Transcript PowerPoint-Präsentation

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 cotreated 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
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
Agonist
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
100%
90%
80%
70%
60%
Agonist
Antagonist
50%
40%
30%
20%
10%
0%
2005
2006
2007
2008
2009
2010
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
60
50
40
30
20
10
2.8
2.7
2.4
2.4
1.5
0
2006
2007
CPR
2008
Mean Tr embryo
2009
2010
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 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
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
200
180
160
140
51%
120
100
80
60
39.1%
40
20
0
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 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
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
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
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
45
40
38.8
36.2
33
35
30
25
20
15
10
5
2.39
2
1.7
0
USA 2009
EU 2007
CPR
Mean Tr Embryo
Turkey 2010