Patient tailored ovarian stimulation for IVF

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

Eff

ica

cy

Safe

ty

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 P

ati

en

t p

op

ula

tio

n

A

B

EBM

hete

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en

eo

us

95% CI

difference

Response differences in

ovarian stimulation for IVF O

vari

an

resp

on

se

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) P

ati

en

t p

op

ula

tio

n

Intervention

A

B

X

Primary

Outcome Standardized

phenotyping

EBM

PTM

Multi-variate

prediction models

hete

rog

en

eo

us

hete

rog

en

eo

us

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 protocol

Results 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

TGFβ 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

So

cie

ty

pers

pec

tive

Ch

ild

pers

pectiv

e

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

The heart of the matter …… !

Safety women

How long will it take

Child health

Intervention -  Effective

-  Cost effective

(cumulative outcomes)