Principles and practices in individualizing in ART

Principles and Prac-ces of Individualiza-on in ART

UAE Reproductive Symposium 2015 - Dubai

Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT

Andrology & Human Reproduc=on Clinic Campinas, BRAZIL

Learning Objec-ves

1.  Individualiza-on: a quality concept 2.  How to individualize COS to different

pa-ent subgroups 3.  How to individualize triggering 4.  How to individualize luteal support

ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015

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Why individualize?


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Maximize beneficial effects of treatment Minimize complica-ons and risks

Why individualize?


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Top 3 clinical dimensions for quality improvement in infer-lity care

•  Effec-veness: Technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumula=ve LBR)

•  Safety: Complica=ons (OHSS), adverse effects, risks (pa=ent & offspring), errors/mistakes

•  Pa-ent-‐centeredness: Informa=on and pa=ent involvement, competence and aPen=on of clinic and staff, accessibility, coordina=on and integra=on, emo=onal support


ANDROFERTDancet et al. Hum Reprod 2011; Mainz Int J Qual Health Care 2013

How stakeholders value the top 3 quality dimensions of infer-lity care


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0% 50% 100%

Doctors & embryologists

Nurses

Pa-ents Safety

Effec-veness

Pa-ent-‐centeredness

Dancet et al. Hum Reprod 2013

Lack of psychological support and poor quality of service ~60% treatment discon-nua-on


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22 studies 21,453 pa=ents 8 countries

Individualiza-on is a quality concept


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Safety

Pa-ent-‐ centeredness

Effec-veness

How to individualize?


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Individualizing S-mula-on Protocols


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• Clinical characteris-cs

• Ovarian biomarkers

Iden-fy who is who

• Pa-ent-‐centered • Effec-ve • Safe

Protocol

What biomarker do you value more?

a. Basal FSH b. AMH c. AFC d. Age

AMH ~ AFC > FSH > Age


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Popula-on Cutoff Sensi-vity Specificity Accuracy

AMH

ng/m

L

High-‐responder1 2.1 85% 79% 0.82

Poor responder2 0.82 76% 86% 0.88

*Beckman-‐Couter genera-on II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16

AMH & AFC should be internally validated


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Quality-‐based individualiza-on in COS


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High responders*

Normal responders*

Low responders*

Biom

arkers Safety


Effec-veness

*expected

High responders


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• Main goal: Safety •  Clinical quality indicator: OHSS •  Protocol of choice*: Antagonist (flexible; cetrorelix) Tailored recFSH (112.5-‐150 IU/d; follitropin alfa; pen injector)

*Androfert, Brazil

GnRH antagonists in high responders


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9 RCT; 966 PCO women Rela-ve Risk Dura-on of ovarian s-mula-on -‐0.74 (95% CI -‐1.12; -‐0.36) Gonadotropin dose -‐0.28 (95% CI -‐0.43; -‐0.13) Oocytes retrieved 0.01 (95% CI -‐0.24-‐0.26) Risk of OHSS

Mild Moderate and Severe

20% vs 32% 1.23 (95% CI 0.67-‐2.26) 0.59 (95% CI 0.45-‐0.76)

Clinical PR 1.01 (95% CI 0.88; 1.15) Miscarriage rate 0.79 (95% CI 0.49; 1.28)

Pundir J et al. RBM Online 2012; 24:6-22

iCOS (n=118): rec-‐hFSH 112.5-‐150 IU + GnRH antagonist (flexible) cCOS (n=131): rec-‐FSH 150-‐225 IU + GnRH agonist (nafarelin)

39.3

18.5 14.0

57.0

14.3 14.7 4.8

56.0

0 10 20 30 40 50 60

Observed Excessive

Response (%)

Oocytes retrieved (N)

OHSS (%) Pregnancy (%)

cCOS iCOS *p<0.05

* *

Individualized vs conven-onal COS in high responders

Excessive response >20 oocytes retrieved; Mild/severe OHSS reported; Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16


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*

Poor responders


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• Main goal: pa-ent-‐centeredness •  Clinical quality indicators: – Compliance (drop-‐out rate) – Pa-ent burden (cancela-on rate)

