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?