L6: DuoStim: the alternative of oocytes/embryos accumulation programs

Carlo Alviggi Italy

What is the aim of IVF?

Cumulative live birth rate

per started cycle

What is the measure of

success in IVF ?

Live birth of an

healthy baby

Courtesy by F. Ubaldi

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

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

number of oocytes that

best optimized LBR was 15

Can we ever collect too many oocytes?

… if we retrieve many oocytes this means that

we will have less competent oocytes and less

competent blastocysts?

Courtesy by F. Ubaldi

More oocytes means more euploid blastocysts

Mea

n n

um

ber

of

MII

oo

cyte

s

Mean number of euploid blastocyst

Pearson’s correlation R=0,426 P<0,01

Colamaria, Ubaldi oral presentation, ESHRE 2015

27,6%

35,2%

34,8%

Mea

n n

um

ber

of

MII

oo

cyte

s

Mean number of blastocyst

Pearson’s correlation R=0,636 P<0,01

915 PGS cycles (2610 blastocysts, 24 chr analysis, one Centre),

mean female age 39,2 years

Euploidy rate is consistent across the number of MII oocytes retrieved

Euploidy rate is independent from the number

of obtained blastocysts but not from female age

Number of blastocysts

% normal embryos

egg donors

<35 y

35-37 y

38-40 y

41-42 y

>42 years

1-3 58% 61% 51% 39% 22% 13%

4-6 62% 60% 52% 38% 23% 17%

7-10 65% 62% 51% 36% 21% 14%

>10 68% 63% 55% 37% 25% n/a

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 (2012) Reprod Biomed Online and unpublished data

The more oocytes, the higher is the CLBR

The more oocytes, the higher is the CLBR

Ji et al Hum Reprod 2013 Fatemi et al Hum Reprod 2013

Can we overcome POR/poor prognosis

by increasing the FSH dose?

Yes, if the cause of POR is:

- Not reaching the threshold for stimulation

- SNPs for FSH-R associated with lower follicular sensitivity

NO, if the cause of POR is:

- The presence of very few antral follicles

- Higher doses of Gn will not create follicles de-novo

… and then how to increase the number

of oocytes to maximize live birth rates? Courtesy by F. Ubaldi

GROUP 1

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

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

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)

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)

Poseidon groups where oocyte/blastocyst accumulation

is an option…

Four Groups of Patient with Low Prognosis

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)

… But how many eggs we need?

Four Groups of Patient with Low Prognosis

Mean number of oocytes needed and age

<35 39-40 42-43

Euploidy rate 60%

1 euploid blastocys

t

1 euploid blastocys

t

1 euploid blastocys

t

Euploidy rate 30% Euploidy rate 20%

2 blastocysts ≈

4 fertilized oocytes ≈

5 MII oocytes ≈

6 COCs ≈

Age

3 blastocysts ≈

7 fertilized oocytes ≈

9 MII oocytes ≈

11 COCs ≈

5 blastocysts ≈

13 fertilized oocytes ≈

16 MII oocytes ≈

18 COCs ≈

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

How can we do it if no Gn can compensate?

Four Groups of Patient with Low Prognosis Four Groups of Patient with Low Prognosis

Previous studies have shown that existing antral follicles in the luteal phase enable ovarian stimulation (Huang et al. 2013)

Luteal-phase stimulation was originally used to produce mature oocytes and embryos for cryopreservation in case reports of emergency fertility preservation and letrozole cycle (Huang et al. 2013 Bedoschi et al. 2010; Sonmezer et al. 2011)

Introduction

DUO-STIM

In 2003, based on ultrasonographic studies, two or three follicular waves during the intraovulatory period of healthy women. It was suggested that follicles developing during the LP may have the potential to ovulate in the presence of an luteinizing hormone (LH) surge, offering new possibilities for ovary stimulation (Baerwald et al. 2003)

Documentation of major and minor follicular waves during the menstrual cycle challenges the traditional theory that a single cohort of antral follicles grows only during the follicular phase of the menstrual cycle.

