Management of low prognosis patients

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BEST DATA PLANLorem Ipsum has two main statistical methodologies are used in data analysis which
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Management of low
prognosis patients
Dr. Matheus Roque
ORIGEN – Center for Reproductive Medicine -
BRAZIL
Singapore

Presentation Goals
THE BEST OVARIAN STIMULATION
THE BEST TRIGGER
THE BEST MOMENT
- Low prognosis patients – new stratification
- To add or not to add LH ?
- hCG?
- GnRH agonist?
- Dual trigger?
- Fresh vs. Freeze-all
Are we forgetting something?

INDIVIDUALIZATION
Management of low prognosis patients
Similar Groups
Compare Results
Research
Select the best protocol for each group
Individualized Controlled
Ovarian Stimulation
(iCOS)
Individualized
LAboratory TEchniques
(iLATE)
Individualized
Embryo Transfer
(iET)
Biomarkers of ovarian response
STRATIFICATION

INDIVIDUALIZATION
Select the best protocol for each group
Individualized Controlled
Ovarian Stimulation
(iCOS)
Individualized
Embryo Transfer
(iET)
STRATIFICATION

NORMAL HIGHPOOR
Stratification
Traditional
Stratification
1-3
oocytes
4-15
oocytes
> 15
oocytes
?

16.9%
29.7%
33.4%
32.1%
1-3 oocytes4-9 oocytes10-15 oocytes>15 oocytes
Drakopoulos et al., Hum Reprod 2016
21.7%
39.7%
50.5%
61.5%
LIVE-BIRTH FRESH CYCLE CUMULATIVE LIVE-BIRTH
SUB-OPTIMAL RESPONDER
Stratification

Sub-optimal / Hypo-responders
• 10%-15%ofpatients withnormalAFCandAMHwillpresent aninadequate
response
• Granulosa cellsHypo-sensitivity toFSH;Suboptimal response (4-9oocytes)
• Associatedwithhigher FSHdoses (>2,500IUFSH);lowerpregnancy rates
• Genomic profile->Polymorphisms (most commonFSHreceptor andv-betaAlviggi et al., Springer 2016
5º. – 6º. day
COS

Genro et al., Hum Reprod 2011
Follicular Output RaTe (FORT)
Antral follicle responsiveness to FSH

Genro et al., Hum Reprod 2011
Antral follicle
(3-8mm) count (AFC)
at baseline
Pre-ovulatory follicle
(16-22 mm) count (PFC)
on day of hCG
PFC x 100
AFC
FORT
Calculation
Follicular Output RaTe (FORT)

Sub-optimal / hypo-responders
Polymorphism
FSH receptor gene LHβ gene
Laan et al., Curr Opin Endocrinol Diabetes Obes, 2012 Manna et al., Hum Mol Genetics, 2002

Stratification
Traditional
Stratification
1-3
oocytes
4-15
oocytes
> 15
oocytes
POOR
SUB
OPTIMAL
OPTIMAL
HIGH
NORMAL HIGHPOOR
New stratification ?
What about the
POOR RESPONDERS?

Stratification
POOR RESPONDERS - BOLOGNA CRITERIA
Ferraretti et al., Hum Reprod 2011
OR
≧40y
OR
follicles
2 of 3
EvenBologna criteria canbeHETEROGENEOUS…
Decreasedoocytequality/increasedembryoaneuploidy

All available stratifications
POOR
SUB
OPTIMAL
OPTIMAL
HIGH
Only
QUANTITY !
What about
QUALITY !

The importance of the NUMBER / QUALITY of
oocytes
The importance of the number of oocytes

oocytes
NEW CONCEPT - POSEIDONPOSEIDON Group
Patient-Oriented Strategies Encompassing
IndividualizeD Oocyte Number
LOW PROGNOSIS PATIENTS
POSEIDON Group, Fertil Steril 2016

POSEIDON GROUP
Created in 2015 (Carlo Alviggi_Itália)
Peter Humaidan
(Dinamarca)
Klaus Bühler
(Alemanha)
Robert Fischer
(Alemanha)
Alessandro Conforti
(Itália)
Sandro Esteves
(Brasil)
Claus Andersen
(Dinamarca)
Filippo Ubaldi
(Itália)
Founders:

* Individualized treatment based on prognostic
categories
*Ability to retrieve the number of oocytes necessary to
obtain at least one euploid embryo for transfer in
each patient
oocytes
NEW CONCEPT - POSEIDON