•  Protocol of choice*: Antagonist (flexible; cetrorelix) recFSH + recLH (follitropin alfa + lutropin alfa 2:1 ra=o: 300 IU recFSH + 150 IU recLH); start D1 s=mula=on

*Androfert, Brazil

Pregnancy rates increased by 30% in poor

responders treated with

rLH+rFSH

Lehert et al Reprod Biol Endocrinol 2014, 12:17


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Lehert et al 2012

Increase of ≈1 oocyte per 1,000

UI in poor responders

treated with rLH+rFSH

Lehert et al Reprod Biol Endocrinol 2014, 12:17


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Individualized vs. Conven-onal COS in Expected Poor Responders (N=118)

72.0

3.5

45.0

20.0

46.6

4.8

23.3 26.8

0

20

40

60

80

Observed Poor Response (%)

Oocytes retrieved (N)

Cancella=on (%) Pregnancy/cycle (%)

cCOS (Long GnRHa + 300-‐450 IU recFSH alone) iCOS (GnRH antagonist + rFSH (225-‐300 IU) +rLH (75-‐150 IU))

Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved;

Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16

*p<0.05

*

* *


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Normal responders


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•  Main goal: effec-veness •  Clinical quality indicators: number oocytes •  Protocol of choice*: <35yr: Antagonist + recFSH

cetrorelix (flexible); 187.5-‐262.5 IU/d follitropin alfa pen injector

>35yr: Antagonist + recFSH/recLH cetrorelix (flexible); follitropin alfa + lutropin alfa

2:1 ra=o; 225-‐300 IU/d; from s=mula=on D1

*Androfert, Brazil

Nega-ve predictor

Posi-ve predictor

van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589

Female Age (OR=0.95; CI: 0.94-‐0.96) Number of oocytes retrieved (OR=1.04; CI: 1.02-‐1.07)

Level

1a Predictors of pregnancy in IVF

14 studies >30,000 pa=ents


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What is the optimum number of retrieved oocytes to

increase pregnancy rates ?

a.  4 to 8 b.  9-12 c.  13-17 d.  The higher the better

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

Live

birt

h ra

te (%

)

Oocyte number

Observed live birth rate Predicted live birth rate

Sunkara et al. Hum Reprod 2011

450,135 IVF cycles

Best chance of live birth is associated with ~15 oocytes

number of oocytes that best optimized LBR was 15


ANDROFERT


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...irrespec-ve of age group

Do you take into account the severity of male factor

infertility when planning COS?

a.  Yes b.  No c.  Never though about it

41.4 47 43.3 20

100 64 61 34.2

Sperm retrieval (%)

2PN Fertilization

(%)

Top Quality Embryos (%)

Live Birth (%)

Non-obstructive (N=365) Obstructive (N=146)

P<0.01


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3,412 cycles

Oocyte number and LBR at Androfert (ICSI cycles involving severe male factor)


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0%

10%

20%

30%

40%

50%

60%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 Number of oocytes

Clinical pregnancy

Live birth

Each addi-onal warming cycle increases the chance of achieving a live birth

40.4% 48.0%

ET #3 (FET) 49

ET #2 (FET) 239

ET #1 (fresh) 822

50.5% +18.8%

+25.0% Female Age ≤38

332/822 63/239 17/49


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Oocyte yield by gonadotropin

↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012

↑ 3.1 oocytes (GnRH antagonist) Bosch et al., 2008

↑ 1.8 oocytes (GnRH agonist cycles) MERIT Study, 2006

↑ 2.8 oocytes (GnRH agonist cycles) Hompes et al., 2008

↑ 2.1 oocytes (16 RCT; different protocols) Lehert et al., 2010

Higher with rec-‐FSH vs. hMG, HP-‐hMG, and uFSH


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LH supplementa-on improves clinical pregnancy in women >35 yr

Hill et al. Fer5l Steril 2012


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LH ac-vity by rec-‐LH vs hMG

Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.

