H ow can w e i m pr ove st i m u l at i on
pr ot ocol s? Can w e of f er m or e?
E Heijnen MD PhD
Clinical Research Scientist NV Organon
Changing Treatment Paradigm – is it associated with increasing success?
1

H ow to define
success in I VF ?
Heijnen HR 2004 2

I n vitr o fer tilization
- the tr ue balance -
Substitute outcome
parameters
Oocyte number risks / complications
Follicle number
Embryo number
Implantation rate
patient discomfort
Pregnancy rate/cycle
Healthy term ‘babies’
costs
per treatment period
Vail HR 2003; Johnson HR 2003; Heijnen HR 2004 3

Mild ovarian stimulation for IVF
Edwards
Olivennes, HR ’98 ‘friendly’ stimulation’
4

Mild Stimulation Protocol
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Tr eatment Pr otocol
-Standar d ver sus M ild-
Standard Treatment Protocol
GnRH-agonist + 2 embryos
Rec-FSH 150 IU
CD21 M P
Mild Treatment Protocol
GnRH-antag
+ 1 embryo
Rec-FSH 150 IU
M CD5 Foll 14mm P
Eijkemans HR 2006 6

Randomised Contr olled,
N on-infer ior ity, E ffectiveness Tr ial
Standard Strategy
2 embryos 2 embryos 2 embryos
200 patients
Mild Strategy
1 embryo 1 embryo 1 embryo 1 embryo
200 patients
1 year
• 400 patients
• Two-centres (Erasmus MC Rotterdam, UMC Utrecht - NL)
• Inclusion period 2002-2004
• power:80%; : 0.05; maximal difference non inferiority -12,5%
Eijkemans HR 2006 7

Pr imar y Outcomes
Medical
1.
Cumulative pregnancy rate within one year after
randomization leading to term live birth
2. Economical
Total costs per couple per year
3. Psychological
Overall patient discomfort within one year
Eijkemans HR 2006 8

Char acter istics per I VF cycle
Mild Standard P
(n = 444) (n = 325)
8.3 ± 2.2 11.5 ± 3
Duration stimulation (days) <0.001
8.5 ± 2.7 25.3 ± 6.8
Duration injections (days) <0.001
1,307 ± 529 1,832 ± 758
Total dose FSH (IU) <0.001
Cancellation (%) 18.0 8.3 <0.001
6.9 ± 4.8 8.5 ± 4.3
Number oocytes/ retrieval <0.001
2.8 ± 2.7 3.8 ± 2.9
Number good quality embryos/ retrieval <0.001
0.9 ± 1.8 0.6 ± 1.4
Number cryo embryos/ fresh embryo transfer 0.04
Ongoing pregnancy/ started cycle (fresh) (%) 17.6 28.6 <0.001
Ongoing pregnancy/ started cycle (cryo) (%) 1.4 1.2 0.8
Term live birth/ started cycle (fresh) (%) 15.8 24.0 0.003
Term live birth/ started cycle (cryo) (%) 1.1 0.9 0.8
OHSS (%) 1.4 3.7 0.04
Heijnen Lancet 2007 9

Cumulative 1-year pr egnancy r ate leading to
ter m live bir th
% Pregnancies leading to term live birth
60%
Mean number of cycles:
404 couples
769 cy cles
Standard: 1.7 Mild: 2.3
40% . 6 #*
78
Standard $8
9 6
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78
20%
Mild
0
% Multiple Pregnancy 0 3 6 9 12
Per Couple:
Time since randomization (months)
Mild: 0.5%
Standard: 13.1%
Heijnen Lancet 2007
Price winning paper, ESHRE 2006 10

