The Latest and Greatest on Egg Freezing Jennifer Hirshfeld-Cytron, MD/ MSCI

TIME IS NOT OUR FRIEND

Impact of age: decreased fecundability Fertility and fecundity decrease with age Increased number of US women delay childbearing Speroff L and M Fritz 2005; Chapter 27; 1016. Ventura SJ et al. 2008 National vital statistics reports 2008:16(5) Malizia BA et al. NEJM 2009; 360: 236-43.

Aneuploidy increases with maternal age n=5,515 Blastocysts; p<0.0001 CCRM unpublished, personal communication

Surrogate markers of ovarian reserve Ovarian reserve testing Age Day 3 FSH >10mIU/mL abnormal Day 3 estradiol Anti-müllerian hormone Related to onset of menopause <0.16 predicts onset of menopause within 9 years Decrease precedes changes in other conventional parameters Ovarian volumes Antral follicle count

Ovarian reserve summary Age is most important predictor of reserve Ovarian reserve testing predicts # oocytes that can be retrieved Abnormal testing demonstrates a smaller resting follicular pool and is correlated with worse outcomes

ART canNOT overcome age Success of ART is dependent on age In woman with DOR and/or advanced age donor egg is often necessary Donor oocytes Autologous oocytes

Learning Objectives Explore ART technologies that have allowed for improvement in egg freezing Discuss ASRM recommendations regarding egg freezing Describe current clinical success with egg freezing Address potential patient and societal costs with egg freezing

HISTORY OF OOCYTE VITRIFICATION

Oocyte Cryopreservation Chen, 1986: First reported live birth No partner needed Time, hyperstimulation required, poor thaw techniques Why poor survival of frozen oocytes vs embryo? Initial slow freeze method Fragility of meiotic spindle Ice crystal formation (mature oocyte large H20 vol) Hardening zona pellucida effect fertilization Advantage no partner needed. Still require ovarian hyperstimulation and time. Vitrification use of highly concentrated cryoprotectant solution combined high cooling rate achieves a glassy, solid state without ice formation. *decrease ice formation and improve. Mature (metaphase II) oocytes larger water content. Vs immature (germinal vesicle)

Oocyte Cryopreservation: Improve Survivability How? Vitrification Protocols: Fast freeze ↓ ice formation; ↑ oocyte survival Pregnancy rates from vitrification EQUIVALENT to embryo in young woman Not considered investigational in Europe Not considered experimental by ASRM Subcellular damage chromosomal instability Slow freeze 32 preg c perinatal outcome: VSD, triplet Vitrification Outcomes little known

Two basic techniques currently rule the field of cryopreservation Traditional slow freezing (Whittingham, Leibo & Mazur, Science; 1972; Wilmut, Life Sci, 1974) Vitrification (Rall & Fahy, Nature; 1985) 24°C 24°C -196°C Slide Courtesy of Dr. Juergen Liebermann

Egg Freezing AS GOOD AS fresh

Oocyte vitrification does NOT increase aneuploidy Sibling oocyte study Pts < 35y/o undergoing 1st IVF cycle Normal ovarian reserve parameters CCS on blastocysts Double embryo transfer, one from each group Gender determination or DNA fingerprinting in singletons to learn which embryo implanted No differences in aneuploidy rates, implantation rates, pregnancy rates , live birth rates between groups Forman E., et al. Fertil Steril 2012

Infant Outcomes Initial retrospective data suggest frozen eggs BETTER outcomes as infants are larger

Infant Outcomes Noyes 2009  systematic review Over 900 babies born without an apparent increase in congenital anomalies Overall anomaly rate was 1.3% To date >1500 babies born without an increase in anomalies noted. Registries are needed Noyes N. et al., Reprod Biomed Online 2009

Egg Freezing AS GOOD fresh THEREFORE ASRM REMOVED EXPERIMENTAL LABEL TO MATURE EGG FREEZING STILL EXPERIMENTAL ACCORDING TO INSURANCE COMPANIES AND NOT COVERED ASRM Practice Committee, Fertil Steril 2013

ASRM GUIDELINES

Fertilization/pregnancy rates from IVF/ICSI are similar for fresh oocytes vs vitrified/warmed oocytes No increase in chromosomal abnormalities, birth defects, or developmental deficits Insufficient evidence to recommend for egg donation or for “circumventing reproductive aging in healthy women” -Fertility and Sterility in 2013, was the guideline in which they declared oocyte cryopreservation should no longer be considered experimental, which really opened the door for clinics… -Stated “there is a good evidence…”, caution that probably only applies to clinic with high volumes (think medical fert pres programs!) and that data in young patients -But data is limited -Recommended in patients undergoing gonadotoxic therapies

