prognostic models

Prognostic models in

Infertility

Basic fertility work up

referral gyn

HistoryPhysical examination

Cycle evaluation

Ovulation

Semen analysis

? PCT

Tubalpatency:

CATHSGDLS

FSH, E2AFC

Causes of infertility

• Azoospermia• Anovulation• Double sided tubal occlusion• Sexual dysfunction

Causes of subfertility

• Unexplained subfertility• One-sided tubal pathology• Cervical factor subfertility• Endometriosis• Decreased semen quality • Decreased intercourse frequency

Evers JL, Lancet 2002

Infertility or subfertility?

Clinical problem

• Distinction between couples who need treatment and couples who are likely to conceive spontaneously

Clinical Problem II

• You scheduled a couple to do ICSI and the woman asked you : What is my chance to get a baby after doing ICSI???

Gynaecologists differ widely in estimating pregnancy chances of subfertile couples

Van der Steeg et al.,HR, 2006

Why Models!!

• Prediction models are intended to help gynaecologists in patient communication and decision making about treatment

How to Choose: Expectant management or intervention

• Prediction models for Chance to concieve naturally (home conception) (treatment independent pregnancy)

• Prediction models for pregnancy after IVF• Prediction models for pregnancy after IUI

EimersCollinsSnick HunaultFemale age+ + - +Duration subfertility+ + + +F.A. manUrethritis vg. man

+

-

-

-

-

-

-

-prim/ sec subfertility+ + - +Anovulation- - + -Tubal pathology- + + -Semen-analysis + + - +Endometriosis- + --PCTReferral status

+ - + -/+

+

Hunault et al. HR 2004Hunault et al. HR 2004

Prediction models for spontaneous pregnancy

Calculation Prognosis

P = 1-0,0166P = 1-0,0166EXP(-0,053*EXP(-0,053*ageage-0,152*-0,152*durationduration-0,447*-0,447*prim/secprim/sec+0.0035*+0.0035*prog.motprog.mot-0,949*-0,949*PCTPCT-0,321*-0,321*referralreferral))

External validation

the agreement between predicted probabilities and the outcome event rates

CalibrationCalibration

Calibration plot for unexplained subfertility

Synthesis model without PCT

Predicted probability

0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0

Obs

erve

d pr

obab

ility

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

10 groups of N~260

Calibration Synthesis model

Van der Steeg HR 2007

http://http://www.amc.nl/prognosticmodelhttp://http://www.amc.nl/prognosticmodel

Clinical consequences

• Couples with prognosis <30% = IVFCouples with prognosis <30% = IVF• Couples with prognosis > 40% = Couples with prognosis > 40% =

expectant management expectant management • Couples with prognosis 30-40% = IUICouples with prognosis 30-40% = IUI

Expectant management or intervention

• Prediction models for Chance to concieve naturally (home conception) (treatment independent pregnancy)

• Prediction models for pregnancy after IVF• Prediction models for pregnancy after IUI

Protocols for IVF GnRH AntagonistGnRH AntagonistProtocolsProtocols

GnRH GnRH AgonistAgonistProtocolsProtocols

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe) Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

250 250 g per day antagonistg per day antagonist

Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

GnRHa 1.0 mg per day GnRHa 1.0 mg per day up to 21 daysup to 21 days 0.5 mg per day of GnRHa0.5 mg per day of GnRHa

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe)

Day 6Day 6of FSH/HMGof FSH/HMG

DayDay

of of hCGhCG

Day 1 Day 1 of FSH/HMGof FSH/HMG

Day 6Day 6of FSH/HMGof FSH/HMG

DayDayof hCGof hCG

7 – 8 days7 – 8 daysafter estimated ovulationafter estimated ovulation

Down regulationDown regulation

Day 2 or 3Day 2 or 3of mensesof menses

Day 1 Day 1 FSH/HMGFSH/HMG

Which day!!!

• Day of start of cycle• Day of start of stimulation• Day of OPU• Day of ET• the time of embryo transfer will be more

accurate • but limited since the couple has already gone

through the whole process of IVF.

Ideal model

• the probability of live birth in an IVF cycle prior to start of ovarian stimulation.