Product LH ac-vity (IU/vial)

LH content* Purity

hMG 75 hCG ~5% HP-‐hMG 75 hCG ~70% Lutroprin alfa (rec-‐hLH) 75 LH >99% 2:1 Follitropin alfa + Lutroprin alfa (rec-‐hFSH + rec-‐hLH)

75 LH >99%

*hCG concentrated or added during purifica-on process (8IU hCG ~ 75IU LH)


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LH and hCG elicit different gene expression

LH hCG

LHR and FSHR expression (Trafficking of re=noic acid : RXRB, TTR, ALDH8A1) Meiosis and follicular matura-on (TRA : RXRB, TTR, ALDH8A1; IL11; AKT3)

Follicular development (IL11; AKT3) Cellular growth (RXRB, TTR, ALDH8A1; IL11;AKT3)

Ovarian stereodogenesis (TRA : RXRB, TTR, ALDH8A1)

Embryo development & survival (AKT3)

Aromatase inhibi-on (PPARS) Apoptosis

enhancement (DNAsi)

LH hCG

Grondal ML et al. FerCl Steril 2009; Menon KM et al. Biol Reprod 2004; Ruvolo et al. Fer=l Steril 2007


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COS with LH ac-vity delivered by rec-‐LH vs hMG in IVF

Authors, yr. Design N Main findings Buhler & Fisher, 2011

Matched case-‐control

4719 Higher CPR in fixed 2:1 rec-‐FSH + rec-‐LH (31%) vs hMG (26%) and vs combo (rec-‐FSH + hMG, 25%); p=0.02

Fábregues et al, 2013

Cross-‐over study

66 Higher N oocytes in fixed 2:1 rec-‐FSH + rec-‐LH (9.8) vs HP-‐hMG (7.3); p<0.01. Higher N frozen embryos in recLH

Dahan et al, 2014

Observa=onal 201 Higher N oocytes in rec-‐LH (12) vs hMG (10); p=0.008. Higher CPR rec-‐LH (36% vs 20%; p=0.02)


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Individualizing trigger and LPS


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High responders

Normal responders

Low responders

Safety


Effec-veness

14h

14h 20h

48h 0 20 h

Natural LH surge

hCG

Adapted from Chan et al. Hum Reprod. 2003;18:2294-‐7

Day 6

hCG and GnRHa elicit final follicular matura-on as surrogates for the mid-‐cycle LH surge

GnRHa

36-48 h


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Day 8

GnRH-‐agonist vs hCG trigger

Fresh autologous cycles

Moderate/ severe OHSS

OR 0.10 0.01-‐0.82

Live birth OR 0.44 0.29-‐0.68

Youssef et al. Cochrane Database Syst Rev. 2011

High responders

Fresh ET Freeze all

GnRH-‐a trigger

One size trigger does not fit all


ANDROFERT

Freeze-‐all embryo policy: is it for all? •  Non-‐inferior in effec-veness in high-‐quality vitrifica-on programs, but… •  Safety –  Increase ART unit workload – Perinatal outcome •  Higher rate of large for gesta-onal age (Wennerholm HR 2013)

•  Pa-ent-‐centeredness – Psychological & cost burden


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Modified LPS for fresh ET in GnRH-‐a trigger

No. follicles day OPU 1,500 IU hCG at OPU & 1,000

OPU+5 & standard LPS ≤ 14

1,500 IU hCG at OPU + standard LPS 15-‐25

1,000 IU hCG at OPU + standard LPS or Freeze all 26-‐30

Freeze all >30 Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21


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14h

14h 20h

48h 0 20 h

4h

GnRHa

Natural LH surge

Luteal phase defect

Individualizing trigger


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Normal & poor responders

rec-‐hCG u-‐hCG

hCG trigger

RCT N Effect

Oocytes retrieved 9 1409 MD: -‐0.04

95% CI: -‐0.69 to 0.61

Live birth 6 1,019 OR: 1.04 95% CI: 0.79 to 1.37

Miscarriage 7 1,106 OR: 0.69 95% CI: 0.41 to 1.18

Severe OHSS 3 549 OR: 1.49 95% CI: 0.54 to 4.1

Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719 Databases searched up to January 2010


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Farrag et al. JARG 2008; 25:461-6

8.4 7.3 7.1 4.7

0 2 4 6 8

10

No. Retrieved oocytes No. MII with mature cytoplasm

rec-hCG (250 mcg; n=42)

u-hCG (10,000 IU; n=47)