POSEIDON
Low Prognosis Patients
YOUNG
Poor response
ADVANCED REPRODUCTIVE AGE
Poor response
YOUNG
Poor response
ADVANCED MATERNAL AGE
Poor response
GOOD OVARIAN RESERVE
POOR OVARIAN RESERVE

POSEIDON
*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 3
< 35 years
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
GOOD OVARIAN RESERVE
(AFC ≥5; AMH ≥1.2ng/mL)
*Group 4
≥35 years
POOR OVARIAN RESERVE
(AFC<5; AMH<1.2 ng/mL)
Hypo-
responders

POSEIDON CALCULATOR
* POSEIDON Calculator – process of validation – Courtesy from Sandro Esteves

Presentation Goals

LH and Folliculogenesis
Courtesy from Dr Sandro Esteves

LH and Folliculogenesis
Courtesy from Dr Sandro Esteves
Who needs LH supplementation ?

Indications for LH supplementation:
• Hypo- / Suboptimal response
Who needs LH supplementation?

• Advanced maternal age (>35 years old)

• Advanced maternal age (>35 years old)
• Poor Ovarian Responders ?

I will add LH, however...
Rec-LH or hCG (hMG) ???

Esteves SC, 2015
LH vs hCG
Differences in LH activity of gonadotropins

LH vs. hCG
Esteves and Alviggi, Springer 2015
LH vs. hCG – are there differences in embryo
quality?

The effect of stimulation protocols in embryo quality
Embryo Viability Assessment
Unpublished data - Marcos Meseguer
N= 319 ICSI cycles
• r-FSH + r-LH vs. hMG
LH vs. hCG
Oocyte / Embryo Quality

N= 319 ICSI cycles
LH vs. hCG

N= 319 ICSI cycles
• r-FSH + r-LH vs. hMG 0
2
4
6
8
10
12
14
hMG (n=1005) FSH+LH (n=427)
7.86
12.18
% of HIGH EMBRYOS p=0,035
*
LH vs. hCG

N= 319 ICSI cycles
% of HIGH quality embryos (Eeva) according to stimulation
protocols;
Logistic Regression analysis
Model effect values OR p value
Gonadotrophin FSH+LH vs. hMG 1.88 (1.17-3.02) 0.010
Oocyte recovered number 0.99 (0.97-1.03)
per oocyte
NS
Age Years 0.96 (0.97-1.03) NS
BMI Units 0.94 (0.94-1.02) NS
FSH+LH protocol produce 1.88 times more HIGH quality
embryos according to Eeva Algorithm
LH vs. hCG

LH vs hCG
Clinical evidence ?

Fábregues et al., Gynecol Endocrinol 2014
LH vs hCG
Clinical evidence
* Disclaimer: Lutropin alfa concomitantly administered with Follitropin Alfa for injection is indicated for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L)’.

Bühler and Fischer, Gynecol Endocrinol 2012
LH vs hCG
Clinical evidence
* Disclaimer: Lutropin alfa concomitantly administered with Follitropin Alfa for injection is indicated for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L)’.
0
5
10
15
20
25
30
35
No. Oocytes Implantation Rate Clinical Pregnancy Rate
9
19
31.3
7.8
13.9
26
%
r-hFSH + r-hLH (n=1,573) hMG (n=1,573)
German IVF Register

Revelli et al, Reprod Biol and Endocrinol 2015
LH vs hCG
Pregnancy rate / embryo transfer vs. No. MII

Revelli et al, Reprod Biol and Endocrinol 2015
LH vs hCG
OR pregnancy

Presentation Goals
THE BEST TRIGGER
- hCG?
- GnRH agonist?
- Dual trigger?

• Traditionally -> hCG
• Mimic LH surge
• Resumption of meiosis
Trigger

• OHSS
• Moreover...
• hCG
Trigger
Problems with hCG trigger

Evans and Salamonsen, Hum Reprod 2013
Trigger

• Experimental model of
chronic low-dose and
acute high-dose hCG
exposure
hCG secreted by the blastocyst
hCG for triggering
Trigger

• Experimental model of
chronic low-dose and
acute high-dose hCG
exposure
hCG secreted by the blastocyst
hCG for triggering
Chronic low-dose hCG exposure mediated a down regulation and
internalization of the LHCGR in endometrial epithelial cells
Trigger

• Mimic LH surge
Thus…
Potential problems with hCG trigger:
1. Safety – OHSS risk
2. Efecttiveness – altered endometrial pattern
hCG Trigger