Sixty-eight percent of women exhibited two waves of follicle development during the IOI and 32 %exhibited three waves. Waves were characterized by an increase and subsequent decrease in the number of follicles 5 mm occurring in association with the growth of 2 follicles to 6 mm.

Baerwald et al Hum Reprod Update 2013 Adams GP et al., J Reprod Fertil, 1992

n. of follicles >5 mm diameter of the largest follicle Baerwald et al, Fertil Steril 2003

2

1

14 8 20 26

Day of cycle

Follicle waves in a menstrual cycle

DUOSTIM in low prognosis patients

Ubaldi, Vaiarelli, Alviggi, Trabucco, Zullo, Capalbo, Cimadomo, Rienzi ASRM, 2015

Patient Age AMH AFC (1°stim) 1° stim oocytes retrieved 2° stim

CA 38 0,6 7

DV 38 0,4 6

DG 35 0,5 4

IM 38 1,0 7

LS 32 1,3 6

BA 41 0,1 5

SI 37 0,6 5

VS 43 0,5 5

DO 37 1,2 9

MS 36 0,7 5

BF 40 0,2 4

SMF 42 0,7 6

SC 34 0,4 5

SE 38 0,8 2

no follicles

oocytes blastocysts

1° stimulation 2° stimulation P

Oocytes (mean SD) 4.94 + 1.86 5.83 + 3.99 ns

DUOSTIM in low prognosis patients

DuoStim in POR/poor prognosis patients

51 patients with poor ovarian

reserve (AMH <1,5 ng/ml, AFC < 6

follicles and/or < 5 oocyte retrieved

in previous COH) undergoing ICSI

treatment and PGT-A

51 patients started the first stimulation cycle

6 excluded: -no response to the

stimulation

45 patients to egg retrieval

43 patients to egg retrieval

18 FP stimulation cycles with euploid

blastocyst obtained

42 patients performing FP ICSI

42 patients performing LP ICSI

2 excluded: -2 no sperm available

Ub

ald

i et al Fertil Steril 2

01

6

23 LP stimulation cycles with euploid

blastocyst obtained

Primary outcome measure:

euploid blastocyst rate.

Secondary outcome measures:

#of retrieved COCS and MII oocytes

Huge intra & inter-cycle variability

MII oocytes that did not reach blasto- cyst stage

MII oocytes that made aneuploid blastocyst

MII oocytes that made euploid blastocyst

DuoStim in POR/poor prognosis patients

18 23

30

25 20

13

Follicular phase (FP) stimulation

Luteal phase (LP) stimulation

Cumulative

Patients with ≥1 euploid blastocyst

Patients with no euploid blastocysts

70% 53% 42%

Courtesy by F. Ubaldi

Cumulative live birth rates per started cycle should be considered as a

measure of success in IVF

The number of oocytes is a key factor to maximize CLBR and it must

optimized according to the ovarian reserve of the patients

Luteal phase stimulation gives competent oocytes with live births

In low prognosis patients (Groups 3 – 4 Poseidon) DuoStim can maximize

the number of oocytes per menstrual cycle increasing the chance of

obtaining the embryo that can give a live birth and it could be applied

in all patients with few “fertile time” left available

Take-home message

a) Consists of two consecutive ovarian stimulation taken during two consecutive menstrual cycles

b) Could be suggested in Poseidon groups 3 or 4

c) Requires maximum gonadotropin dosage during controlled ovarian stimulation

d) Usually allows fresh embryo transfer

25

The Duo-Stim approach

*The correct answer is the green one

G. De Placido I. Strina

T. Pagano

A. Conforti

P. De Rosa

R. Vallone

S. Picarelli

C. Buonfantino

I.Nuzzo

F.M. Ubaldi

Università degli Studi di Napoli “Federico II”