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 2012 Total Cycles:165172 Procedure Frequency ICSI 67% Fertiaid: 67 replies. 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. 2003 55% 2004 57% 2005 59% 2006 62% 2007 63% 2008 64% 2009 64% 2010 66% 2011 66% 2012 67% Total Cycles:165172 Procedure Frequency ICSI 67% Unstimulated 1% PGD 5% 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

Semen parameters: “Indeterminant range” Guzick et al N Engl J Med 2001;345:1388-93

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.