (Osmanagaoglu, 1999; Stolwijk 2000) High costs Poor prognosis (Goverade, 2000) Stress and side effects as- sociated with the treatment itself (Olivius, 2004)

3. Human Reproduction Human Reproduction vol. 11 no. 5 pp. 917-919, 1996 Time to revolutionize ovarian stimulation EDITORIAL Edwards o Felberbaum Hum Reprod 1998 o Olivennes Hum Reprod 1998 “friendly stimulation” Human Reproduction Human Reproduction vol. 14 no. 11 pp. 2661-2666, 1999 EDITORIAL Minimal ovarian stimulation for IVF: appraisal for potential benefits and drawbacks Bart C.J.M. Fauser, Paul Devroey, Roger Gosden, William F. Crowley Jr., David T. Baird and Philippe Bouchard Approximately 25% of patients refrain from a second attempt after a first unsuccessful IVF cycle (Devroey, unpublished observations), even where the costs are

4. Introduction www.generaroma.it Patient-friendly stimulation protocols may involve: (Edwards, 1996, 1997; Fauser, 1999; Macklon, 2000; (Edwards, 1996, 1997; Fauser, 1999; Macklon, 2000; The European Orgalutran Study Group, 2000) The European Orgalutran Study Group, 2000) o Less emotional stress o Less injections and monitoring o Less abdominal discomfort o Less short-term (OHSS) and long-term complications o Reduced costs

5. Introduction www.generaroma.it Patient-friendly stimulation protocols may: (Eijnen, 2004) (Eijnen, 2004) o Reduce drop-outs o Increase the overall number of cycle per patients o Increase the overall birth rates

6. Introduction www.generaroma.it Heijnen, Lancet 2007 Mild vs standard protocol: non inferiority trial The drop-out rate for mild stimulation was 5,1% after the first cycle and 11,2% after the second compared with 9,1 and 19,5% for standard treatment. The drop-out rate per cycle was significantly lower in the mild treatment group than in the standard group (OR 0,53, 95% CI 0,2-0,9, p=0,04)

7. Introduction www.generaroma.it Heijnen, Lancet 2007 High scores represent high anxiety, depression and phisical discomfort

8. Introduction www.generaroma.it Heijnen, Lancet 2007 Mild vs standard protocol: non inferiority trial …the reduced number of oocytes obtained after mild ovarian stimulation, may impair outcome? mild ovarian stimulation, may impair outcome? (Fauser, 1999) (Fauser, 1999)

9. www.generaroma.it A Randomized Comparison of Two Ovarian Stimulation Protocols with Gonadotropin-Releasing Hormone (GnRH) Antagonist Cotreatment for in Vitro Fertilization Commencing Recombinant Follicle-Stimulating Hormone on Cycle Day 2 or 5 with the Standard Long GnRH Agonist Protocol 0013-7227/03/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 88(1):166-173 The Journal of Clinical Endocrinology & Metabolism 88(1):166-173 Copyright 2003 by the Endocrine Society FEMKE P. HOHMANN, NICHOLAS S. MACKLON, AND BART C.J.M. FAUSER Division of Reproductive Medicine, Department of Obstetrics and Gynaecology (F.P.H., N.S.M., B.C.J.M.F.), Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands Group A: Long 21 GnRH agonist r-FSH hCG Group C: Day 5 FSH GnRH antagonist r-FSHhCG Leading follicle > 14 mm Group B: Day 2 FSH r-FSH GnRH antagonist hCG Leading follicle > 14 mm

10. Introduction www.generaroma.it Long 21 agonist Day 2 rFSH+ant Day 5 rFSH+ant 100 80 60 40 20 0 N = % of women 84 63 73 383531 % oocyte retrieval per started cycle per started cycle P = 0.02 22 2020 101010 % pregnant % pregnant per started cycle per started cycle P = 0.96 68 90 71 262528 % ET per % ET per oocyte retrieval oocyte retrieval P = 0.04 39 36 40 101010 % pregnant % pregnant per ET per ET P = 0.95 Hohmann, JCEM 2003

11. Embrionic chromosomal competence www.generaroma.it Milder stimulation protocols may result in selection of good quality oocytes, which may result in better quality embryos Embryonic chromosomal competence ?

