ICSI Not ICSI - ASRM · Palermo et al., 2015 Semin Reprod Med ICSI Indications Ejaculated...

ToICSIorNotToICSIGianpiero D Palermo, MD, PhD, FACOG

Ronald O. Perelman & Claudia Cohen

Center for Reproductive Medicine

Weill Cornell Medicine

New York, New York

LEARNING OBJECTIVES

At the conclusion of this presentation, participants should be able to:

● Identify the circumstances that have led to the broad utilization of ICSI

● Examine the laboratory and clinical prerequisites that would support ICSI-for-All

DISCLOSURE

● None

Assisted Reproduction

IVF

Steptoe & Edwards,Lancet, 2:336

1978

Male factor

Cohen et al.,Acta Eur Fertil, 15:455-465

1984

SUZI

Ng et al.,Lancet, ii:790

1988

ZD

Gordon et al.,Fertil Steril, 50:68-73

1988 1989

PZD

Malter & Cohen,Fertil Steril, 51:139-148

ICSI Landmarks

ICSI TESE MESA

CryoMESA

CryoTESE

Palermo et al.,Lancet, 340:17

Schoysman et al.,Lancet, 342:1237

Tournaye et al.,Fertil Steril, 61:1045

Devroey et al.,Hum Reprod, 10:903

Podsiadly et al.,Hum Reprod, 11:1306

1992 1993 1994 1995 1996 1997 1999 2000

CryoOocyte

Porcu et al.,Fertil Steril, 68:724

PGT-MFragile X

Sermon et al.,Prenat Diagn, 19:1223

IVMOocyte

Cha et al.,Fertil Steril, 73:978

Infertility Indications

CDC – Reproductive Health, 2008

Andersen et al., 2008ESHRE 2009; 2010; 2012

ART in Europe

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Cycles

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

IVF ICSI

ART in Europe

40.6

46.2 43.2 44.148.6

52.4

55.0

63.3

55.951.4

45.040.7 36.7

32.030.7

Andersen et al., 2008ESHRE 2009; 2010; 2012

59.3

66.5

68.0

69.333.5

47.6

56.8

53.8

59.4

Cycles

1993n = 397

ICSI Prevalence

IVF67.8

ICSI32.2

1995n = 2,689

ICSI Prevalence

IVF51.2

ICSI48.8

2002n = 12,723

ICSI Prevalence

IVF26.4

ICSI73.6

2012 to 2018n = 217,805

ICSI Prevalence

IVF19.5

ICSI80.5

Cornell ART

1993-2018Cycles 53,332

Ser 20-100IVF 15323ICSI ejac 34857ICSI SR 3152TOTAL 53332 Updated 1/15/2019

Series 20-100 Dec 31, 2018

Ejaculated (n = 34233)Surgically retrieved (n = 3,743)

37,976 ICSI CyclesSeptember 1993 – December 2018

Updated 1/15/2019Series 20-100 Dec 31, 2018

ICSI Ejaculated Spermatozoa

Cycles 34,531

Mean maternal age (± SD) 38.2 ± 5

Semen parametersNormal 5,828

Abnormal 28,785*WHO, 2010


MII Injectedn = 296,800

Fertilization patternsn = 288,728

Surviving oocytes = 269,266Lysed = 7,908

2PN = 324,546 (75.7)1PN = 7130 (2.4)3PN = 10,182 (3.4)no fert = 46070 (15.5)

Survival and Fertilization CharacteristicsEjaculated Spermatozoa


Semen Origin and ICSI OutcomeSemen origin Cycles Fertilization (%) Clinical pregnancies (%)

Fresh

Ejaculate 28,572 178,415/236,900 (75.3) 11,626 (40.7)

Electro 61 470/616 (76.3) 29 (47.5)

Retrograde 51 377/483 (78.1) 20 (39.2)

Frozen

Ejaculate 3,831 24,625/32,435 (75.9) 1,395 (36.4)

Electro 26 180/262 (68.7) 11 (42.3)

Retrograde 8 27/45 (60.0) 1 (14.2)


Severe Oligozoospermia≤ 1 x 106

Cycles 2,289

Mean density (106/ml ± SD) 1.1 ± 0.3

Mean motility (% ± SD) 19.6 ± 23

Mean morphology (% ± SD) 1.5 ± 2

Fertilization (%) 14,047/22,515 (62.4)

