1. PREVENTION OF MULTIPLES FROM A CLINICIAN’S STANDPOINT Bulent Urman M.D. American Hospital of Istanbul

2. TRENDS IN EMBRYO TRANSFER PRACTICE NO LEGAL OR ETHICAL RESTRICTIONS IN THE NUMBER OF TRANSFERRED EMBRYOS FROM SINGLE TO MULTIPLE EMBRYO TRANSFERS PREVENTION OF TRIPLETS AND HOMP PREVENTION OF TWINS EARLY 1980s 1985-1995 1995-2000 2000-TODAY PREGNANCY========HEALTHY BABIES========HEALTHY SINGLE BABY

3. Current Turkish Legislation A maximum of 3 embryos are allowed to be transferred The number can be increased if the clinician feels that it is indicated under special circumstances

4. How many embryos do we actually transfer?

6. Is there a need to change the current policy? Should we decrease the number of transferred embryos?

7. If yes: Questions! Why should we reduce the number of transferred embryos? How is the success of ART affected? SET vs DET Are we ready to do it in Turkey? A proposed national model

8. Factors affecting embryo transfer policy Pressure to be successful Insurance non coverage Pressure form patients-twins are the ideal outcome Implantation rates of the individual center Cryopreservation –Availability –Uptake

10. From Blennborn et al. Hum Reprod 2005 The couple’s decision-making in IVF: one or two embryos at transfer?

11. Probabilities for singleton and multiple pregnancies after in vitro fertilization Peter M. Martin, M.D.,*† and H. Gilbert Welch M.D., M.P.H.†‡ FERTILITY AND STERILITYt VOL. 70, NO. 3, SEPTEMBER 1998

12. Probabilities for singleton and multiple pregnancies after in vitro fertilization Peter M. Martin, M.D.,*† and H. Gilbert Welch M.D., M.P.H.†‡ FERTILITY AND STERILITYt VOL. 70, NO. 3, SEPTEMBER 1998

13. Probabilities for singleton and multiple pregnancies after in vitro fertilization Peter M. Martin, M.D.,*† and H. Gilbert Welch M.D., M.P.H.†‡ FERTILITY AND STERILITYt VOL. 70, NO. 3, SEPTEMBER 1998

14. Probabilities for singleton and multiple pregnancies after in vitro fertilization Peter M. Martin, M.D.,*† and H. Gilbert Welch M.D., M.P.H.†‡ FERTILITY AND STERILITYt VOL. 70, NO. 3, SEPTEMBER 1998

15. Pregnancy and live birth rates after the transfer of 2-3 embryos Number of embryos transferred No of transfer procedures Number of pregnancies PR/ET %Live birth / transfer % Two from only two available 81182220 Two from more than two available 58521336 Three98282928 From Brinsden RBM Online 2003

16. Factors affecting success in IVF Age Tubal infertility Previous IVF outcome Gonadotropin dose –Initial –Total Good quality embryos –Available –Transferred –Cryopreserved From Strandell et al. 2000

17. Is there a subset of couples who would benefit from (no compromise in PR and no twins) from single embryo transfer?

18. Pregnancy rate according to the number of embryos transferred From Zhang et al. 2008

19. Multiple pregnancy rate according to the number of embryos transferred From Zhang et al. 2008

20. From Saldeen and Sundstom Hum Reprod 2005 Results of SET and DET according to embryo morphology

21. Optimal number of embryos to be transferred based on quality From Hu et al. Fertil Steril 1998

22. From Roberts et al. Hum Reprod 2009

23. Cohort studies of SET vs DET StudyCyclesSingle ETDouble ET PR %Twins %PR %Twins % Gerris 2002115235.11/12436.235.6 De Sutter 2003 289828.21/16331.730.4 Tiitinen 2003 149434.52/16236.730.1 Catt 200338544.11/4958.844.1 Gerris 200436740.3040.430.8 Martikainen 2004 111134.71/10731.8NA TOTAL740733.91.035.032.6 From Gerris et al. Hum Reprod Update 2005

24. Prospective evaluation of elective single-embryo transfer versus double-embryo transfer following in vitro fertilization: a two-year French hospital experience From Leniaud et al. Gynecol Obstet Fertil. 2008 Feb;36(2):159-65

25. Randomized trials of SET vs DET StudyCyclesSingle ETDouble ET PR %Twins %PR %Twins % Gerris 1999 5338.5107437 Martikainen 2001 14432.44.147.118.2 Gardner 2004 4860.907647.4 Thurin 2004 66127.61.143.536.1 TOTAL90630.72.147.636.1 From Gerris et al. Hum Reprod Update 2005

26. From Fiddelers et al. Hum Reprod 2006 Single versus double embryo transfer: cost-effectiveness analysis alongside a randomized clinical trial

27. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial From van Monfoort et al. Hum Reprod 2006

