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 (2012) Reprod Biomed Online and unpublished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
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
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
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
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
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