Mild versus conventional ovarian stimulation for IVF/ICSI treatment

in women with poor ovarian reserve (PRIMA Trial)

Youssef M.A.F.M

Al-Inany H.

Background

• The age of women giving birth to

their first child is rising

• Older women have decreased

fecundity

• Consequently, more older women

will request IVF

of poor ovarian response is 9-

24%

Background

Broekmans et al. 2009 Endocrine Reviews

Conventional ovarian stimulation Mild ovarian stimulation

Quality versus Quantity

Aim of PRIMA trial

• To evaluate the effectiveness and safety of a mild stimulation IVF versus a conventional simulation IVF in women with poor ovarian reserve undergoing IVF treatment

394 couples poor ovarian reserve

197 couplesMild IVF

197 couplesConventional IVF

treatm

en

t ti

me

OCP+ 150 IU FSH + GnRH antagonist

Mid-Luteal Long GnRH agonist + 450 IU HMG

Ongoing Pregnancy

recru

itm

en

ten

d p

oin

t

PRIMA trial design

Couples

Inclusion criteria•Women with an indication for IVF•Aged > 35 years •and/or women who have FSH >10 IU/ml •and/or women who have AFC (< 7 follicles)•Women who responded poorly during their 1st IVF cycle irrespective of their age.

Exclusion criteria•Women with pre-existing medical conditions, •Women > 43 years old; •Women with uterine anomalies; polycystic ovary syndrome and anovulation

450 IU HMG /day

mid-luteal GnRH agonist

hCG OPU ET

Menstr.

Mild Ovarian stimulation IVF

Conventional Ovarian stimulation/IVF

Interventions

150 IU FSH/day

5 days After laatste pil

GnRH antagonist

Sd 6

hCG OPU ET

PIL ( 10 days)

Cd2-3

Menstr.

Outcomes Primary outcome•Ongoing pregnancy rate

Secondary outcomes• Clinical pregnancy

• Biochemical pregnancy

• Multiple pregnancy

• Mmiscarriage rate,

• Total FSH/HMG doses used for ovarian stimulation,

• Cancellation rate

• No. oocytes retrieved, no. metaphase II oocytes,

• Fertilization rate

• No. embryos obtained, embryo transfers, embryos frozen

• Drop-out rate

Analysis

Sample size calculation

• Non inferiority design• Considering an ongoing pregnancy rate of 15 % in both treatment

groups, with an alpha of 5% and a beta of 20%, 197 patients per group were required to exclude a difference of 10% to the determent of the mild protocol.

• preplanned blinded interim analysis was performed when 200 women had completed follow-up

Intention to treat Trial registeration: NTR2788

Mild stimulation Conventional stimulation

394 women randomized

Lost to follow-up/drop out (n=16)

Discontinued intervention (n= 43)

1 woman discontinue dthe intervention: no suppression

26 Women cancelled due to poor ovarian response & 2 women changed to IUI

4 no oocytes/MII

10 fertilization failure

Lost to follow-up/drop out (n=18)

Discontinued intervention (n= 56)

3 women discontinued the intervention: spontaneous ovulation/no suppression/ financial reason

35 Women cancelled due to poor ovarian response & 2 women changed to IUI

4 no oocytes/MII

12 cycles with fertilization failure

Received allocated intervention:191

Did not receive allocated intervention: 6 2 women antagonist was not available, 1 declined consent, 1 insisted on sex selection, 1 had fibroids

Received allocated intervention:195

Did not receive allocated intervention:21 woman received fault drug,1 decline their consent,

Flow chart

Allocation

Follow up

AnalysisAnalyzed : ITT: 197 Analyzed : ITT: 197

Baseline characteristics

Mild stimulation

(N=197)

conventional stimulation

(N=197)

Age in years (µ ±SD) 36.52± 3,963 36.63±4.287

BMI in Kg/m2 (µ ±SD) 27.19±4.486 27.45±5.282

D. Infertility in years ( µ ±SD) 9.43±5.6 9.28±5.7

Primary infertility, n (%) 143 (74.9) 138 (71.9)