12. Mild vs conventional protocol: embryonic chromosomal competence www.generaroma.it Baart et al, 2007

13. Mild vs conventional protocol: embryonic chromosomal competence www.generaroma.it 20 16 10 8 4 0 Average number 2 6 12 14 ConventionalMild 18 Oocytes Normal embryos Baart et al, 2007 P < 0,01 Embryos P = 0,03

14. Mild vs conventional stimulation protocols: embryonic chromosomal competence www.generaroma.it Baart, Hum Reprod 2007 MILD PROTOCOL: significant negative correlation between the number of oocytes obtained and the morphological score of the embryos and the percentage of the euploid embryos % abnormal embryos sup- ports the physiological concept of natural selection of oocytes during follicular development

15. Costs www.generaroma.it Polinder, 2008 Mild vs standard protocol: medical costs/cycle Medication costs: 40%-50% of the IVF costs/cycle

16. Study design www.generaroma.it Retrospective study comparing long luteal GnRH-a protocol with mild GnRH antagonist protocol Patients < 40 y with serum basal FSH < 12 mUI/mL who underwent OPU from sept. 2007 to sept. 2008 Main outcomes: clinical pregnancy and impalntation rates, days of stimulation, IU of gonadotropins used, IU of gonadotropins/clinical pregnancy

17. Study design www.generaroma.it Long luteal GnRH-a protocol: Suprefact s.c. 0,2 ml twice daily from mid luteal phase to menstrual cycle than 0,05 ml s.c. twice daily hCG. From cycle day 3, if the ovaries were ”basal”, ovarian stimualtion was started with a patient taylored dose GnRH agonist r-FSH hCG Day 21 menses

18. Study design www.generaroma.it Mild GnRH-antagonist protocol: Ultrasound performed on cycle day 2-3: if the ovaries were “basal” with follicles <8-10 mm, ovarian stimula- tion was started on day 4 with a patient taylored dose. GnRH-antagonist was started when the leading follicle was 14-15 mm with serum LH<10 mIU/mL menses GnRH antagonist r-FSH hCG Leading follicle > 14 mm day 4 US

19. Results www.generaroma.it Antag Long 84 162 76 156 36,8+3,0 34,7+3,7 8,5+2,1 8,1+2,2 OPUET Age (mean+sd) FSH (mean+sd)

20. Antag Long 8,8+1,3 11,3+1,8 3,3+0,8 23,0+2,9 1841,4+649 2464,3+993 Days of stimulation Days of analog IU of gonadotropin Results www.generaroma.it

21. (Hohmann, JCEM 2003) Results (Hohmann, JCEM 2003) www.generaroma.it 6 8 10 12 14 Days of r-FSH stimulation 1200 1500 1800 2100 900 Total r-FSH dose (IU/cycle) n = 38 Long 21 agonist n = 35 Day 2 Day 2antagonist n = 31 Day 5 Day 5antagonist P < 0.001

22. Results www.generaroma.it Antag Long 30/79 (38) 71/156 (45) 41/185 (22) 94/405 (23) 0/84 (0) 2/162 (1) Clinical preg. rate/ET Implantation rate OHSS rate

23. IU gonadot./clinical pregnancy Results : IU gonadot./clinical pregnancy www.generaroma.it Antag (30) Long (71) Antag (30) Long (71) IU of gonadotropins / clinical pregnancy 54144849 € /clinical pregnancy 27693200 CI 95% 2971 3200 2881 2656

24. Results: cost saving/clinical pregnancy www.generaroma.it 2769 3200 2769 3200 € / clinical pregnancy Antag Long Difference (€) 431 The mean cost saving of 431 € / clinical pregnancy allows 1 additional preg. for every 6,5 pregnancys

