Mild stimulationMild stimulation

Filippo Maria UbaldiFilippo Maria Ubaldi M.D. M.Sc.M.D. M.Sc.

CLINICA VALLE GIULIA, Rome

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3° Congress of Society of Reproductive Medicine

Antalya 5-9 October 2011

Introduction

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About 50% of patients who initiate IVF, will not conceive About 50% of patients who initiate IVF, will not conceive

partially due to the high drop-out rates: 25% of patientspartially due to the high drop-out rates: 25% of patients

who fail first IVF cycle will refrain from further cycles.who fail first IVF cycle will refrain from further cycles.

(Osmanagaoglu, 1999; Stolwijk 2000)(Osmanagaoglu, 1999; Stolwijk 2000)

High costsHigh costs

Poor prognosisPoor prognosis(Goverade, 2000)(Goverade, 2000)

Stress and side effects as-Stress and side effects as-

sociated with the treatmentsociated with the treatment

itself itself (Olivius, 2004)(Olivius, 2004)

Human ReproductionHuman Reproduction vol. 11 no. 5 pp. 917-919, 1996

Time to revolutionize ovarian stimulation

EDITORIAL EDITORIAL EdwardsEdwards

o Felberbaum Felberbaum Hum Reprod 1998Hum Reprod 1998

o Olivennes Olivennes Hum Reprod 1998Hum Reprod 1998 “friendly stimulation”“friendly stimulation”

Human ReproductionHuman Reproduction vol. 14 no. 11 pp. 2661-2666, 1999

EDITORIALMinimal ovarian stimulation for IVF: appraisal for potential benefitsand drawbacks

Bart C.J.M. Fauser, Paul Devroey, Roger Gosden, William F. Crowley Jr.,David T. Baird and Philippe Bouchard

Approximately 25% of patients refrain from a secondattempt after a first unsuccessful IVF cycle (Devroey,unpublished observations), even where the costs are

Introduction

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Patient-friendly stimulation protocols may involve:Patient-friendly stimulation protocols may involve:

(Edwards, 1996, 1997; Fauser, 1999; Macklon, 2000; (Edwards, 1996, 1997; Fauser, 1999; Macklon, 2000;

The European Orgalutran Study Group, 2000)The European Orgalutran Study Group, 2000)

o Less emotional stressLess emotional stress

o Less injections and monitoringLess injections and monitoring

o Less abdominal discomfortLess abdominal discomfort

o Less short-term (OHSS) and long-term complicationsLess short-term (OHSS) and long-term complications

o Reduced costsReduced costs

Introduction

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Patient-friendly stimulation protocols may:Patient-friendly stimulation protocols may:

(Eijnen, 2004)(Eijnen, 2004)

o Reduce drop-outsReduce drop-outs

o Increase the overall number of cycle per patientsIncrease the overall number of cycle per patients

o Increase the overall birth ratesIncrease the overall birth rates

Introduction

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Heijnen, Lancet 2007Heijnen, Lancet 2007

Mild vs standard protocol: non inferiority trial Mild vs standard protocol: non inferiority trial

The drop-out rate for mild stimulation was 5,1% after theThe drop-out rate for mild stimulation was 5,1% after the

first cycle and 11,2% after the second compared with 9,1 first cycle and 11,2% after the second compared with 9,1

and 19,5% for standard treatment. and 19,5% for standard treatment. The drop-out rate per The drop-out rate per

cycle was significantly lower in the mild treatment groupcycle was significantly lower in the mild treatment group

than in the standard group (OR 0,53, 95% CI 0,2-0,9, p=0,04)than in the standard group (OR 0,53, 95% CI 0,2-0,9, p=0,04)

Introduction

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Heijnen, Lancet 2007Heijnen, Lancet 2007

High scores representHigh scores represent

high anxiety, depressionhigh anxiety, depression

and phisical discomfort and phisical discomfort

Introduction

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Heijnen, Lancet 2007Heijnen, Lancet 2007

Mild vs standard protocol: non inferiority trial Mild vs standard protocol: non inferiority trial

……the reduced number of oocytes obtained after the reduced number of oocytes obtained after

mild ovarian stimulation, may impair outcome?mild ovarian stimulation, may impair outcome? (Fauser, 1999)(Fauser, 1999)

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A Randomized Comparison of Two Ovarian StimulationA Randomized Comparison of Two Ovarian StimulationProtocols with Gonadotropin-Releasing HormoneProtocols with Gonadotropin-Releasing Hormone(GnRH) Antagonist Cotreatment for (GnRH) Antagonist Cotreatment for in Vitroin Vitro Fertilization FertilizationCommencing Recombinant Follicle-Stimulating HormoneCommencing Recombinant Follicle-Stimulating Hormoneon Cycle Day 2 or 5 with the Standard Long GnRHon Cycle Day 2 or 5 with the Standard Long GnRHAgonist ProtocolAgonist Protocol

