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

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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

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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

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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

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CPR Mean Tr Embryo

Thank you