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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 - PowerPoint PPT Presentation
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LIFE AFTER NEW IVF LEGISLATION IN TURKEY Hakan Ozornek, MDEUROFERTILIstanbul
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 randomisednon-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
ANTAGONİST 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
Cycles CPR/ETAgonist 7712 37.8Antagonist 1852 36.1
Engel, et al., 2006
Tubal infertility - DIR
Normoresponder-AntagonistAgonist Antagonist
Patients 109 226
Gonadotropin usage 1800 1350*
Stimulation length 26 9*
E2 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 GnRH 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
CE665n665l CE665n665l CE665n665l0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
AgonistAntagonist
Analog use in EUROFERTIL 2006-08
Agonist AntagonistCycles 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
CE665n665l CE665n665l CE665n665l CE665n665l CE665n665lCE660n660l
CE660n660l
CE660n660l
CE660n660l CE660n660l CE660n660l CE660n660l CE660n660l
CPR Mean Tr embryo
LETRAZOL STİMULATİON
Milder stimulation
3 4 5 6 7 8 9 10 11 12 13 14 15
HCGOPU
US/LH testLetrazol 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
Indomethacin Non-indomethacinPremature ovulation (%) 6 16 P=0.02
Oocyte retrieval/cycle (%) 76 64 P=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 (2009-2010)
Cycle 177Age 30,3
# of oocytes 1,67
Fertilization rate % 70,8
Mean transferred embryos 1,27
Milder stimulation
Cycle Retrieval IVF/ICSI ET CPCE660n660l
CE660n660l
CE660n660l
39.1%
51%
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 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 2010 • 775 cycles done before and 502 cycles done after regulation. • All stimulations started at 2nd-3rd 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 6th 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
Before legislation After legislationCycle 775 502Age 30,8 31,7Number of oocytes 8,8 6,9*Fertilisation rate % 62,8 67,6*Blastocyste transfer rate % 1,5 16,3*# of transferred embryos 2,4 1,3*SET rate % 23,5 67,4*
* P<0.05
Before and after study
Before legislation After legislationClinical pregnancy/ET % 50,3 45,0Multipl pregnancy rate % 35,3 8,8*Kryopreservation/cycles % 16,9 38,0*OHSS rate % 5,8 1,6*Severe OHSS rate % 1,8 0,2*
* 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
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 Data32 countries and 1016/1187 (87.8%) clinics479 288 cycles
Countries with > 10 000 cycles 20072007
Belgium 26275
Czech Republic 16916
Denmark 14067
France 66706
Germany 62322
Italy 43708
Netherlands 19699
Russia 26983
Spain 54620
Sweden 15061
Turkey 37468UK 46688
Pregnancy rate per transfer 1997 - 2007
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 cycles127 centers
EUROFERTIL Centers
3.400 cycles4 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
USA 2009 EU 2007 Turkey 2010CE660n660l
CE660n660l
CE660n660l
CE660n660lCE660n660l
CE660n660l CE660n660l CE660n660l
CPR Mean Tr Embryo
Thank you