Total costs per I VF tr eatment cycle
Mild Standard
(Mean ± SD) (Mean ± SD) P
Medication
GnRH analogue 155 ± 71 235 ± 70 <0.001
FSH 585 ± 236 816 ± 337 <0.001
Technical Procedures
Oocyte retrieval/laboratory 323 ± 210 352 ± 184 0.038
Embryo transfer 151 ± 112 222 ± 110 <0.001
Embryo cryo transfer 17 ± 68 14 ± 60 NS
Intramural care
Ultrasound 151 ± 69 157 ± 94 NS
Hospital admission 26 ± 167 72 ± 471 0.059
Control visits 42 ± 51 43 ± 59 NS
Laboratory 108 ± 123 65 ± 82 <0.001
Total Costs 1.559 ± 608 1.977 ± 803 0.001
Polinder Submitted 11

Costs
4,000 Mild treatment strategy
Standard treatment strategy
Costs ( ) per cycle
Time between subsequent
Time between subsequent
3,000
treatment cycles:
treatment cycles:
2,000
Mild: 88 days
Mild: 88 days
1,000
Standard: 109 days
Standard: 109 days
0
0 3 6 9 12
Time since randomisation (months)
Mild treatment strategy
6,000 Standard treatment strategy
Cumulative IVF costs ( )
4,000
2,000
0
0 3 6 9 12
Time since randomisation (months)
Polinder Submitted 12

Total cost per couple up to 6 week s
after expected deliver y
Mild Standard
(Mean ± SD) (Mean ± SD) P
IVF Treatment
Technical procedures 1,083 ± 734 991 ± 584 0.16
Medication 1,626 ± 1,088 1,737 ± 1069 0.3
Monitoring 750 ± 561 576 ± 693 0.006
Indirect costs 1,948 ± 2,280 1,740 ± 1845 0.3
Pregnancy and
Neonatal period
Medical costs 2,547 ± 4,553 4,899 ± 10,746 0.01
Indirect costs 379 ± 1,177 802 ± 2,270 0.03
Total Costs 8,333 ± 5,418 10,745 ± 11,225 0.006
Heijnen Lancet 2007 13

Over all patient discomfor t
Physical discomfort
Depression score
Anxiety score
N= N= N=
Physical Discomfort Anxiety Depression
Cycle number Cycle number Cycle number
Protocol: Mild Standard
Heijnen Lancet 2007 14

D r op Out Rate dur ing tr eatment
P=0.04
,
%
Mild
,
Standard
,
,
Cycle Cycle
Heijnen Lancet 2007 15

Psychological I mpact F ir st Cycle
De Klerk HR 2006 16

Per centages of women with clinically
r elevant depr ession and anxiety scor es
Treatment Strategy
Standard Mild
38.8 (19/49) 19.4 (13/67)
Possible depression
HADS-D > 7
8.2 (4/49) 11.9 (8/67)
Probable depression
HADS-D > 10
40.8 (20/49) 31.3 (21/67)
Possible anxiety
HADS-A > 7
26.5 (13/49) 14.9 (10/67)
Probable anxiety
HADS-A > 10
Women without cryopreserved embryos who did not get pregnant
Women without cryopreserved embryos who did not get pregnant
after standard IVF showed:
after standard IVF showed:
•more symptoms of depression (P < 0.05)
•more symptoms of depression (P < 0.05)
•more symptoms of anxiety (P < 0.05)
•more symptoms of anxiety (P < 0.05)
De Klerk Submitted 17

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CD 2 5 foll > 14 mm
Baart HR 2007
18
Price winning paper ESHRE 2005

K ey findings
20 **
Conventional
Mild
16
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Average
per patient 12
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Baart HR 2007 19

Or g 36286
20

Or g 36286 - M ech an i sm of A ct i on
FSH Activity
threshold
1 2 3 4 5 6 7 8 9
Stimulation days
Org Daily dose of rFSH
36286
IVF or ICSI
procedure
Cycle day 2-3 = hCG as 3 follicles 17 mm
Stimulation
Stimulation Day 1 Day 8
21

Or g 36286 r egimen - example
FSH
Org 36286
1 2 3 4 5 6 7 8 9 10
GnRH antagonist
22

F inal Conclusion
Substitute outcome
parameters
Oocyte number risks / complications
Follicle number
Embryo number
Implantation rate
patient discomfort
Pregnancy rate/cycle
Healthy term ‘babies’
costs
per treatment period
23