• Mimic LH surge
Thus…
Potential problems with hCG trigger:
1. Safety – OHSS risk
2. Efecttiveness – altered endometrial receptivity?
SOLUTION???
hCG Trigger

• In natural / antagonist cycles
• LH surge and also FSH surge
GnRH agonist Trigger

• Concerned about the longer half-life of hCG compared to LH

FSH surge:
1. + plasminogen activator activity with granulosa cells (GC) ->
dissociating the oocyte from the follicular wall and weakening the
wall (Strickland et al., 1976; Morioka et al., 1989)

FSH surge:
2. Improved oocyte recovery with ↑ follicular fluid FSH levels
(Rosen et al., 2009)

FSH surge:
2. Improved oocyte recovery with ↑ follicular fluid FSH levels
(Rosen et al., 2009)
3. FSH -> + LH receptors in GC; gap junctions opened between the
oocyte and cumulus cells; nuclear maturation; cumulus expansion
(Atef et al., 2005; Zelinski-Wooten et al., 1998; Andersen et al., 1999)

•Deficient luteal phase support
The problem with GnRHa trigger

• Luteal phase support
Youssef et al, Cochrane 2014
Live Birth Rate GnRH agonist vs. hCG for triggering
OR 0.47 (95% CI: 0.31-0.70)

• Luteal phase support
Youssef et al, Cochrane 2014
Live Birth Rate GnRH agonist vs. hCG for triggering
OR 0.47 (95% CI: 0.31-0.70)
HOWEVER…

• Modified luteal phase support with LH activity
Haahr and Roque et al, ESHERE 2017
Figure 2. GnRHa trigger + modified LPS with LH activity versus hCG trigger, critical outcome live birth - ITT
Live Birth Rate GnRH agonist + modified LH activity LPS vs. hCG for
triggering
OR 0.77 (95% CI: 0.56-1.05)

• POTENTIAL ADVANTAGES OF GnRH agonist + hCG TRIGGER
• Increased luteal function with supplementation of hCG -> optimal support for
pregnancy
Dual trigger

• RCT – hCG group (n=106) vs. hCG + triptorelin (n=105)
• hCG 5,000 IU vs. Triptorelin 0.2mg + hCG 5000 IU
Schachter et al, Fertil and Steril 2008
29.1
22.3
44.3
36.1
0
5
10
15
20
25
30
35
40
45
50
PR per ET Ongoing PR per ET
%
hCG only Dual trigger
Dual trigger

Lin et al, Fertil and Steril 2013
• Retrospective study – hCG group (n=187) vs. hCG + triptorelin (n=191)
• R-hCG 6,500 IU vs. Triptorelin 0.2mg + hCG 6,500 IU
10.1
8
1.6
12.4
10.5
1.97
0
2
4
6
8
10
12
14
No. retrieved oocytes No. MII oocytes No. embryos cryop
%
hCG only Dual-trigger
P<0.05
Dual trigger

• Retrospective study – hCG group (n=187) vs. hCG + triptorelin (n=191)
• R-hCG 6,500 IU vs. Triptorelin 0.2mg + hCG 6,500 IU
Lin et al, Fertil and Steril 2013
18.43
40.11
30.4929.68
50.79
41.36
0
10
20
30
40
50
60
Implantation Rate CPR per ET LBR per ET
%
hCG only Dual-trigger
Dual trigger

Presentation Goals
THE BEST TRIGGER
THE BEST MOMENT
- hCG?
- GnRH agonist?
- Dual trigger?

Freeze-all for all? Better outcomes?

Ongoing Pregnancy
Clinical Pregnancy
INTENTION-TO-TREAT
32%
31%
Roque et al., Fertil. Steril. 2013
Fresh vs. FREEZE-ALL

INTENTION-TO-TREAT
32%
31%
Ongoing Pregnancy
Clinical Pregnancy

- D+3 / Fresh embryo transfer only with P<1.5 ng/mL
- Observational study
RR = 1.33 (1.07-1.65)
RR = 1.28 (1.01-1.62)
26.5
39.7
19.9
31.1
0
5
10
15
20
25
30
35
40
45
Implantation rate Ongoing pregnancy rate
%
FREEZE-ALL (n= 179) FRESH (n=351)
Roque et al., Fertil. Steril. 2015
Logistic Regression- Freeze-all e OPR
OR 1.73 (1.16-2.58)

Chen et al., NEJM. 2016
RCT - PCOS

Chen et al., NEJM. 2016
RCT - PCOS
Freeze-all vs. Fresh
Live birth– RR 1.17 (1.05-1.31)
Miscarriage (clinical pregnancies) – RR 0.58 (0.44-0.77)

Coates et al., Fertil. Steril. 2017
Randomized clinical trial – PGS (D+5)
Intention-to-treat analysis
62.6 61.5
40.9 39.8
0
10
20
30
40
50
60
70
Ongoing Pregnancy Live Birth Rate
%
Freeze-all (n=91) Fresh (n=88)

Freeze-all for all
What about obstetric and perinatal outcomes?