29. Better embryo selection? Blastocyst transfer PGS

30. Single vs double blastocyst transfer: randomized trial

31. Papanikolaou, E. et al. N Engl J Med 2006;354:1139-1146

32. A prospective randomized controlled trial of preimplantation genetic screening in the "good prognosis" patient From Meyer et al. Fertil Steril 2008

33. Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis From Kjellberg et al. Hum Reprod 2006

34. Transfer policy in the American Hospital Prior to August 2000 –Up to 3-4 embryos until the age of 39 –5-6 embryos after 40 After August 2000 –Maximum 2 good quality fresh or frozen thawed embryos up to 37 If embryo quality is suboptimal 3 is allowed –Maximum 3 good quality fresh or frozen thawed embryos after 37 If embryo quality is suboptimal 4 is allowed after 40

35. Transfer edilen ortalama embryo sayısı

36. 7300 D3 embryo transferinde klinik gebelik oranları

37. 1100 D5 embryo transferinde klinik gebelik oranları

38. Incidence of singletons, twins, and HOMPs in the American Hospital

39. Number of embryos transferred in view of Efficacy –Implantation and pregnancy rates Side effects –Multiple pregnancies Cost effectiveness –Society resources –Can the system handle increasing multiples?

40. <3030-3435-3940 ve üzeri İyi prognozlu 11-223 Normal prognozlu 222-33 Kötü prognozlu 2-3334 TRANSFER EDİLEBİLİR EMBRYO SAYISI İLE İLGİLİ TÜRKİYE MODELİ ÖNERİSİ

41. İyi prognoz kriterleri İyi yanıt veren kadında ilk ART siklusu Kryoprezervasyon için uygun olan embryoların varlığında selektif embryo transferi yapma olasılığı Doğum ile sonuçlanan ART gebeliği öyküsü 2 veya 3. günde 4 veya 8 hücreli G1 veya G2 embryoların varlığı 5. günde G1 veya G2 blastokistlerin varlığı

42. Kötü prognoz kriterleri 3. veya sonraki ART siklusları Over stimülasyonuna kötü yanıt (3 veya daha az oositin toplandığı durumlar) Kötü kaliteli embryoların varlığı

43. Is the Scandinavian model of SET valid in Turkey Pregnancy and implantation rates in Turkish IVF centers are largely unknown In unselected patients, single embryo transfer decreases twin pregnancy rate but also decreases the pregnancy rate Pregnancy rate is dependent on embryo quality, women's age, rank of IVF attempt and also other variables That is the reason why a flexible policy of transfer adapted to each couple is preferable Each couple and each IVF team must keep the freedom to choose how many embryos must be transferred to obtain healthy babies, and to avoid twin pregnancies

44. CONCLUSIONS Q: Should we prevent multiples? A: Yes Q: Should we decrease the number of embryos we transfer? A: Yes Q: Is IVF the only problem? A: No

45. Conclusions Infertile couples with good prognosis should be encouraged to wait Life style changes improving fertility should be promoted IUI should be considered in the natural cycle. If COH is instituted nor more than 2 follicles should be the aim Mild stimulation protocols for IVF should be adopted Elective SET should be considered in good prognosis couples Transfer policy according to prognostic factors should be adopted

48. Ülkelerde IVF merkezi başına düşen nüfus (x 1000)

49. IVF VE TURKİYE Sektörel sorunlar Etik sorunlar Standardizasyon Denetim Yönetmelikler Başarı Çoğul gebelikler Veri toplama

54. SB VE SGK SORUNLARIMIZA HASSASİYET GÖSTERİYOR MU?

55. TSRM SURVEY ON MULTIPLES AND DATA COLLECTION www.tsrm.org.tr

56. Increasing multiple pregnancies in IVF is an important health issue in Turkey

57. Twin pregnancies significantly increase maternal and fetal morbidity and mortality

58. The allowed number of 3 embryos that can be transferred according to the current legislation is reasonable

59. Decreasing the number of embryos to be transferred from 3 to 2 will prevent triplets without significantly affecting overall pregnancy rates

60. Elective single embryo transfer is an acceptable option in good prognosis couples

61. Single embryo transfer should be mandatory for all couples undergoing their first and second IVF cycle

62. The number of embryos that is allowed for transfer should be variable according to the prognostic factors

63. Decreasing the number of embryos to be transferred from 3 to 2 will prevent triplets without significantly affecting overall pregnancy rates

64. <3030-3435-3940 ve üzeri İyi prognozlu 11-223 Normal prognozlu 222-33 Kötü prognozlu 2-3334 TRANSFER EDİLEBİLİR EMBRYO SAYISI İLE İLGİLİ TÜRKİYE MODELİ ÖNERİSİ

65. The model proposed by the TSRM is logical for our country

66. Who should collect the data?

67. How should the data be collected