Transcript ART’de ICSI’nin Yeri

ART’de ICSI’nin Yeri
(ICSI Indications)
ORHAN BUKULMEZ, MD
Associate Professor & Division Director
Division of Reproductive Endocrinology & Infertility
Department of Obstetrics and Gynecology
University of Texas Southwestern Medical Center
Dallas, Texas
ICSI
• 1974-Frogs
• 1988-Rabbits
• 1992-Humans
SART 2012Fertiaid: 67 replies.
• Total Cycles:165172
Procedure Frequency
• ICSI 67%
• Unstimulated 1%
• PGD 5%
2003 55%
2004 57%
2005 59%
2006 62%
2007 63%
2008 64%
2009 64%
2010 66%
2011 66%
2012 67%
Principle type of
fertilization for majority
of women under 35: 29%
said IVF, 48% ICSI and 23%
for all cases had ICSI.
In other words, in the
small census, only 23%
would use IVF routinely
on
younger women.
Diagnosis Frequency
• Tubal Factor 6%
• Male Factor 17%
• Ovulatory Dysfunction 7% Other Factor 8%
• Diminished Ovarian Reserve 17% Unknown Factor 12%
• Endometriosis 3% Multiple Female Factor 12%
• Uterine Factor 1% Female and Male Factor 17%
ICSI criteria ?
Group 1: Based on poor semen history/advised to include ICSI in the treatment plan
•
Count ≤ 5 million/ml
•
Sperm Motility ≤20%
•
Strict morphology ≤3% normal
•
Sperm ASA ≥30% head
•
Failed fertilization in previous cycle by conventional insemination
•
History of poor fertilization (<50% of 4 or more oocytes)
•
Prior ICSI
•
TESE/PESA/Retrograde ejaculation/electroejaculation samples
•
Oncofertility patients
•
PGD for PCR/WGA
•
History of calcium channel blockers
•
Male partner is positive for infectious disease
•
Frozen semen sample (either donor or partner for any reason)
Group 2: Based on the poor semen analysis on the day of insemination
•
Inform pts about conversion to ICSI on the day of the retrieval if the semen sample presents the following
values:
•
Fresh count ≤5 million/ml or swim-up/rise count ≤2 million/ml
•
Swim-up/rise strict morphology ≤3% normal
•
Fresh sperm motility ≤20% or swim-up/rise motility ≤50%
•
Signs of infection/round cell count >10 million/ml
•
Abstinence ≥10 days
WHO CRITERIA CHANGE OVER TIME
Menkveld R. Asian J of Andrology 2010:12:47-58
Semen Parameters
WHO 4th edition
Minimal standards of adequacy
Not a test of fertility
No absolute cut-off to define infertility
Semen Parameters
WHO 5th Edition-Correlates with Fertility but is this the right
cut-off? Why must we have a single cut-off?
Cooper TG et al. Hum Reprod Update 2010;16:231-45
ICSI for Male factor
• Over past 25 years WHO revised its criteria 3 times with
lowering threshold values to describe normal semen
analysis
– Cooper TG et al Human Reprod Update 2010;16(3):231-245
• IUI threshold as low as TMC of 1 million
– Ombelet W et al. Hum Reprod 1997;12(7):1458-1463
• ICSI over conventional IVF in male factor generally arbitrary
• Total inseminating motile count cutoff below 0.5 to one
million for ICSI?
– Kastrop et al. Hum Reprod 1999;14(1):65-69
– Verheyen G, et al. Hum Reprod 1999;14(9):2313-2319
Teratozoopsermia & ICSI
• >2 million post-wash motile sperm,<5% strict
• Retrospective
• Fertil Steril 2007;88: 1583-8
Hall J et al. Intracytoplasmic sperm injection versus high insemination concentration in-vitro
fertilization in cases of very severe teratozoospermia.
Human Reprod 1995;10(3):493-496.
Mansour RT et al. The effect of sperm parameters on the outcome of intracytoplasmic sperm
injection. Fertil Steril 1995;64(5):982-986.
Robinson JN et al. Does isolated teratozoospermia affect performance in in-vitro fertilization and
embryo transfer? Hum Reprod 1994;9(5):870-874.
• 16 studies (10 IVF and 6 ICSI): the presence of ASA does not
influence pregnancy rates after IVF or ICSI (HR 2011)
ICSI FOR ALL!
•
•
•
•
USA: 2/3 of IVF cycles with ICSI but male factor was coded in 35%
Remember the PRCT in 415 couples with non-male-factor infertility
ICSI vs. conventional IVF.