0013-7227/03/$15.00/0Printed in U.S.A.Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 88(1):166-173The Journal of Clinical Endocrinology & Metabolism 88(1):166-173Copyright 2003 by the Endocrine SocietyCopyright 2003 by the Endocrine Society

FEMKE P. HOHMANN, NICHOLAS S. MACKLON, FEMKE P. HOHMANN, NICHOLAS S. MACKLON, ANDAND BART C.J.M. FAUSER BART C.J.M. FAUSER

Division of Reproductive Medicine, Department of Obstetrics and Gynaecology (F.P.H., N.S.M., B.C.J.M.F.), Division of Reproductive Medicine, Department of Obstetrics and Gynaecology (F.P.H., N.S.M., B.C.J.M.F.), Erasmus Medical Center, 3015 GD Rotterdam, The NetherlandsErasmus Medical Center, 3015 GD Rotterdam, The Netherlands

Group A:Group A:Long 21Long 21

GnRH agonistGnRH agonist

r-FSHr-FSH hCGhCG

Group C:Group C:Day 5 FSHDay 5 FSH

GnRH antagonistGnRH antagonist

r-FSHr-FSH hCGhCG

Leading follicle Leading follicle >> 1414 mm mm

Group B:Group B:Day 2 FSHDay 2 FSH r-FSHr-FSH

GnRH antagonistGnRH antagonist

hCGhCG

Leading follicle Leading follicle >> 1414 mm mm

Introduction

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Long 21 agonistLong 21 agonist

Day 2 rFSH+antDay 2 rFSH+ant

Day 5 rFSH+antDay 5 rFSH+ant

100100

8080

6060

4040

2020

00N =N =

% o

f w

om

en%

of

wo

men

8484

6363

7373

3838 3535 3131% oocyte retrieval% oocyte retrieval per started cycleper started cycle

PP = 0.02 = 0.02

2222 2020 2020

1010 1010 1010

% pregnant% pregnant per started cycleper started cycle

PP = 0.96 = 0.96

6868

9090

7171

2626 2525 2828

% ET per% ET per oocyte retrievaloocyte retrieval

PP = 0.04 = 0.04

3939 36364040

1010 1010 1010

% pregnant% pregnant per ETper ET

PP = 0.95 = 0.95

Hohmann, JCEM 2003Hohmann, JCEM 2003

Embrionic chromosomal competence

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Embryonic chromosomal competenceEmbryonic chromosomal competence??

Mild vs conventional protocol: embryonic chromosomal competence

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Baart et al, 2007

Mild vs conventional protocol: embryonic chromosomal competence

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2020

1616

1010

88

44

00

Ave

rage

num

ber

Ave

rage

num

ber

22

66

1212

1414

ConventionalConventional

MildMild

1818

OocytesOocytes Normal embryosNormal embryos

Baart et al, 2007

P < 0,01

EmbryosEmbryos

P = 0,03

Mild vs conventional stimulation protocols:

embryonic chromosomal competence

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Baart, Hum Reprod 2007

MILD PROTOCOL: significant negative correlation between the number of oocytes obtained and the morphological score of the embryos and the percentage of the euploid embryos

% a

bnor

mal

em

bryo

s

sup- ports the physiological concept of natural selection of oocytes during follicular development

Costs

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Polinder, 2008

Mild vs standard protocol: medical costs/cycle Mild vs standard protocol: medical costs/cycle

Medication costs:

40%-50% of the

IVF costs/cycle

Study design

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Retrospective study comparing long luteal GnRH-aRetrospective study comparing long luteal GnRH-a

protocol with mild GnRH antagonist protocol protocol with mild GnRH antagonist protocol

Patients Patients << 40 y with serum basal FSH 40 y with serum basal FSH << 12 mUI/mL 12 mUI/mL

who underwent OPU from who underwent OPU from sept. 2007 to sept. 2008sept. 2007 to sept. 2008

Main outcomes:Main outcomes: clinical pregnancy and impalntation clinical pregnancy and impalntation

rates, days of stimulation, IU of gonadotropins used, rates, days of stimulation, IU of gonadotropins used,

IU of gonadotropins/clinical pregnancyIU of gonadotropins/clinical pregnancy

Study design

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Long luteal GnRH-a protocol:Long luteal GnRH-a protocol:

Suprefact s.c. 0,2 ml twice daily from mid lutealSuprefact s.c. 0,2 ml twice daily from mid luteal phasephase

to menstrual cycle than 0,05 ml s.c. twice daily hCG.to menstrual cycle than 0,05 ml s.c. twice daily hCG.