AFC (µ ±SD) 6.2±2.8 6.5± 2.9

FSH (µ±SD) 11.4±4.3 10.5±4.0

E2(µ±SD) 43.8±22.6 42.8±25.7

AMH (µ ±SD) (n= 301) 0.52±0.62 0.6±0.66

Baseline characteristicsMild stimulation

(N=197)

Conventional stimulation

(N=197)

poor ovarian response

Expected n (%) 143 (74.9) 145 (75.5)

Non expected n (%) 48 (25.1) 47 (24.5)

Previous IVF/ICSI cycles

Yes 89 (47.6%) 94 (50.3)

No 98 (52.4) 93 (49.7)

Causes of infertility, n (%)

Diminished ovarian reserve (IOF) 99 (51.8) 98 (52.0)

IOF + Poor semen quality 47 (24.6) 46 (24)

IOF+ Tubal 16 (8.4) 11 (5.7)

IOF+ Endometriosis 5.0 (2.6) 5.0 (2.6)

IOF+ Multiple factors 16 (8.4) 22 (11.5)

IOF+ Others (..i.e. failed IUI) 8.0 (4.1) 10 (5.2)

Pregnancy outcomes

Mild ovarian stimulation

(N=197)

Conventional stimulation

(N=197) RR (95% CI)

Ongoing pregnancy rate, n (%) 23 (12) 28 (14.6) 0.82 (0.49-1.37)

Clinical pregnancy rate, n (%) 30 (15.7) 35 (18.2) 0.86 (0.55-1.34)

Biochemical pregnancy rate, n (%) 41 (21.5) 38 (19.8) 1.08 (0.73- 1.60)

Early Miscarriage rate, n (%) 7.0 (23) 7.0 (20) 1.0 (0.36-2.80)

Multiple pregnancy rate 2.0 (6.0) 2.0 (5.0) 1.0 (0.14- 7.03)

Ovarian stimulation outcomes

Mild stimulation

(N=197)

Conventional stimulation (N= 197)

p

No. of stimulation days ( µ ±SD) 95% CI) 8.9±2.6 10.2± 2.5 0.00

Total amount of FSH ( µ ±SD) 1394.4 ±366.4 ---

0.00 Total amount of HMG (µ ±SD) ----- 4852.4±3650.6

No. cycle cancellation rate due to poor ovarian response, n (% )

35 (18.7) 26 (13.9) 0.32

No. of follicles ≥ 15 mm on hCG day ( µ ±SD) 3.4± 3.0 4.7± 3.6 0.06

Ovarian stimulation outcomes Mild stimulation

(n=197)

Conventional stimulation

(n=197)

p

No. of oocytes (µ ± SD) 3.58 ± 3.7 5.2 ± 4.1 0.59

No. of MII oocytes (µ± SD) 2.8±3.0 4.2±3.7 0.01

Fertilization rate (µ ± SD) 2.4±2.6 3.5±3.1 0.39

Total number of embryos 349 365

No. of top quality embryos (95% CI) 0.54 (0.37- 0.71) 0.75 (0.51-1.0) 0.94

No. of embryos transferred (µ ± SD) 1.5±1.4 1.7±1.2 0.056

No. embryos frozen (µ ± SD) 0.82±1.1 0.64±1.9 0.45

Summary

• Mild ovarian stimulation is non-inferior to conventional ovarian

stimulation in terms of pregnancy outcomes

• Mild ovarian stimulation is associated with shorter duration of stimulation

and lower amount of gonadotropins.

• Mild ovarian stimulation is associated with less MII oocytes.

Take home message

Mild ovarian stimulation is the preferred alternative to

conventional stimulation in women with poor reserve

undergoing IVF treatment

Acknowledgment

Dr. M. Van WelyDr. M. MochtarProf. F.van der Veen

Prof. Dr. Tahereh MadaniDr. Nadia JahangiriDr. Shabnam Khodabakhshi

Prof. Dr. M. Akhondi

Dr. S. Abouzar

Prof. Dr. Marwan Halabi

Prof. Dr. S.KhattabProf. Dr. Ismail .AboulfoutouhDr. Maged El-mohamedyDr. Eman Kamal shoair

Prof. Dr. Ahmed Youssef Rizk

m.a.youssef@amc.uva.nl

Mild stimulation