Roque et al., ESHRE 2016
Fresh vs. FET: Ectopic Pregnancy
Last 20 years
929,431 pregnancies
FET vs. Fresco – OR = 0.80 (0.67-0.95)

Last 20 years– CLEAVAGE
70,871 pregnancies
FET vs. Fresh – OR = 0.73 (0.65-0.81)

Last 20 years – Blastocyst
179,541 pregnancies
FET vs. Fresh – OR = 0.52 (0.42-0.64)

FET vs. Fresh: Pre-term
219,356 pregnancies
FET vs. Fresh – adjusted OR = 0.90 (0.84-0.96)

Roque et al., 2016 – unpublished data
FET vs. Fresh: Small for Gestational Age
Age
104,180 pregnancies
FET vs. Fresh – OR = 0.59 (0.56-0.63)

Roque et al., 2016 – unpublished data
FET vs. Fresh: Low Birth Weight
126,503 pregnancies
FET vs. Fresco – OR = 0.72 (0.65-0.80)

Freeze-all
for all ???
Why ???
NO!
INDIVIDUALIZATION

Placenta Accreta: FET vs. Fresh
48,158 pregnancies
FET vs. Fresco – adjusted OR = 3.51 (2.04-6.05)

FET vs fresh: hypertensive disorders
48,926 pregnancies
FET vs. Fresh – adjusted OR = 1.82 (1.24-2.68)

FET vs fresh: Macrossomia
Santucci and Roque et al., 2016 – unpublished data
69,826 pregnancies
FET vs. Fresco – OR = 1.64 (1.37-1.96)

Wong et al., Cochrane 2017

Freeze-all in Normal responders
*Prospective Observational / D+3
N=938 IVF cycles
Roque et al., JARG 2017
Freeze-all for all?

Roque et al., JARG 2017
SUB-OPTIMAL (4-9 oocytes) – no benefit with Freeze-all
NORMAL (10-15 oocyte) – BENEFIT with Freeze-all
Freeze-all in Normal responders
*Prospective Observational / D+3
N=938 IVF cycles
Freeze-all for all?

Freeze-all – stratification
Ongoing Pregnancy
13.4
31
34
13.7
33
47
0
5
10
15
20
25
30
35
40
45
50
1-3 oocytes 4-9 oocytes 10-15 oocytes
Fresh Freeze-all
N=277 N=156
N=380 N=243
N=143 N=172
No benefit
No benefit
Freeze-all for all?
9.5 10.1

Ongoing Pregnancy
Roque et al., ESHRE 2017; Roque et al., JARG 2017
13.4
31
34
13.7
33
47
0
5
10
15
20
25
30
35
40
45
50
Fresh Freeze-all
N=277 N=156
N=380 N=243
N=143 N=172
No benefit
No benefit
Freeze-all for all?
9.5 10.1

Ongoing Pregnancy
13.4
31
34
13.7
33
47
0
5
10
15
20
25
30
35
40
45
50
Fresh Freeze-all
N=277 N=156
N=380 N=243
N=143 N=172
No benefit
No benefit
Freeze-all for all?
9.5 10.1
Benefit

Ongoing Pregnancy
13.4
31
34
13.7
33
47
0
5
10
15
20
25
30
35
40
45
50
Fresh Freeze-all
N=247 N=131
N=380 N=243 N=143 N=172
No benefit
No benefit
Freeze-all for all?

Testicular vs Ejaculated Sperm in high SDF

Esteves SC, AJA 2017

Esteves SC, Unpublished data

Take-Home
MessageTHE BEST OVARIAN STIMULATION
THE BEST TRIGGER
THE BEST MOMENT
- hCG?
- GnRH agonist?
- Dual trigger?
Are we forgetting something?

To make our patients’ dream come
true…
The details can really make the difference!

Thank you!
matheusroque@origen.com.br
matheusroque_mr
pt.slideshare.net/MatheusRoque1

Management of low prognosis patients

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