*p<0.01 *


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Effec-veness RCT comparing trigger with rec-‐hCG (250 mcg) vs

u-‐hCG (10,000 IU) on delivery rates in eSET antagonist cycles

26.7% 44.1%

Delivery rate (%)

u-hCG rec-hCG

N=119 aged<32

OR: 2.16 (95% CI: 1.01-‐4.67; p=0.04) Papanikolaou EG et al. Fer5l Steril 2010; 94:2902-‐4


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RCT N Odds-‐ra-o

Local site reac-ons* rec-‐hCG vs. u-‐hCG 3 374 0.39

95% CI: 0.25 to 0.61

Driscoll et al. 2000: 27% vs 42% ERHCG group 2000: 23% vs 45%

Abdelmassih et al. 2005: 23% vs 45%

Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719

* Pain and/or inflammation


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hCG preferences in treatment-‐experienced pa-ents at Androfert

Total (n=76) 60% 29%

3%

8%

prefer new pen prefer pre-filled syringe prefer lyophilized powder to reconstitute Not matter


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Individualizing LPS


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Normal & poor responders

Fresh ET FET

In FET cycles, all of the current methods of endometrial prepara-on appear to be equally effec-ve in terms of ongoing pregnancy rate*

•  Meta-‐analysis of 20 compara=ve studies •  ~13,000 cycles •  Natural and ar=ficial cycles with and w/o GnRH agonist

•  Safety & pa-ent-‐centeredness not addressed Groenewoud ER et al. Hum Reprod Update. 2013;19:458-‐70

*in eumenorrhoic pa-ents


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Luteal phase abnormal in s-mulated cycles

•  Corpus luteum func-on dependent on pulsa-le LH release from pituitary

•  Supraphysiologic steroid levels (by mul-follicular development) inhibits LH secre-on

•  Low LH levels causes luteolysis, implanta-on failure and shortened luteal phase

Jones 1996; Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Fauser & Devroey 2003; Trinchard-Lugan et al 2002; Sherbahn 2013


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LPS mandatory in s-mulated cycles

•  hCG vs. Placebo or No treatment: Higher ongoing PR (OR=1.75; 95% CI: 1.09-2.81)

•  Progesterone vs. Placebo or No treatment: Higher clinical PR (OR=1.83; 95% CI: 1.29-2.61) Higher ongoing PR (OR=1.87; 95% CI: 1.19-2.94) Higher live birth rates (OR=2.95; 95% CI: 1.02-8.56)

Level 1a


ANDROFERT

Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011

High-‐quality evidence on LPS in s-mulated cycles


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P routes & types Evidence Effect Conclusion Vaginal as effective as IM/oral

13 RCT; 2 MA; >2,000

cycles Similar CPR, LBR

& miscarriage True Vaginal safer and more patient-friendly than IM/oral

3 RCT; 1 MA; >2,000

cycles

Lower side effects; Increased patient

satisfaction True

Among vaginal P, patients prefer gel

7 RCT; 1 MA; >2,400

cycles

Easier to use; better adherence; lower discharge

True Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010;

van der Linden et al Cochrane 2011

High-‐quality evidence on LPS in s-mulated cycles


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Principles and Prac-ces of Individualized ART at Androfert


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High responders

Normal responders

Low responders Cl

inical fe

atures + AMH Antagonist protocol; tailored COS rec-‐FSH

(112.5-‐150 IU) + tailored trigger (GnRHa or rec-‐hCG); tailored LPS (modified LPS or vaginal P gel OPU)

Antagonist protocol; tailored COS w/rec-‐FSH (<35yr) or rec-‐FSH+rec-‐LH 2:1 ra-o (>35 yr); rec-‐hCG trigger; LPS vaginal P gel

Antagonist protocol; recFSH + recLH 2:1 ra-o + rec-‐hCG trigger; LPS vaginal P gel

Principles and Prac-ces of Individualiza-on in ART

Conclusions •  Individualiza-on is a quality concept •  Safety, effec-veness and pa-ent-‐centeredness are important principles in a quality-‐based individualized infer-lity care

•  Novel biomarkers combined with new devices & drug regimens can be used to deliver a high quality evidence-‐based individualized ART


ANDROFERT

Thank you Obrigado شكرا

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sandroesteves

Health & Medicine

Principles and practices in individualizing in ART