From cycle day 3, if the ovaries were ”basal”, ovarian From cycle day 3, if the ovaries were ”basal”, ovarian

stimualtion was started with a patient taylored dosestimualtion was started with a patient taylored dose

GnRH agonistGnRH agonist

r-FSHr-FSH hCGhCG

Day 21Day 21 mensesmenses

Study design

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Mild GnRH-antagonist protocol:Mild GnRH-antagonist protocol:

Ultrasound performed on cycle day 2-3: if the ovaries Ultrasound performed on cycle day 2-3: if the ovaries

were “basal” with follicles <8-10 mm, ovarian stimula-were “basal” with follicles <8-10 mm, ovarian stimula-

tion was started on day 4 with a patient taylored dose.tion was started on day 4 with a patient taylored dose.

GnRH-antagonist was started when the leading follicleGnRH-antagonist was started when the leading follicle

was 14-15 mm with serum LH<10 mIU/mL was 14-15 mm with serum LH<10 mIU/mL

mensesmenses

GnRH antagonistGnRH antagonist

r-FSHr-FSH hCGhCG

Leading follicle Leading follicle >> 14 mm 14 mm

day 4day 4

USUS

Results

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Antag Antag Long Long

8484 162 162

7676 156 156

36,836,8++3,03,0 34,7 34,7++3,73,7

8,58,5++2,12,1 8,1 8,1++2,22,2

OPUOPU

ETET

Age Age (mean(mean++sd)sd)

FSH FSH (mean(mean++sd)sd)

Antag Antag Long Long

8,88,8++1,31,3 11,3 11,3++1,81,8

3,33,3++0,80,8 23,0 23,0++2,92,9

1841,41841,4++649649 2464,3 2464,3++993993

Days of stimulationDays of stimulation

Days of analogDays of analog

IU of gonadotropinIU of gonadotropin

Results

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Results (Hohmann, JCEM 2003)(Hohmann, JCEM 2003)

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66

88

1010

1212

1414

Day

s o

f r-

FS

H s

tim

ula

tio

nD

ays

of

r-F

SH

sti

mu

lati

on

12001200

15001500

18001800

21002100

900900

To

tal r

-FS

H d

ose

(IU

/cyc

le)

To

tal r

-FS

H d

ose

(IU

/cyc

le)

n = 38n = 38

Long 21Long 21agonistagonist

n = 35n = 35

Day 2Day 2antagonistantagonist

n = 31n = 31

Day 5Day 5antagonistantagonist

PP < 0.001 < 0.001

Results

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Antag Antag Long Long

30/79 (38)30/79 (38) 71/156 (45) 71/156 (45)

41/185 (22)41/185 (22) 94/405 (23) 94/405 (23)

0/84 (0)0/84 (0) 2/162 (1) 2/162 (1)

Clinical preg. rate/ETClinical preg. rate/ET

Implantation rateImplantation rate

OHSS rateOHSS rate

Results: IU gonadot./clinical pregnancyIU gonadot./clinical pregnancy

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Antag (30) Antag (30) Long (71) Long (71)

IU of gonadotropins / IU of gonadotropins / clinical pregnancyclinical pregnancy 5414541448494849

€€ /clinical pregnancy/clinical pregnancy 27692769 32003200

CI 95%CI 95% 29712971

3200320028812881

26562656

Results: cost saving/clinical pregnancy

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2769 32002769 3200€ € / clinical pregnancy/ clinical pregnancy

Antag Antag Long Long

Difference (€)Difference (€) 431431

The mean cost saving of 431 € / clinical pregnancyThe mean cost saving of 431 € / clinical pregnancy

allows 1 additional preg. for every 6,5 pregnancys allows 1 additional preg. for every 6,5 pregnancys

Antag Antag Long Long

6,36,3++3,63,6 9,1 9,1++4,94,9

5,05,0++3,13,1 6,9 6,9++3,53,5

192/222 (86)192/222 (86) 413/472 (87) 413/472 (87)

N. of oocytesN. of oocytes

N. of MII oocytesN. of MII oocytes

Fertilization rate (%)Fertilization rate (%)

Results

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Antagonist vs Long protocol

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Cumulative pregnancy rateCumulative pregnancy rate

??