Clinical pregnancies (%) 1053 (46.0)


CryptozoospermiaCycles 358

Initial sperm count 0

After ultracentrifugation

Concentration (106/ml ± SD) 0.34 ± 1.2

Mean motility (% ± SD) 32.6 ± 36

Fertilization (%) 2,045/3,758 (54.4)

Transfers 398

Mean embryos replaced 1.1

Clinical pregnancies (%) 161 (45.0)

0-0.000001Updated 1/15/2019Series 20-100 Dec 31, 2018

Chan et al., 2004

Male Infertility Indications

New bad sperm photos

Drawing

different spermhead morphology

0 10 20 30 40 50 60 70 80 90

TESE

MESA

Ejaculated

48.9

71.0

75.8

49.7

71.6

75.6

Fresh

Frozen

Fertilization rate (%)

219,802/290,671

7,598/15,280

3,548/7,261

29,753/39,258

2,948/4,116

5,937/8357


0 10 20 30 40 50 60 70

35.2

44.6

40.2

60.0

Clinical pregnancies (%)

*

*

*P < 0.00001

†

†

†P < 0.0001

‡

‡ ‡P < 0.00001

Fre

shC

ryo

pre

serv

ed

∫

∫

∫P = 0.04

ME

SA

TE

SE

228/380

358/803

517/1287

210/596


Control

0

Control

0

Ejaculates

TESE

Sperm Quest

Search time

30 – 60 61 – 120 121 – 180 ≥ 181

225 mins

61 - 120 121 - 180 ≥ 181

390 mins

30 – 60

Palermo et al., 2014 Plos One

0

20

40

60

80

control1 - 30

31 - 60 61 - 120 121 - 180 ≥ 181

38.9

31.8

41.0

11.1

25.0

35.3

42.4 43.9

29.8

44.8

Clin

ical pregn

ancy/cycle (%)

Search time (min)

Ejaculated

Testicular

Clinical Pregnancy

Updated 10/9/2017Series 20-97 June 30, 2017Palermo et al., 2014 Plos One

Maternal Age & ICSI Deliveries

%

Maternal age (yrs)

0

10

20

30

40

50

60

≤ 33 34 - 35 36 - 37 38 - 39 40 41 42 43 44 45 ≥ 46

47.4

40.837.4

31

23.7

19.3

13.6

9.1

5.64.2 3.8

Deliveries/cycles 9356 29750

Updated 11/9/2017



0

10

20

30

40

50

60

70

80

90

100

0 1 2 3

IVF vs ICSIICSIIVF

6,737

13,915 Newborns

FertilizationTotal # of eggs

Clinical pregnanciesTotal # of cycles

DeliveryTotal # of cycles

%


Pregnancy Loss

%

0

2

4

6

8

10

12

14

9.1 9.2

0.7 0.7

IVF ICSI

Therapeutic AbortionMiscarriage

Palermo et al., 2015 Semin Reprod Med

ICSI Indications

Ejaculated Oligozoospermia

Asthenozoospermia

Teratozoospermia

Antisperm antibodies

Fertility preservation

Ejaculatory disordersElectroejaculation

Retrograde ejaculation

Globozoospermia

Cryptozoospermia

Male Factor

Palermo et al., 2015 Semin Reprod Med

EjaculatedPrior failed fertilization with IVF

Oocyte dysmorphism

Low number of oocytes

Low oocyte maturity

Cryopreserved oocytes

In vitro maturation

PGT-A/PGT-M (FISH or NGS)

HIV and HCV discordant couples

Restrictive legislation

Non-Male Factor

TesticularNecrozoospermia

All indications for epididymal sperm

Non-obstructive azoospermia

Hypospermatogenesis

EpididymalObstructive azoospermia

CBAVD

Young syndrome

Failed vasoepididymostomy

Failed vasovasostomy

Age (yrs old) Results5 • IVF (81) = ICSI (81), comparable perinatal outcome,

health, growth and medical care needs• NC (85) > ICSI (87), poorer perinatal outcome (P < 0.05)

