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IVF’te GnRH Antagonistleri: Dikkat Edilmesi Gereken Konular
Prof. Dr. Tayfun BagisAcıbadem University
Meta-analyses of GnRH Antagonistsvs GnRH Agonists: Pregnancy Outcomes
The 2 studies had different results for pregnancy outcomes
*Live birth rate included ongoing pregnancies (Al-Inany) or calculated rates (Kolibianakis).OR = odds ratio.1. Al-Inany et al. Cochrane Database Syst Rev. 2006;3:CD001750.2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Al-Inany1 Kolibianakis2
OR 0.82 0.86
95% CI 0.69-0.98 0.72-1.02
P value 0.03 0.085
Live Birth Rate* in Meta-analyses,GnRH Antagonists vs GnRH Agonists
Differences in Study Design/Data Handling May Have Affected Results of Meta-analyses of GnRH Antagonists vs GnRH Agonists
3,1763,865Total patients
Live birth rate* (All 22 studies included;
in 12/22 studies, live births estimated)
Ongoing pregnancy or live birth rate
(Only 15 studies evaluable, n=2,973)
Primary outcome
2227No. of studies included
Dec 2005Feb 2006Last date searched
Kolibianakis2Al-Inany1Characteristic
NoYesIncluded non–peer-reviewed data
*Ongoing pregnancies were converted to live birth equivalents. Live births = 84% of number viable at week 7 or 92% of number viable at week 12 of gestation.1. Al-Inany et al. Cochrane Database Syst Rev. 2006;3:CD001750.2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
NoYesIncluded studies on IUI
IUI = intrauterine insemination.
Meta-analyses Confirm That GnRH Antagonists Have a Better Safety Profile vs GnRH Agonists
Al-Inany1 Kolibianakis2
Duration of analog treatment
−20.90 days(95% CI −22.20, −19.60)
−19.48 days(95% CI −21.05, −17.91)
Duration of ovarian stimulation
−1.54 days(95% CI −2.42, −0.66; P=0.0006)
−1.13 days(95% CI −1.83, −0.44)
Risk ofsevere OHSS
OR 0.61(95% CI –0.42, 0.89; P=0.01)
RR 0.46*(95% CI 0.26, 0.82; P=0.01)
Interventionsto prevent OHSS
OR 0.44(95% CI 0.21, 0.93; P=0.03)
*For every 59 women treated with a GnRH agonist vs GnRH antagonist, 1 additional case of severe OHSS will occur.RR = risk ratio.1. Al-Inany et al. Cochrane Database Syst Rev. 2006;3:CD001750.2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Kolibianakis2
LH rise OR 8.27(95% CI 3.82-17.90)
LH surge OR 4.05(95% CI 1.53-10.72)
2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Siklus öncesi problemler
Estrogen Progesteron
Senkronizasyon (oosit sayısı)Fleksibilite (hafta sonu plan)
OKS
Does the efficacy of GnRH antagonists change with contraceptive pill pre-treatment?