Primary outcome of implantation rate was higher with conventional
IVF than that was achieved with ICSI (30% vs. 22% with p<0.05).
• Fertilization rate per oocyte retrieved and the pregnancy rate were
also higher in IVF group, (58% vs. 47% with p<0.0001 and 33% vs.
26% with p=0.11 respectively)
• ICSI resulted in a higher fertilization rate per oocyte injected,
whereas this could be due to a better detection of the oocyte
maturational status after cumulus cells were removed.
– Bhattacharya S, et al. Lancet 2001;357(9274):2075-2079
Total Fertilization Failure
• IVF in normospermia TFF and low fertilization (defined as <25%
fertilization rate) 5 to 15%, and 20%, respectively.
• Recurrence of TFF in a subsequent IVF cycle is between 30% and 50% (not
100%!!).
Kinzer DR et al.Fertil Steril 2008;90(2):284-288
• Retrospective:ICSI among 65 non-male factor pts h/o TFF/low FR in IVF vs
219 male factor pts: CPR 19.6% vs. 33.5%, respectively. Egg factor??
Tomas C et al. Hum Reprod 1998;13(1):65-70
• Prospective studies showing benefit of ICSI in TFF, while splitting eggs
between IVF and ICSI, shows benefit of ICSI for fertilization but CPRs, LBRs
cannot be estimated due to ETs of both IVF and ICSI embryos.
“although subsequent total failed fertilization may be related to the IVF
stimulation, utilizing IVF/ICSI may decrease the risk of subsequent fertilization
failure”
ASRM. Fertil Steril 2012;98(6):1395-1399
ICSI &Unexplained Infertility
• TFF seen in 5-25% with IVF
• Oocytes for ICSI assessed for nuclear maturity unlike
IVF
• Comparison of PRs & LBRs between the two groups
could not be made-few reported, widely different
embryo selection criteria.
• Pooling of embryos obtained from ICSI & IVF for ET
embryo transfer
• Relatively few numbers of transfers
• Better fertilization rates with ICSI, lower TFF in UEI
• Would you rather do split ICSI/IVF?
ICSI for Diminished Ovarian Reserve
• “based on current evidence, the use of ICSI for
low oocyte yield does not significantly improve
fertilization rates, embryo number and quality,
or pregnancy rates”
– ASRM Committee opinion Fertil Steril
2012;98:1395
Rescue ICSI - IVM &ICSI
• Rescue ICSI: Not recommended
Increased polyploidy. Concerns about safety!
Very low PRs
Tsirigotis M et al. Fertil Steril 1995;63(4):816-819
Plachot et al. Hum Reprod 1988;3(1):125-127 (late fertilization of eggs and
chromosomal imbalance)
• ICSI does not appear to be necessary to
achieve fertilization in oocytes matured in
vitro
ASRM Comittee opinion Fertil steril 2013;99:663-6
Other debated or empirical ICSI
indications
• ICSI for poor quality oocytes-Markers? Granulosa cell
apoptosis??
• ICSI for prevention of triploidy- Egg or sperm issue? IVF
issue? Published data are poor in quality
• ICSI to prevent HIV transition-ICSI is contraindicated for
that indication in Holland!!
• ICSI for PGT-Currently yes for PCR but the proper
identification of maternal and paternal DNA as well as
the embryonic DNA will be possible
• ICSI for frozen eggs-More studies would be required
Gangnam Style
(Murine blastocysts)
Fresh ET>Frozen ET but still ICSI>IVF
ASRM Response to NEJM Article
• “Some results in this study are reassuring for
patients: in cycles not including ICSI, the
adjusted odds ratio for IVF conceived children
did NOT show a significant difference in birth
defects children born following embryo
freezing had no higher risk of birth defects
than naturally conceived children”
ICSI & monozygotic twinning
• The risk of monozygotic twinning increases x2
in IVF and it further increases with ICSI.
• Monozygotic twinning up to 24-fold increase
in risk in cycles involving both ICSI and
extended culture (blastocyst transfer-2.7% to
13.2%)
ASRM practice bulletin. Fertil Steril 2012;97:825
ICSI Indications?
• Not rigorous at all, mostly empirical
• In the field of ART it is common to see widespread adoption
of new technology with ever expanding indications but
without sufficient evidence to support these uses
unequivocally.
• We need evidence based medicine for any treatment, but it
looks like we do not require EBM directing us for ICSI and
we can always ignore the data not supporting ICSI
• Patients need to be extensively counseled about what we
actually know about ICSI
• ICSI indications need to be revisited by designing more
prospective studies investigating meaningful clinical
outcomes.