Patient tailored ovarian stimulation for IVF
Prof.Dr. Bart CJM Fauser
Ovarian response to exogenous stimulation
- the dose - response illusion !!
Ovarian response
Gonadotropin dose
Low Desired High
Efficacy Safety
Ovarian stimulation for IVF
- finding the optimal protocol
GnRH analog Gonadotropins added compounds
Final oocyte maturation
Luteal phase supplementation
Pretreatment interventions
Cycle day
Current evidence based medicine paradigm
Patient population
A B
EBM
heterogeneous
95% CI difference
Response differences in ovarian stimulation for IVF
Ovarian response
Ovarian stimulation
? Hyporesponse
= poor outcome Hyperresponse
= danger
Ovarian response prediction
! Female age
! AFC
! Body weight
! AMH
The paradigm shift in medicine
One size fits all
Patient tailored
treatment algorithms
Paradigm shift from evidence based to patient tailored medicine (2)
Patient population
Intervention
A B
X
Primary Outcome Standardized
phenotyping
EBM
PTM
Multi-variate prediction models
heterogeneous heterogeneous
95% CI difference
Complementary approaches:
“evidence’ vs patient based medicine
Evidence based
è Focus is the
intervention independent from the environment
Patient based
è Focus is context/
patient influencing any
given intervention
The EBM paradigm
Background
Compare individual dose based on nomogram (100-250 IU/d) vs standard dose (150 IU/d)
Design
RCT, 267 first IVF cycles GnRH ag long protocolResults
ü Good response 77 vs 65% (P<0.05) ü Low response 1.5 vs 10.7% (P<0.05) ü Hyperresponse 21 vs 20%
Conclusions
Individual dose regimen more
appropriate response and reduced need for dose adjustments
HR 2003
Oocyte distribution in the individual and standard dose group
Popovic, HR 2003
HRU 2009
Olivennes, RBM’09 Popovic, HR’03
FSH Total follicle no
BMI Total ovarian volume Age Total doppler score
AFC Age
Smoking
Response predictors for ovarian stimulation for IVF
RBMO 2015
Study design
! Consort calculator; age, height, weight, FSH, AFC
! Starting dose rFSH: 112½,
150, 187½, 225, 300, 450 IU/d
! 23 centers
! 200 women randomized
(MIS=AMH)
Gonadal AMH synthesis
Dimeric glycoprotein TGF β superfamily
MALE FEMALE
AMH and its potential clinical applications
AMH
Fecundity
IVF
PCOS
POI Menopause
Cancer treatment
Ovarian surgery
GC
tumours
Anorexia
AUC age: 0.60 (0.57-0.64) AUC age+FSH: 0.69 (0.66-0.72) AUC age+AFC: 0.76 (0.72-0.80) AUC age+AMH: 0.80 (0.76-0.84) AUC AMH: 0.81 (0.77-0.84)
AUC age+AMH+AFC+FSH: 0.81 (075-0.86)
Prediction poor ovarian response
(< 5 oocytes)IPD meta analysis, n = 5800, Broer HRU 2012
Cut off levels
AMH: 0.5 ng/ml FSH: 13 IU/l AFC(2-10): 7 fo
Prediction excessive ovarian response
(> 15 oocytes):IPD, n = 5800; Broer HRU 2012
AUC age: 0.61 (0.58-0.64) AUC age+AFC: 0.75 (0.71-0.79) AUC age+AMH: 0.81 (0.77-0.85) AUC AMH: 0.82 (0.77-0.86) AUC AMH+AFC: 0.85 (0.80-0.90)
AUC age+AMH+AFC+FSH: 0.85 (080-0.90)
Cut off levels AMH: 2.5 ng/ml AFC(2-10): 16 fo
F&S 2014
Summary of findings, more is NOT …. better
Arce, F&S 2014
Optimal number of oocytes for IVF - the more the better ??
Patient perspective
Society perspective Child perspective
HR 2012
Iive birth in relation to oocyte yield
22
ESTHER
Ferring
What ovarian response is optimal?
4 -- 5 8 --15
Poor response
optimal
Disturbed risk/
benefit balance
(oocyte number)
Next step: individualized dosing based
on ovarian response prediction
In vitro fertilization - the true balance -
Substitute outcome parameters
! Oocyte number
! Follicle number
! Embryo number
! Implantation rate
! Pregnancy rate/cyle
risks / complications
patient discomfort
costs Healthy term live birth
per treatment
Heijnen, HR 04
Ovarian hyperstimulation for IVF
- the bigger context
Ovarian stimulation
cost Burden of
treatment
Drop out
(cum outcomes)
monitoring complex
Complications (OHSS)
contribute to success?
Drop out Access to
treatment
