Post on 12-Aug-2020
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
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
Updated 1/15/2019Series 20-100 Dec 31, 2018
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)
Updated 1/15/2019Series 20-100 Dec 31, 2018
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)
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
Updated 1/15/2019Series 20-100 Dec 31, 2018
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
%
Updated 1/15/2019Series 20-100 Dec 31, 2018
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
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ICMART Adamson et al., 2018 Fertility and Sterility
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ICMART Adamson et al., 2018 Fertility and Sterility
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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
ICMART Adamson et al., 2018 Fertility and Sterility
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