Knoester et al., 2008Pediatrics, The Netherlands

8 NC (147) vs ICSI (150)3.3% 10.0% major malformation (P < 0.0001)

17.2% 24.1% minor malformation

Belva et al., 2007Medical Genetics, Brussels Belgium

IVF and ICSI children's overall IQ within the normIVF (34) > ICSI (35), lower IQ (P < 0.005)

Goldbeck et al., 2009Child & Adolescent Psychiatry, Ulm Germany

10 NC (147) vs ICSI (150)• NC = ICSI, motor skills and IQ

Leunens et al., 2008LifeSpan Psychology, Brussels Belgium

12 IVF (143) vs ICSI (166) vs matched NC (173)• comparable head circumference, height, and weight at any time point analyzed

Basatemur et al., 2010Adolescent and Pediatric Unit, London England

14 Serum inhibin B levels in ICSI boys (50) are WNLNC (116 boys) = ICSI (115 boys)

(101 girls) (108 girls)

Belva et al., 2010Belva et al., 2012Genital development

Hair developmentmenarche

Henningsen et al., 2015

• Perinatal outcome of ART has improved over the last 20 years

• IVF singletons had an increased risk of low birthweight compared to ICSI (OR 1.12 95%CI 1.03-1.23)

• IVF and ICSI twins had comparable risk for adverse outcomes

• Perinatal outcomes of cryopreserved embryos has improved due to ICSI Pinborg et al., 2013

• "In general, women conceiving after ICSI are more reproductively healthy than women conceiving after IVF, as the main indication for ICSI, especially in Nordic countries, is still severe male infertility."

• Span from 1988-2007

• Four Scandinavian countries

• Over 92,000 ART children

Age (yrs old) Results19 NC (57 boys) > ICSI (54 boys)

• significantly lower sperm concentration, total sperm count and total motile sperm count

Belva et al., 2016

19

20

NC (81 girls) = ICSI (71 girls)• comparable antral follicle count and circulating reproductive hormone levels (AMH, FSH, LH and DHEAS)

NC (57 boys) = ICSI (54 boys)• comparable FSH, LH, testosterone and inhibin B

Belva et al., 2017a

Belva et al., 2017b

19 NC (80 girls, 53 boys) = ICSI (70 girls, 56 boys)• comparable Metabolic Syndrome ComponentsNC (53 boys) > ICSI (56 boys), lower HDL

Belva et al., 2018

"Evidence regarding the outcome of singletons born at term following ART is generally

reassuring." Basatemur and Sutcliffe, 2008

"The increased risk of perinatal morbidity and mortality associated with singleton births has

been linked to the infertility of the couple rather than the techniques used."

Steel and Sutcliffe, 2009

REBUTTAL

ToICSIorNotToICSI

0

500

1000

1500

2000

2500

3000

Cycles

ART at WCM

0

500

1000

1500

2000

2500

3000

IVF ICSI

ART at WCM

42.0

56.1 61.1 66.1 71.2

69.6

72.3

76.0

34.0

28.8

27.7

27.9

24.014.9

8.2

72.1

81.5

85.1

91.8

18.5

30.4

38.943.958.0C

ycles

4.6

95.4

ICMART Adamson et al., 2018 Fertility and Sterility

��


��


��


Global ART in 2011

65 Countries

IVF ICSI Total

Cycles 373,616 (33.5) 741,656 (66.5) 1,115,272

Newborns 132,212 262,450 394,662


120000

130000

140000

150000

160000

170000

180000

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

ART cyclesCyc

les

Year

3000000

4000000

5000000

6000000

7000000

8000000

Impaired Fecundity

Infertility

CDC, 2017

Infertility and ART Trend

SART, 2018

3000

4000

5000

6000

7000

8000

9000

10000

11000

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

120000

130000

140000

150000

160000

170000

180000

ART cycles

PGT cycles

Cyc

les

Year

ART/PGT-A Trend

Society for Assisted Reproductive Technology (SART), 2018

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Nu

mb

er o

f cy

cles

Year

Oocyte Cryopreservation(2009-2016)

Society for Assisted Reproductive Technology (SART), 2018

0

10

20

30

40

50

60

70

80

90

100

Fertilization Clinical Pregnancy Rate Deliveries

%

Standard IVF ICSI Non-male factor ICSI Male factor

ICSI in Non-Male Factor

Considerations

• ICSI is more versatile• ICSI is more sensitive and precise• ICSI allows verification of oocyte maturity