“Based on the current state of evidence, modern procedures to cryopreserve oocytes should no longer be considered experimental. The American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice endorses the joint document and encourages its use by Fellows. There are not yet sufficient data to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in healthy women.” Okay, so what can we tell our patients who want to pursue elective fert pres??? We’ll start with age and success rates…

USES OF OOCYTE VITRIFICATION

Uses of oocyte vitrification Limited insemination Ethical indications Autologous banking Cancer Cytotoxic chemotherapy Conditions that cause POF Turner/Mosaic Turner syndrome Elective Donor egg banks

Limited insemination Feb 2004 Italian legislature passed Limitations on ART No more than 3 oocytes can be fertilized at one time during an IVF cycle All resultant embryos must be transferred Supernumary oocytes could be cryopreserved but supernumary embryos could not Pregnancy rates were low Triplet rates were high Advances in field of oocyte vitrification

EGG VS. EMBRYO Hirshfeld-Cytron et al 2011 Married – freeze embryos Single – freeze eggs Hirshfeld-Cytron et al 2011

Autologous oocyte banking: mosaic Turner syndrome Born with same size follicular pool Follicles undergo rapid atresia Ovarian failure in late teens/early 20s Potential to undergo ovarian stimulation/oocyte banking before onset of ovarian failure Would require PGD in future Careful cardiac screening

Autologous oocyte banking: other indications Fragile X/Fragile X pre-mutation 15% chance of ovarian failure in 20’s and 30’s BRCA mutation Recommended oophorectomy by age 40

Autologous oocyte banking: delayed motherhood “Social egg banking” Increasing area of interest and application of technology Many unanswered questions Who should freeze? balance between waiting too long and unnecessary procedure What is the optimal age to freeze? How long are frozen eggs good for? How old is too old to use eggs?

Donor oocyte banks- DEBU Excellent application of the available technology # oocytes banked 14521 #oocytes survived 6518 (86%) # Day 3 ET /# Embryos 463/1.9 # Day 5/6 ET /# Embryos 649/1.5 D3 ongoing Preg % / ET 151 (33%) D5 ongoing Preg % / ET 336 (52%) CLINICAL PREGNANCY/ET 51.80% ONGOING/ET 43.79% # of Cycles with Vit Blasts 551 (45%)

HOW MANY IS ENOUGH?

Number of Eggs Retrieved Fertile = Infertile Data? Number of Eggs Retrieved Bergin, RMA New York. Would suggest that maybe we can look into infertility literature, although this is porbably not good news for patients >40, since success is low

How many frozen eggs does one need? Sibling oocyte study age 30-39 Infertile patients undergoing IVF 22 patients who had > 8 oocytes at retrieval Half of each cohort were vitrified and half were used fresh Only embryos from vitrified oocytes were transferred Chang et al., Fertil Steril 2013

How many frozen eggs does one need? Outcomes compared between patients 30-36 and 37-39 n=12 N=29 Chang et al., Fertil Steril 2013

How many frozen eggs does one need? Limitations History of infertility At least one prior failed IVF cycle Likely an over-estimation of numbers needed for a patient without infertility

Success STILL age dependent 6 oocytes age 25 = 40% chance live birth 6 oocytes age 35 = 23% chance live birth Cil AP, et al., Fertil Steril 2013

Egg Freezing Risk Calculator http://www.fertilitypreservation.org/

Don’t Wait to Freeze Your Eggs… Brower et al, UCLA; 350 pts undergoing IVF for gender selection through PGS

Do women who freeze their eggs use them?

Mucowski et al, USC. Survey study of 62 fertility clinics offering elective oocyte cryopreservation

51% anticipated future use 95% would do it again 76% at a younger age 10% non-bankers had regret 45%would have banked if cheaper No differences in relationship status, attempting conception or not conceiving within 1 year -Human Repro, last month; cohort study, 140 women who had consulted clinic; called 12-45 months later comparing bankers vs nonbankers -96% would recommend to others -Women usually happy with their decision; human tendency

Summary Age related infertility is one of the biggest challenges of modern medicine Oocyte pool is fixed and declines with age Ovarian reserve testing shows size of recruitable follicle pool Oocytes can be cryopreserved with IVF success rates similar to fresh IVF cycles

Conclusions Oocyte vitrification is a viable option for fertility preservation Multiple cycles may be needed to have an adequate group of available oocytes Oocyte banks will likely become as ubiquitous as sperm banks

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