OCP pre-treatment
Rate difference in ongoing pregnancy per woman:
-5% (95% CI: -10 to -1), p = 0.02
1. Griesinger et al. Fertil Steril. 2008:90;1055-1063.2. Update Griesinger et al. submitted
Siklus başındaki problemler
Gn ne zaman başlanmalı (2-3)?Korpus luteum rescue (P4 yüksekliği)
D2 P4 ölçümü
Problems at the beginning of cycle.Cycle day 2
Transvaginal US + (if desired) hormonal profile
Ongoing PR Normal-P
groupHigh-P group
P
Per started cycle
31.8 (124/390)
5 (1/20) 0.011
Per oocyte retrieval
33.8 (124/367)
6.3 (1/16) 0.026
Per ET 36.9 (124/336)
6.3 (1/16) 0.014
Ongoing IR 21.1 (151/714)
3.6 (1/28) 0.028
Progesterone on HCG day
1.1 (0.8) 1.2 (1.3) NS
Kolibianakis 2004
AN=102
MODAN=66
P
Female age 32.02±4.9
31.74±4.8 0.711
Duration of infertility (years)
4.3±3.1 3.9±3.3 0.444
BMI (kg/m2) 24.07±4.3
23.4±3.6 0.374
Gravida 0.64±1.03
0.37±0.8 0.077
Cycle no 1.63±0.90
1.92±1.29 0.102
Antral follicle count 13.6±6.4 14.6±5.3 0.381
ACIBADEM EXPERIENCE
ANTN=20
MODAN=20
P
Total gonadotrophin dose 1829.7±734 1661.2±482 0.116
E2/HCG day 1483.1±1319.9
1858.9±1452.5
0.140
P/HCG day 0.68±0.33 0.84±0.46 0.032
Endometrium/HCG day 10.9±2.07 11.2±2.59 0.419
No. Follicle >10mm/HCG 11.05±5.8 12.64±5.27 0.091
Antagonist MODA0
2
4
6
8
10
12
14
3.8 3.9
3.6 4.09
4.015
17-22 mm14-16 mm10-13 mm
A MODA PP/HCG
day ≥ 1.2% 6.8 %16.4 0.108
Oocyte no MII oocyte no Cleavage no Grade I no Total embryo no
0
2
4
6
8
10
12
8.6
6.7
4.7
2.3
4.6
11.3
8.6
6.11
2.8
5.8ANTMODA
A MODA0
10
20
30
40
50
60
70
47.4
61
HCG (+)
HCG (+)
50/95
36/59
OR 1.409 CI %95 (0.728-2.726)
Antagonist başlama problemleri
SD 4? SD5? SD6? Fleksible?Siklus başından itibaren?
Modifiye protokoller?Antagonist dozu?
1- At least one follicle measuring >14 mm2- Estradiol levels >600 pg/ml3- LH levels >10 IU/l
Retrieved oocytes 12.1
MII % 75.8
Fertilization % 58.7
ET number 1.9
Cryo number 2.4
Ongoing IR % 26.5
Ongoing PR/Cycle 39.7
Ongoing PR/Retri 39.7
Ongoing PR/ET 42.4
oocyte no embryo no good qe0
2
4
6
8
10
12
10
5.4
3.3
8.8
4.6
2.5
9.3
5.3
3.3
8.6
4.9
3.5
0,250,512
The Ganirelix dose-finding study group. Hum Reprod. 1998.
OPR/ET IR Early miscar0
5
10
15
20
25
30
35
40 37.1
21.9
1.6
13
9
3.7
15.3
8.8 8.5
0.1 1.5
13
0,250,512
The Ganirelix dose-finding study group. Hum Reprod. 1998.
E2 response (defined as posttreatment/pretreatment E2 ratio)
Upper quartile
Middle quartile
Lower quartile
P
Oocyte yield 15.2 (7.5) 13.1 (7.9) 11.8 (5.6) <0.01
CPR 45.9 28.7 25 0.01
LBR 38.6 22.3 20 0.02
HCG günü problemler
HCG günü antagonist?HCG kriterleri?
HCG ertelenebilir mi?HCG günü P4?
PHASE III TRIALSLH rises (≥10 IU /L) with
concomitant progesterone rises (>1
ng/mL)
European trial 1.5%
North American trial 1.5%
European and Middle East trial
0.4%
GnRH agonist control group (pooled data)
0.8%
Premature luteinizationp≥1.2 ng/ml
No Premature luteinizationP<1.2 ng/ml
P
No of patients (%)
31/81 (38.3%) 50/81 (61.7%)
CPR/ET 8/31 (25.8%) 27/50 (54%) 0.01
LBR 12/87 (13.8%) 41/128 (32%) 0.007
Overall prevalence of premature luteinization was 18.2 %.
(P>1.5 ng/ml)
Luteal faz problemler
Vaginal & IM Progesteron?GnRH agonist suplementasyonu?