LIFE AFTER NEW IVF LEGISLATION IN TURKEY Hakan

LIFE AFTER NEW IVF LEGISLATION IN TURKEY Hakan Ozornek, MD EUROFERTIL Istanbul

LIFE AFTER NEW IVF LEGISLATION • New legislation • Mild stimulation • Antagonist • Letrazol • SET • IVF in Europe • IVF in Turkey

New IVF legislation • The new IVF legislation since March 2010 • Patients under 35 the first and second cycles should be transferred single embryo, • All other patients should be transferred maximum double embryo.

Mild stimulation • The administration of low doses (fewer days) of exogenous gonadotrophins in Gn. RH antagonist co-treated cycles, and/or oral compounds (like anti-estrogens, or aromatase inhibitors) for ovarian stimulation for IVF, aiming to limit the number of oocytes obtained to less than eight.

Mild stimulation • Less complex • Less time consuming • Cheaper (making IVF more accessible for a broader patient population) • Reduced chances for complications • Reduced chances for discomfort • Reduced chances for drop-out • Effects on oocyte quality • Effects on endometrial receptivity

Mild vs Standart Mild: Gn. RH antagonist and single embryo transfer. Standard: Gn. RH agonist long protocol along with the transfer of two embryos. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial randomized trial. Heijnen et al. , Lancet, 2007

Mild vs Standart Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Baart et al. , Human Reprod, 2007

ANTAGONIST USE

Advantages of Antagonists • No initial flare up • Shorter treatment duration • Less gonadotrophin consumption • Less clinic attendances • Lower risk of OHSS • No hypooestrogenemic effects • Weight gain, headache, hot flushes, mood changes, vomiting

Agonist Antagonist

Antagonist protocols

Disadvantages of Antagonists Lower pregnancy rates ?

Clinical pregnancy rate (PCOS) Grisinger G, RBM Online, 2006

Clinical pregnancy rate (Poor) Grisinger G, RBM Online, 2006

Normoresponder-Antagonist Tubal infertility - DIR Cycles CPR/ET Agonist 7712 37. 8 Antagonist 1852 36. 1 Engel, et al. , 2006

Normoresponder-Antagonist Patients 109 226 Gonadotropin usage 1800 1350* Stimulation length 26 9* E 2 level 1370 1090 Nr of oocytes 9. 6 7. 9 PR/ET 41. 7 35. 8 The European and Middle East Orgalutran Study Group, 2001

Clinical pregnancy rate Al-Inany HG, RBM Online, 2007

Live Birth Rate

Live birth rate Al-Inany HG, RBM Online, 2007

Live birth rate Al-Inany HG, RBM Online, 2007

Live birth rate Kolibianakis EM, Human Reprod Update, 2006

Live birth rate Kolibianakis EM, Human Reprod Update, 2006

Live birth rate (Gonadotropin type) Kolibianakis EM, Human Reprod Update, 2006

Live birth rate (protocol type) Kolibianakis EM, Human Reprod Update, 2006

Live birth rate (agonist type) Kolibianakis EM, Human Reprod Update, 2006

Live birth rate (antagonist protocol) Kolibianakis EM, Human Reprod Update, 2006

Live birth rate (antagonist type) Kolibianakis EM, Human Reprod Update, 2006

Conclusions • Meta-analyses comparing Gn. RH agonists and antagonists have calculated almost identical odds ratios (0. 82 -0. 86) for the probability of live birth, although the difference was statistically significant in one analysis and not in another. The difference is unlikely to be of clinical significance. • Ovarian stimulation with antagonists co-treatment can provide live birth rates comparable to those achieved with the standart long agonist protocol and has advantages in terms of tolerability and safety.

Analog use in EUROFERTIL 100% 90% 80% 70% 60% 50% Agonist 40% Antagonist 30% 20% 10% 0% Genel Genel

Analog use in EUROFERTIL 2006 -08 Agonist Antagonist Cycles 537 2033 Age 28. 4 31. 5* Mean oocytes 12. 5 9. 7* Transferred embryos 2. 9 2. 6 CPR/ET 43. 7 45. 0 * P<0. 05

CPR in antagonist cycles Genel Genel Genel Genel CPR Genel Mean Tr embryo Genel

LETRAZOL STIMULATION

Milder stimulation Letrazol 2. 5 mg US/LH test HCG OPU 3 4 5 6 7 8 9 10 11 12 13 14 15 Progesteron Indomethasin 50 mg

Indomethacin • A non-steroidal anti-inflammatory drug (NSAID), • Anti-prostaglandin effects. • Inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation. • Athanasiou et al. , (1996) have shown that indomethacin administered at the time of a positive urinary LH can delay follicular rupture. The mechanism of action is probably inhibition of the ‘inflammation’ associated with follicular rupture. • Unlike Gn. RH antagonists it does not inhibit the LH surge.

