What is the POSEIDON concept?

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2 Improving Success in ART: how to define it and key strategies to get the best outcomes, Kiev, What is the POSEIDON concept? Alessandro Conforti Italy

3 Objectives Unravel the definition of POR patients Illustrate Poseidon concept and classification Gain a better understanding of Poseidon application in clinical practice

4 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 Polyzos and Devroey, Fertil Steril 2011

5 Conclusions: There is insufficient evidence to support the routine use of any particular intervention either for pituitary down regulation, ovarian stimulation or adjuvant therapy

6 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 ng/ml). o Two episodes of POR after maximal stimulation are sufficient to define a patient as a poor responder; o Patients over 40 years age with an abnormal ovarian reserve test should be more properly defined as expected poor PORs patient.

7 Bologna criteria are being used progressively Search of trials in POR since Jul/2011*: 23 trials (45%) using Bologna criteria! By courtesy of Esteves

8 Bologna POR classification Difficulties to manage 1. Heterogeneity of subgroups young women (<35 years) with low ovarian reserve, with a previous episode of POR young women (<35 years) with normal ovarian reserve, with two episodes of POR old women ( 40 years) with normal ovarian reserve and previous POR Courtesy of Humaidan and Esteves, modified

9 Bologna POR classification Difficulties to manage 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 2016

10 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 (2012) Reprod Biomed Online and unpublished data

11 Ovarian quality is significantly influenced by age

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13 Poseidon classification for low prognosis women GROUP 1 GROUP 2 Young 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 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation 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 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 Group, Fertil Steril 2016

14 POSEIDON Working Group New measure for successful treatment Poseidon Group, Fertil Steril 2016

15 Live birth rate (%) 50% 40% 30% 20% 10% 0% Number of oocytes retrieved and live birth rates in fresh cycles Observed live birth rate 450,135 IVF cycles Predicted live birth rate Oocyte number Sunkara et al. Hum Reprod 2011

16 How many oocytes are needed for at least one euploid embryo? Input variables X Maturation rate 2PN Fertilization rate Cleavage or Blastulation rate Euploidy rate per age group Adjusted according to maternal and paternal age, sperm source, sperm and oocyte status, and type of embryo transfer (fresh; FET) Function Y = f(x) Output variable Y (N oocytes) Courtesy of S.C. Esteves

17 Courtesy of S.C. Esteves Poseidon calculator

18 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

19 Poseidon classification for low prognosis women GROUP 1 GROUP 2 Young 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 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation 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 Unexpected impaired ovarian response (hypo-response) Poseidon Group, Fertil Steril 2016

20 Hypo response reflects a low follicle output rate (FORT) Ernestine Age 32 FSH 8.7 IU/L BMI 24.3 Kg/m 2 ~30% Gwen Hypo! Hypo-sensitivity to FSH (15% of women with good ovarian reserve) Age 31 years FSH 8.7 IU/L BMI 26.3 Kg/m 2 Genro et al., 2011 ~80% Good!

21 Follicle-Oocyte Index (FOI)* = Total number of oocytes number/antral Follicles Count Normal FOI (>0.5) 1 2 Low FOI ( 0.5) 3 4 *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) Alviggi C. and Conforti A., Frontiers in Endocrinology in press

22 Low FOI ( 0.5) Hypothetical Pathogeneisis Low gonadotropin starting dose Genetic or environmental factors Asynchronous follicular development Technical issues involving triggering for final oocyte maturation and/or oocyte pick-up Alviggi C. and Conforti A, Frontiers in Endocrinology in press

23 Group A Low Level Group B High Level Alviggi et al. 2014

24 FSH ampoules (n) FSH-R Ser680 carriers have low FORT/FOI and require more FSH * * Perez Mayorga, et al. 2000; Sudo, et al. 2002; Choi, et al. 2004; Falconer, et al n=46 n=72 n=43 Greb, et al. JCEM, 2005; Gromoll & Simoni TEM Alviggi et al., * Asn/Asn Asn/Ser p < 0.05 Ser/Ser

25 Four Groups of Patient with Low Prognosis Patients with expected low prognosis What strategies could be adopted? and how many eggs we need? 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 prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016

26 Age Mean number of oocytes needed and age < COCs 11 COCs 18 COCs 5 MII oocytes 9 MII oocytes 16 MII oocytes 4 fertilized oocytes 7 fertilized oocytes 13 fertilized oocytes 2 blastocysts 3 blastocysts 5 blastocysts Euploidy rate 60% Euploidy rate 30% Euploidy rate 20% 1 euploid blastocyst 1 euploid blastocyst 1 euploid blastocyst Courtesy of F. Ubaldi

27 Four Groups of Patient with Low Prognosis Four Groups of Patient with Low Prognosis So we need many eggs from women with low reserve! 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 prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016

28 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

29 Increasing dosage during stimulation could be of use in women with low ovarian reserve? Standard dose: 150IU/day High dose: IU/day van Tilborg et al. 2017

30 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 simultaneously Group (LR-fresh) undergoing IVF/embryo transfer with fresh oocytes in each stimulation cycle

31 Accumulation strategy

32 Double stimulation in POR (Shanghai protocol)

33 DuoStim in women with low reserve % 23 53% 30 70% Follicular phase (FP) stimulation Luteal phase (LP) stimulation Cumulative Patients with no euploid blastocysts Patients with 1 euploid blastocyst Courtesy by F. Ubaldi

34 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

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36 Acknowledgments C. Alviggi G. De Placido Special thanks: Poseidon Group I. Strina S. Picarelli R. Vallone B. Buonomo University of Naples Federico II Reproductive Medicine IVF Unit Fertunina

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