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 GnRH 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: GnRH antagonist and single embryo transfer. Standard: GnRH 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

AgonistAntagonist

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 CyclesCPR/ET Agonist Antagonist Engel, et al., 2006 Tubal infertility - DIR

Normoresponder-Antagonist AgonistAntagonist Patients Gonadotropin usage * Stimulation length269* E2 level Nr of oocytes PR/ET 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 GnRH agonists and antagonists have calculated almost identical odds ratios ( ) 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

Analog use in EUROFERTIL AgonistAntagonist Cycles Age * Mean oocytes * Transferred embryos CPR/ET * P<0.05

CPR in antagonist cycles

LETRAZOL STIMULATION

Milder stimulation HCG OPU US/LH test Letrazol 2.5 mg Indomethasin 50 mg Progesteron

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 GnRH 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 Kadoch, et al.,RBM online 2008 IndomethacinNon-indomethacin Premature ovulation (%)616P=0.02 Oocyte retrieval/cycle (%)7664P=0.04

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

Milder stimulation ( ) Cycle177 Age30,3 # of oocytes1,67 Fertilization rate %70,8 Mean transferred embryos1,27

Milder stimulation

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

40%

Mini IVF Clomiphene citrate 50 mg, beginning on day 3 and continued until the follicles were developed sufficiently for ovulation triggering. 150 IU hMG every 48 h was begun on day 5 or 8 depending on the day-3 FSH concentration. GnRHa (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 cycles done before and 502 cycles done after regulation. All stimulations started at 2nd-3rd day of menstruation used FSH or HMG in dosis IU depends the age and the antral follicle count of the patient. An antagonist were added at the 6th day of stimulation until day of HCG 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 Before legislationAfter legislation Cycle Age30,831,7 Number of oocytes8,86,9* Fertilisation rate %62,867,6* Blastocyste transfer rate %1,516,3* # of transferred embryos2,41,3* SET rate %23,567,4* * P<0.05

Before and after study Before legislationAfter legislation Clinical pregnancy/ET %50,345,0 Multipl pregnancy rate %35,38,8* Kryopreservation/cycles %16,938,0* OHSS rate %5,81,6* Severe OHSS rate %1,80,2* * P<0.05

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

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 cycles

Countries with > cycles Belgium26275 Czech Republic16916 Denmark14067 France66706 Germany62322 Italy43708 Netherlands19699 Russia26983 Spain54620 Sweden15061 Turkey37468 UK46688

Pregnancy rate per transfer IVF ICSI FER ED

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 cycles 127 centers

EUROFERTIL Centers cycles 4 centers

IVF in Turkey IVF cost $ 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