RBM online 2008

Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin Indomethacin Non-indomethacin Premature ovulation (%) 6 16 P=0. 02 Oocyte retrieval/cycle (%) 76 64 P=0. 04 Kadoch, et al. , RBM online 2008

Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin Kadoch, et al. , RBM online 2008

Milder stimulation (2009 -2010) Cycle 177 Age 30, 3 # of oocytes 1, 67 Fertilization rate % 70, 8 Mean transferred embryos 1, 27

Milder stimulation Genel 51% Genel 39. 1% Genel Cycle Retrieval IVF/ICSI ET CP

Conclusion • SET is a reality in daily life of IVF centers in Turkey and a shift to milder protocols will be expected in next time. • Letrazol + Indomethasin is a not complex and cheap approach with acceptable pregnancy rate. • Especially powerful to reduce the drop out rates due to the stres during stimulation period. • The mentality should be changed from pregnancy rate per cycle to a cumulative pregnancy rate per patient per year.

Modified natural cycle IVF and mild IVF: a 10 year Swedish experience

Modified natural cycle IVF and mild IVF: a 10 year Swedish experience 40%

Mini IVF • Clomiphene citrate 50 mg, beginning on day 3 and continued until the follicles were developed sufficiently for ovulation triggering. • 150 IU h. MG every 48 h was begun on day 5 or 8 depending on the day-3 FSH concentration. • Gn. RHa (nasal spray, nafarelin acetate) was administered to trigger an endogenous LH surge.

54%

SET

Before and after study • All fresh IVF cycles done in Istanbul EUROFERTIL IVF Center between January 2009 – December 2010 • 775 cycles done before and 502 cycles done after regulation. • All stimulations started at 2 nd-3 rd day of menstruation used FSH or HMG in dosis 150 -300 IU depends the age and the antral follicle count of the patient. • An antagonist were added at the 6 th day of stimulation until day of HCG. • 10. 000 IU HCG were given if at least 3 follicles are above 17 mm, except poor responders. • Oocyte retrieval was done 36 hours after HCG injection. • Luteal phase was supported only with Progesteron.

Before and after study Cycle Age Number of oocytes Fertilisation rate % Blastocyste transfer rate % # of transferred embryos SET rate % * P<0. 05 Before legislation 775 30, 8 8, 8 62, 8 1, 5 2, 4 23, 5 After legislation 502 31, 7 6, 9* 67, 6* 16, 3* 1, 3* 67, 4*

Before and after study Clinical pregnancy/ET % Multipl pregnancy rate % Kryopreservation/cycles % OHSS rate % Severe OHSS rate % * P<0. 05 Before legislation 50, 3 35, 3 16, 9 5, 8 1, 8 After legislation 45, 0 8, 8* 38, 0* 1, 6* 0, 2*

Conclusion • Clinical pregnancy rate were decreased slightly but this is not statistically significant. • The posiblity of a cryopreservation was increased that helps to give a better cumulative pregnancy rates. • As an advantage the multiple pregnancy rate reduced dramatically and the iatrogenic side effect ovarian hyperstimulation syndrome (OHSS) were also decreased.

Effect of the new legislation and single-embryo transfer policy in Turkey on assisted reproduction outcomes: preliminary results

Effect of the new legislation and single-embryo transfer policy in Turkey on assisted reproduction outcomes: preliminary results

Why Mild stimulation & SET? • less drug • less side effects (OHSS) • less injection >> less stress • less monitoring >> less clinical visit, no bloodwork • SET >> no multipl pregnancy • reduced cost >> more patient to treat • improved oocyte, endometrium quality >> acceptable pregnancy rate • reduced stress >> less drop out rate >> good cumulative pregnancy rate/patient >> more babies

IVF IN EUROPE (2007)

EIM 2007 Data 32 countries and 1016/1187 (87. 8%) clinics 479 288 cycles

Countries with > 10 000 cycles 2007 Belgium 26275 Czech Republic 16916 Denmark 14067 France 66706 Germany 62322 Italy 43708 Netherlands 19699 Russia 26983 Spain 54620 Sweden 15061 Turkey 37468 UK 46688

Pregnancy rate per transfer 1997 - 2007 2006 2005 2001 1997 IVF 32. 9 32. 4 30. 4 29. 0 26. 1 ICSI 33. 3 33. 0 30. 3 28. 3 26. 4 FER 22. 5 21. 6 19. 3 16. 4 15. 2 ED 46. 3 43. 5 42. 0 33. 4 27. 1

Multiple deliveries During the 11 years of recording (1997 – 2007) Decline in the overall muliple delivery rates from 29. 5 to 21. 3% A +4 -fold reduction in triplet+ delivery rates from 3. 7 to 0. 8%

IVF IN TURKEY (2010)

IVF in Turkey 44. 000 cycles 127 centers

EUROFERTIL Centers 3. 400 cycles 4 centers

IVF in Turkey • IVF cost 2200 - 2400 $ • Medication 1000 $ • State insurance (two cycles) • IVF 800 $ • Medication 800 $ • 90% self payer, 10% insurance covered

IVF in Turkey • Storage of cryopreserved embryos 5 years • Cryopreservation of gametes is possible just for medical reason • No donor • No surrogacy • Marriage required

CPR/cycles Genel Genel Genel Genel USA 2009 EU 2007 CPR Mean Tr Embryo Turkey 2010

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