Oocyte vitrification: cumulative pregnancy rate

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69/120 = 57,5% ongoing pregnancy rate69/120 = 57,5% ongoing pregnancy rate

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Oocyte vitrification: cumulative pregnancy rate

Study design

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All patients All patients << 40 y with serum basal FSH 40 y with serum basal FSH << 11 mUI/mL 11 mUI/mL

who underwent OPU from who underwent OPU from sept. 2009 to may 2009sept. 2009 to may 2009

Main outcomes:Main outcomes: clinical and ongoing pregnancy and im- clinical and ongoing pregnancy and im-

plantation rates with fresh oocytes, cumulative ongoingplantation rates with fresh oocytes, cumulative ongoing

pregnancy rate after ICSI with vitrified-warmed oocytes pregnancy rate after ICSI with vitrified-warmed oocytes

Materials and Methods

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Antag Antag Long Long

155155 234 234

3838 35 35

1313 8 8

104104 191 191

37 (35%)37 (35%) 124 (65%) 124 (65%)

All OPUAll OPU

> 40 y> 40 y

FSH > 12FSH > 12

OPUOPU

Cycle withCycle withvitrificationvitrification

P<0.0001P<0.0001

Results

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Antag Antag Long Long

104104 191 191

36,236,2++3,33,3 35,2 35,2++3,93,9

8,28,2++2,92,9 8,1 8,1++2,62,6

OPUOPU

Age Age (mean(mean++sd)sd)

FSH FSH (mean(mean++sd)sd)

Antag Antag Long P Long P

7,87,8++3,43,4 10,8 10,8++4,1 <0.014,1 <0.01

6,06,0++2,92,9 8,2 8,2++2,9 <0,052,9 <0,05

234/275 (85)234/275 (85) 439/502 (87) 439/502 (87)

N. of oocytesN. of oocytes

N. of MII oocytesN. of MII oocytes

Fertilization rate (%)Fertilization rate (%)

Results

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Results

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Antag Antag Long Long

2,22,2++0,60,6 2,4 2,4++0,50,5

1,51,5++1,01,0 1,6 1,6++0,80,8

149/217 (69)149/217 (69) 276/422 (65) 276/422 (65)

N. embryo transferredN. embryo transferred

Type A embryo Type A embryo (mean) (mean)

Type A embryo rate Type A embryo rate (%)(%)

Results (fresh cycles)

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Antag Antag Long Long

34/95 (36)34/95 (36) 70/169 (41) 70/169 (41)

27/95 (29)27/95 (29) 59/169 (34) 59/169 (34)

47/217 (22)47/217 (22) 104/422 (24) 104/422 (24)

Clinical preg. rate/ETClinical preg. rate/ET

Ongoing preg. rate/ETOngoing preg. rate/ET

Implantation rateImplantation rate

Antag Antag Long P Long P

27/95 (29) 27/95 (29) 59/169 (34) 59/169 (34)

5/18 (25)5/18 (25) 21/71 (28) 21/71 (28)

32/95 (34)32/95 (34) 80/169 (47) 0,04 80/169 (47) 0,04

Ongoing preg. rateOngoing preg. rate/ET fresh (%)/ET fresh (%)

Ongoing preg. rateOngoing preg. rate/vitrified-warmed (%)/vitrified-warmed (%)

Ongoing preg. rateOngoing preg. rate/ET fresh+vitrified (%)/ET fresh+vitrified (%)

Results (fresh+vitrified ET)

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Antag Antag Long P Long P

32/95 (34)32/95 (34) 80/169 (47) 0,04 80/169 (47) 0,04

9 9 (3)(3) 17 17 (6)(6)

3535/95/95 (37) (37) 86 86/169/169 (51) 0,03 (51) 0,03

Ongoing preg. rateOngoing preg. rate/ET fresh+vitrified (%)/ET fresh+vitrified (%)

Cycles with vitrified Cycles with vitrified oocytes not yet war-oocytes not yet war-med and not pregnant med and not pregnant (expected pregnancies) (expected pregnancies)

Total (%)Total (%)

Results (fresh+vitrified ET)

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Conclusions

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Milder protocol reduces the number of days of stimulation,

the amount of gonadotropins and the discomfort for the pa-

tients improving the drop-out rate

Comparable clinical outcome per cycle between mild and

standard protocol with reduced medication costs per gesta-

tional sac and per clinical pregnancy with mild protocol

In good prognosis patients cumulative pregnancy rate using

vitrified warmed oocytes is significantly higher with standard

protocol. Prospective randomized trials are warrented

La crioconservazione nelle azoospermieLa crioconservazione nelle azoospermie

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Thank you Thank you

for your attentionfor your attention

CLINICA VALLE GIULIA, Roma

SALUS, Marostica (VI)

GENERA, Umbertide (PG)

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Ginecologia:

Filippo Ubaldi

Elena Baroni

Antonio Ciconte

Silvia Colamaria

Fabrizio Fiorini

A. Giallonardo

Madda Giuliani

Fabio Sapienza

Mauro Schimberni

Silvia Venanzi

Embriologia:Laura Rienzi

Stefania Romano

Roberta Maggiulli

Laura Albricci

Antonio Capalbo

Nicoletta Barnocchi

Benedetta Iussig

Sara Fusco

Federica Sanges

Catello Scarica

Elena Ievoli