Improving Success in ART: how to define it and key strategies to get the best outcomes, Kiev, 21-09-2018

What is the POSEIDON concept?

Alessandro Conforti

Italy

Objectives

▪Unravel the definition of POR patients

▪ Illustrate Poseidon concept and classification

▪Gain a better understanding of Poseidon application in clinicalpractice

Polyzos and Devroey, Fertil Steril 2011

The poor responder patient

1. No more than 3 trials using the same definition

2. No one of the criteria was used in more than 50% of trials

3. Threshold were consistently different among trials

Conclusions:

There is insufficient evidence to support the routine use of any

particular intervention either for pituitary down regulation, ovarian

stimulation or adjuvant therapy

At least two of the following three features must be present:

• Advanced maternal age (≥40 years) or any other risk factor for POR(Turner syndrome, X-fragile mutations, hystory of chemotherapy etc.);

• A previous poor ovarian response (POR) (≤3 oocytes with a conventional stimulation protocol);

• An abnormal ovarian reserve test (i.e., AFC 5–7 follicles or AMH 0.5–1.1 ng/ml).

o Two episodes of POR after maximal stimulation are sufficient to define a patient as a poorresponder;

o Patients over 40 years age with an abnormal ovarian reserve test should be more properly definedas expected poor PORs patient.

Bologna criteria are being used progressively

Search of trials in POR since Jul/2011*:

➢ 23 trials (45%) using Bologna criteria!

By courtesy of Esteves

young women (<35 years) with lowovarian reserve, with a previous

episode of POR

young women (<35 years) withnormal ovarian reserve, with two

episodes of PORold women (≥40 years) withnormal ovarian reserve and

previous POR

Bologna POR classification – Difficulties to manage

1. Heterogeneity of subgroups

Courtesy of Humaidan and Esteves, modified

Bologna POR classification – Difficulties to manage

2. The concept of «sensitivity» is not included

⚫ Same age, BMI and hormonal profile: same protocols

⚫ Same age, BMI and hormonal profile: different ovarian reserve

⚫ Same ovarian reserve: different sensitivity to FSH and LH

1990

2016

Bologna POR classification – Difficulties to manage

3. Age related aneuploidies - ovarian quality not considered

N. = 4,747 cycles and 29,803 embryos. O. Ata, Munne et al. (2012) Reprod Biomed Online and unpublished

data

Ovarian quality is significantly influenced by age

GROUP 1

Young patients <35 years with adequate ovarianreserve parameters (AFC ≥5; AMH ≥1.2 ng/ml)and with an unexpected poor or suboptimal

ovarian response

Subgroup 1a: <4 oocytes*

Subgroup 1b: 4-9 oocytes retrieved*

*after standard ovarian stimulation

GROUP 2

Older patients ≥35 years with adequate ovarian

reserve parameters (AFC ≥5; AMH ≥1.2 ng/ml)

and with an unexpected poor or suboptimal

ovarian response

Subgroup 2a: <4 oocytes*

Subgroup 2b: 4-9 oocytes retrieved*

*after standard ovarian stimulation

Poseidon Group, Fertil Steril 2016

GROUP 3

Young patients (<35 years) with poor ovarian

reserve pre-stimulation parameters

(AFC<5; AMH <1.2 ng/ml)

GROUP 4

Older patients (≥35 years) with poor ovarian

reserve pre-stimulation parameters (AFC <5;

AMH <1.2 ng/ml)

Poseidon classification for low prognosis women

POSEIDON Working GroupNew measure for successful treatment

Poseidon Group, Fertil Steril 2016

0%

10%

20%

30%

40%

50%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40

Liv

e b

irth

rat

e (%

)

Oocyte number

Observed live birth rate Predicted live birth rate

Sunkara et al. Hum Reprod 2011

450,135 IVF cycles

Number of oocytes retrieved and

live birth rates in fresh cycles

Input variables

XMaturation rate2PN Fertilization rateCleavage or Blastulation rateEuploidy rate per age group

Output variable

Y (N oocytes)

FunctionY = f(X)

How many oocytes are needed for at least one euploid embryo?

Adjusted according to maternal and paternal age, sperm source, sperm and

oocyte status, and type of embryo transfer (fresh; FET)

Courtesy of S.C. Esteves

Poseidon calculator

Courtesy of S.C. Esteves

The ART Calculator will allow clinicians to estimate the number of oocytes needed to achieve a new marker of successful outcome, i.e., at least 1

euploid embryo for transfer in each patient…

Esteves, 18

Courtesy of S.C. Esteves

Unexpected impaired ovarian response (hypo-response)

GROUP 1

Young patients <35 years with adequate ovarianreserve parameters (AFC ≥5; AMH ≥1.2 ng/ml)and with an unexpected poor or suboptimal

ovarian response

Subgroup 1a: <4 oocytes*

Subgroup 1b: 4-9 oocytes retrieved*

*after standard ovarian stimulation

GROUP 2

Older patients ≥35 years with adequate ovarian reserve parameters (AFC ≥5; AMH ≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response