NURSING STAFFTheresa Lee, RN

Victoria Nowesielski, RNChristine Lu, RNJuliana Shen, RNDebra Henry, RNHolly Nadal, RN

Hanna Murtaugh, RNDevon Klauck, NPSarah Staube, RN

Sheri Fitzpatrick, RNSiobahn Plunkett, RN

Susan Ng, RNChristine Zotto, PARodriq Stubbs, NP

Cheryl Sabatino, RNAmy Prince, RNCindy Acosta

Deanna ArmstrongRosanna Contreras

Jenny Soto

NURSING RESEARCHRodriq Stubbs, NP

Mitasha Joseph, RNJessica G-Abraham, MPH

CLINICAL SCIENTISTSZev Rosenwaks, MDOwen K. Davis, MDPak H. Chung, MD

Dan E. Goldschlag, MDHey-Joo Kang, MDIsaac Kligman, MD

Samantha Pfeifer, MDGlenn L. Schattman, MD

Steven D. Spandorfer, MDRony T. Elias, MD

David Reichman, MDAlexis Melnick, MDNigel Pereira, MD

REI FELLOWSKolbe Hancock, MDAllison Petrini, MD

Lilli Zimmerman, MDRobby Setton, MD

Monica Pasternak, MDJoshua Stewart, MD

PSYCHOLOGYLaura Josephs, PhDElizabeth Grill, PsyD

ICSI & ANDROLOGYGianpiero D. Palermo, MD, PhD

Queenie Neri, MSStephanie Cheung, BS

Alessandra Parrella, MSDerek Keating, BA

Philip Xie, BSJune Wang, BA

Aysha Trout, BABrianne Barker, BS

Sherina Lawrence, BSMatthew Goldman, BS

ENDOCRINOLOGYDaylon James PhD

Limor Man, MDIgna Zhygalo

Jennifer MarinoBarbara Caiazza

Ritaben PatelZong-ying Liu

Carmen Torres

REPRODUCTIVE UROLOGYMarc Goldstein, MDPeter Schlegel, MD

Philip Li, MDDarius Paduch, MD

James Kashanian, MD

PGDKangpu Xu, DVM, PhD

Ali Sharma, PhDJianwen Wei PhDJoseph Marzouk

Benjamin Fang, BSXiaoe Qin

EMBRYOLOGYNikica Zaninovic, PhDRobert Clarke, PhD

Jiying Hao, MDRichard Bodine

Rosemary BerriosCarol-Ann CookZhen Ye, PhDSamuel Jones

June HariprashadDina Weiss

Naomi LourieAbby O’ConnellMyriam Jackson

Rosa RoblesAna Robles

Christopher Norberg Ameeta Bahia

Qiansheng Zhan, MD, PhD

ADMINISTRATIVE STAFFTerry VazquezJulie CartyJustine WitzkeHelena ChicketanoAngie GrullonEileen GarciaSandra EdwardsJeremy DiazAvery BlackJanine JalacLetty CrespoJennifer ClarkEvelyn CoreyMelanie GerenaRaquel Mintah-EllisonMaureen EnnisTy ChicketanoAndres CastilloDiana PakVictoria CamerronRosangeli Russo

Waleska PadilloDee Giovannetti

Una CullenBrenda Burgos

Carolina MoralesTamara EdmeTiffany Reid

Debra LilienthalShanise Jackson

Jaresyss Gordon-ReyAdrianne Gomes

Consuelo SerranoJahaida Reyes

Tramaine ScottJeanine Beudeker

Luis FrancoIan Prince

Erica LuongJane Huang

Joanne Dowling Jessica Gould

STEM CELL DERIVATION LABShahin Rafii MD

Nikica Zaninovic PhDDaylon James PhD

Qiansheng Zhan MD, PhDKenny Chao

Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine

ToICSIorNotToICSI

Ronald O. Perelman & Claudia Cohen Center for Reproductive Medicine

Weill Cornell MedicineNew York, New York

Gianpiero D Palermo, MD, PhD, FACOG

ICSI Not ICSI - ASRM · Palermo et al., 2015 Semin Reprod Med ICSI Indications Ejaculated...

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