Day of start: Baseline factors

• female age,• duration of infertility, • primary cause of infertility, • duration of GnRH agonist use, • Hormonal level• the number of previous IVF cycle

• The age of the woman is still considered to be the most important predictor of IVF success (Broekmans and Klinkert, 2004).

• increasing duration of infertility has also been shown to be negative impact , even after adjustment for age, whereas previous pregnancy increases the likelihood of success (Collins et al., 1995; Templeton et al,1996).

• couples with different infertility diagnoses will likely have different probabilities of achieving a live birth

Ovarian reserve tests

• Basal FSH, inhibin B, and anti-Müllerian hormone concentrations, as well as antral follicles count can be used to measure the

ovarian reserve (Broekmans et al., 2006; Kwee et al., 2008).

AMH

• If kits are available, AMH measurement could be the most useful in the prediction of ovarian response in anovulatory women.

• It is done at any day of cycle• It is too expensive• Exact normal levels not yet well agreed upon

?Pregnancy

• correlation with the degree of response to COH, but identifying poor responders by means of these tests has low prognostic value in relation to the chance of live birth after IVF

Broekmans et al. (2006)

How to build a model!

• Multivariate logistic regression analysis for previous prognostic variables to create prediction models of ovarian response and/or ongoing pregnancy has been used to a lesser extent (e.g., Bancsi et al., 2002).

Existing Models

• Most statistical models for prediction of IVF outcome use both prestimulation parameters and data obtained during the treatment, such as data on embryos

IVF prediction modelsPrediction modelsOutcomeDiscriminationCalibration

Templeton (1996)IVF0.63good

Calculation • The predicted probability (P) of achieving a live birth

after IVF was calculated using the Templeton the model:

• Where y was defined as y = –2.028 + [0.00551x(age – 16)2] –

[0.00028x(age – 16)3] + [i – (0.0690x no. of unsuccessful IVF attempts)] – (0.0711xtubal subfertility) + (0.7587xlive birth after IVF) + (0.2986 x previous pregnancy after IVF which did not result in a live birth) +

(0.2277x live birth which was not a result of IVF) + (0.1117x previous pregnancy, not after IVF and which did not result in a live birth).

IVF prediction modelsPrediction modelsOutcomeDiscriminationCalibration

Templeton (1996)IVF0.63good

Lintsen, A.M.E. et al. Hum. Reprod. 2007

• classified for each woman into one of three groups, i.e.,

• (i) predictor of good prognosis• (ii) intermediate prognosis • (iii) predictor of poor prognosis.

Expectant management or intervention

• Prediction models for Chance to concieve naturally (home conception) (treatment independent pregnancy)

• Prediction models for pregnancy after IUI• Prediction models for pregnancy after IVF

Prognostic factors of pregnancy in intrauterine insemination

• Women with intermediate prognosis

IUI prediction modelprediction modelsOutcomeDiscriminationCalibration

Steures (2004)IUI0.59good

39

PICO

Patientwoman, 34 years, 2ys 1ry unexplained inf.

InterventionIUI

Comparisonwait

OutcomePregnancy

months to ongoing pregnancy363024181260

Cum

ula

tive

ongoin

g p

regnancy

rat

e

1,0

0,8

0,6

0,4

0,2

0,0

IUI-censoredexp-censoredIUIexp

exp=1, IUI=2

-- delayed treatment

-- early treatment

RR: 1,0 (CI: 0,86-1,2)

N= 90 (71%)N= 90 (71%)

Take Home Message

• Prediction models are now available and ready for use

• Female age is the overwhelming factor affecting prediction models

• The prognosis should be discussed clearly with the patients based on scientific evidence and existing models.

However

• Patient preferences• Private vs medical insurance• Patient values

http://http://www.amc.nl/prognosticmodelhttp://http://www.amc.nl/prognosticmodel

Clinical consequences

• Couples with prognosis <30% = IVFCouples with prognosis <30% = IVF• Couples with prognosis > 40% = Couples with prognosis > 40% =

expectant management expectant management • Couples with prognosis 30-40% = IUICouples with prognosis 30-40% = IUI

Lintsen, A.M.E. et al. Hum. Reprod. 2007

Basics

Clinical Expertise

Prediction Model Patient Preferences

THANK You