Multicenter randomized controlled study comparing extremely two different regiments for ovarian stimulation in women with poor ovarian reserve

1. Mild versus conventional
ovarian stimulation for IVF/ICSI treatment
in women with poor ovarian reserve
(PRIMA Trial)
Youssef M.A.F.M
ESHRE 2014 oral presentation

2. 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%

3. Background
Broekmans et al. 2009 Endocrine Reviews

4. Conventional ovarian stimulationMild ovarian stimulation
Quality versus Quantity

5. 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

6. 394 couples poor ovarian reserve
197 couples
Mild IVF
197 couples
Conventional IVF
treatmenttime
OCP+ 150 IU FSH + GnRH
antagonist
Mid-Luteal Long GnRH agonist
+ 450 IU HMG
Ongoing Pregnancy
recruitme
nt
endpoint
PRIMA trial design

7. 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

8. 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.

9. 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

10. 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

11. 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:2
1 woman received fault drug,
1 decline their consent,
Flow chart
Allocation
Follow up
Analysis
Analyzed : ITT: 197 Analyzed : ITT: 197

12. 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

13. Baseline characteristics
Mild 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)

14. 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)

15. 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

16. 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

17. 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.

18. Take home message
Mild ovarian stimulation is the preferred alternative to
conventional stimulation in women with poor reserve
undergoing IVF treatment

19. Acknowledgment
Dr. M. Van Wely
Dr. M. Mochtar
Prof. F.van der Veen
Prof. Dr. Tahereh Madani
Dr. Nadia Jahangiri
Dr. Shabnam Khodabakhshi
Prof. Dr. M. Akhondi
Dr. S. Abouzar
Prof. Dr. Marwan Halabi
Prof. Dr. S.Khattab
Prof. Dr. Ismail .Aboulfoutouh
Dr. Maged El-mohamedy
Dr. Eman Kamal shoair
Prof. Dr. Ahmed Youssef Rizk
Prof. Dr. Hesham Al-inany