25. Antag Long 6,3+3,6 9,1+4,9 5,0+3,1 6,9+3,5 192/222 (86) 413/472 (87) N. of oocytes N. of MII oocytes Fertilization rate (%) Results www.generaroma.it

26. Antagonist vs Long protocol www.generaroma.it Cumulative pregnancy rate ?

27. Oocyte vitrification: cumulative pregnancy rate www.generaroma.it

28. 69/120 = 57,5% ongoing pregnancy rate www.generaroma.it Oocyte vitrification: cumulative pregnancy rate

29. Study design www.generaroma.it All patients < 40 y with serum basal FSH < 11 mUI/mL who underwent OPU from sept. 2009 to may 2009 Main outcomes: clinical and ongoing pregnancy and im- plantation rates with fresh oocytes, cumulative ongoing pregnancy rate after ICSI with vitrified-warmed oocytes

30. Materials and Methods www.generaroma.it Antag Long 155 234 38 35 13 8 104 191 37 (35%) 124 (65%) All OPU > 40 y FSH > 12 OPU Cycle with vitrification P<0.0001

31. Results www.generaroma.it Antag Long 104 191 36,2+3,3 35,2+3,9 8,2+2,9 8,1+2,6 OPU Age (mean+sd) FSH (mean+sd)

32. Antag Long P 7,8+3,4 10,8+4,1 <0.01 6,0+2,9 8,2+2,9 <0,05 234/275 (85) 439/502 (87) N. of oocytes N. of MII oocytes Fertilization rate (%) Results www.generaroma.it

33. Results www.generaroma.it Antag Long 2,2+0,6 2,4+0,5 1,5+1,0 1,6+0,8 149/217 (69) 276/422 (65) N. embryo transferred Type A embryo (mean) Type A embryo rate (%)

34. Results (fresh cycles) www.generaroma.it Antag Long 34/95 (36) 70/169 (41) 27/95 (29) 59/169 (34) 47/217 (22) 104/422 (24) Clinical preg. rate/ET Ongoing preg. rate/ET Implantation rate

35. Antag Long P 27/95 (29) 59/169 (34) 5/18 (25) 21/71 (28) 5/18 (25) 21/71 (28) 32/95 (34) 80/169 (47) 0,04 Ongoing preg. rate /ET fresh (%) Ongoing preg. rate /vitrified-warmed (%) Ongoing preg. rate /ET fresh+vitrified (%) Results (fresh+vitrified ET) www.generaroma.it

36. Antag Long P 32/95 (34) 80/169 (47) 0,04 9 (3) 17 (6) 9 (3) 17 (6) 35/95 (37) 86/169 (51) 0,03 Ongoing preg. rate /ET fresh+vitrified (%) Cycles with vitrified oocytes not yet war- med and not pregnant (expected pregnancies) Total (%) Results (fresh+vitrified ET) www.generaroma.it

37. Conclusions www.generaroma.it Milder protocol reduces the number of days of stimulation, the amount of gonadotropins and the discomfort for the pa- tients improving the drop-out rate Comparable clinical outcome per cycle between mild and standard protocol with reduced medication costs per gesta- tional sac and per clinical pregnancy with mild protocol In good prognosis patients cumulative pregnancy rate using vitrified warmed oocytes is significantly higher with standard protocol. Prospective randomized trials are warrented

38. La crioconservazione nelle azoospermie www.generaroma.it Thank you for your attention

39. CLINICA VALLE GIULIA, Roma SALUS, Marostica (VI) GENERA, Umbertide (PG) www.generaroma.it Ginecologia: Filippo Ubaldi Elena Baroni Antonio Ciconte Silvia Colamaria Fabrizio Fiorini A. Giallonardo Madda Giuliani Fabio Sapienza Mauro Schimberni Silvia Venanzi Embriologia: Laura Rienzi Stefania Romano Roberta Maggiulli Laura Albricci Antonio Capalbo Nicoletta Barnocchi Benedetta Iussig Sara Fusco Federica Sanges Catello Scarica Elena Ievoli