Subgroup 2a: <4 oocytes*

Subgroup 2b: 4-9 oocytes retrieved*

*after standard ovarian stimulation

Poseidon Group, Fertil Steril 2016

Poseidon classification for low prognosis women

~30%

~80%

Hypo!Hypo-sensitivity to FSH

(15% of women with good ovarian reserve)

Good!Genro et al., 2011

Hypo response reflects a low follicle output rate (FORT)

Age 32FSH 8.7 IU/L BMI 24.3 Kg/m2

Age 31 yearsFSH 8.7 IU/LBMI 26.3 Kg/m2

Ernestine

Gwen

Normal FOI (>0.5)

Low FOI (0.5)

Follicle-Oocyte Index (FOI)* = Total number of oocytes number/Antral Follicles Count

*Ratio between the number of oocytes retrieved at oocyte pick-up and the number of antral follicles at start of stimulation (FOI ranges from 0 to 1)

1

2

3

4

Alviggi C. and Conforti A., Frontiers in Endocrinology in press

Low FOI (0.5)

Hypothetical Pathogeneisis

Lowgonadotropin starting dose Technical issues involving

triggering for final oocyte maturation and/or oocyte

pick-up

Genetic or environmental

factors

Asynchronous follicular development

Alviggi C. and Conforti A, Frontiers in Endocrinology in press

Group B High Level

Group A Low Level

Alviggi et al. 2014

FSH-R Ser680 carriers have low FORT/FOI and require more FSH

Greb, et al. JCEM, 2005; Gromoll & Simoni TEM 2005.

Alviggi et al., 2016.

Asn/Asn Asn/Ser Ser/Ser0

10

20

30

40

50

n=46 n=72 n=43

FS

H a

mp

ou

les

(n

)

*

*

p < 0.05

*Perez Mayorga, et al. 2000; Sudo, et al. 2002;

Choi, et al. 2004; Falconer, et al. 2005.

Four Groups of Patient with Low Prognosis

Poseidon Group, Fertil Steril 2016

GROUP 3

Young patients (<35 years) with poor ovarian

reserve pre-stimulation parameters (AFC <5; AMH

<1.2 ng/ml)

GROUP 4

Older patients (≥35 years) with poor ovarian reserve pre-

stimulation parameters (AFC <5; AMH <1.2 ng/ml)

… What strategies could be adopted?and how many eggs we need?

Patients with expected low prognosis

<35 39-40 42-43

Euploidy rate 60%

1 euploidblastocyst

1 euploidblastocyst

1 euploidblastocyst

Euploidy rate 30% Euploidy rate 20%

2 blastocysts≈

4 fertilizedoocytes

≈

5 MII oocytes≈

6 COCs≈

Age

3 blastocysts≈

7 fertilizedoocytes

≈

9 MII oocytes≈

11 COCs≈

5 blastocysts≈

13 fertilizedoocytes

≈

16 MII oocytes≈

18 COCs≈

Mean number of oocytes needed and age

Courtesy of F. Ubaldi

Four Groups of Patient with Low Prognosis

Poseidon Group, Fertil Steril 2016

GROUP 3

Young patients (<35 years) with poor ovarian

reserve pre-stimulation parameters

(AFC <5; AMH <1.2 ng/ml)

GROUP 4

Older patients (≥35 years) with poor ovarian reserve pre-

stimulation parameters (AFC <5; AMH <1.2 ng/ml)

… So we need many eggs from women with low reserve!

Four Groups of Patient with Low Prognosis

In Young women with low ovarian reserve (Poseidon Group 3 ) pre-treatment with coenzyme Q10 could /200 mg thrice daily for 60 days preceding the IVF cycle) could improve the number of oocytes retrieved

Xu et al. 2018

Increasing dosage during stimulation could be of use in women with low ovarian reserve?

Standard dose: 150IU/day

High dose: 225-450IU/day

van Tilborg et al. 2017

What about accumulation program?

242 low-responder (defined as women in whom 5 oocytes were retrieved in a single ovarian stimulation)

Group (LR-Accu-Vit) mature oocytes accumulated by vitrification and inseminated simultaneouslyGroup (LR-fresh) undergoing IVF/embryo transfer with fresh oocytes in each stimulation cycle

Accumulation strategy

Double stimulation in POR (Shanghai protocol)

DuoStim in women with low reserve

18 2330

25 2013

Follicular phase(FP) stimulation

Luteal phase (LP)stimulation

Cumulative

Patients with no euploid blastocysts

Patients with ≥1 euploid blastocyst

70%53%42%

Courtesy by F. Ubaldi

Take home messages

● Better stratification of low prognosis women (i.e., Poseidon classification) may help to manage heterogeneicity among patients and identifying subgroups who benefit specific treatments

● Hypo-response to standard doses of FSH (Poseidon 1-2) could be a genetic trait –pharmacogenomic approach for FSH starting dose

● Accumulation program DuoStim is a valid option for women with low ovarian reserve (Poseidon 3-4)

● Poseidon calculator can be an useful tool for counselling and to define the optimal number of oocytes in these two groups

C. Alviggi

G. De Placido

I. Strina

S. Picarelli

R. Vallone

B. BuonomoUniversity of Naples Federico II

Reproductive Medicine

IVF Unit

Fertunina www.fertunina.it

Special thanks:Poseidon Group

Acknowledgments