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

3. TIME IS NOT OUR FRIEND

4. 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 National vital statistics reports 2008:16(5)
Malizia BA et al. NEJM 2009; 360:

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CCRM unpublished, personal communication

6. 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

7. 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

8. 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

9. 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

10. HISTORY OF OOCYTE VITRIFICATION

11. 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)

12. 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

13. 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

14. Egg Freezing AS GOOD AS fresh

15. 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

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

17. 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

18. 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

19. ASRM GUIDELINES

20. 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

21. “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…

22. USES OF OOCYTE VITRIFICATION

23. 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

24. 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

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

26. 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

27. 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

28. 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?

29. 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%)

31. HOW MANY IS ENOUGH?

32. 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

33. 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

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

35. 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

36. 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

37. Egg Freezing Risk Calculator

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

39. Do women who freeze their eggs use them?

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

41. 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 months later comparing bankers vs nonbankers
-96% would recommend to others
-Women usually happy with their decision; human tendency

42. 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

43. 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

44. THANK YOU

45. LIFEFINDSAWAY.ORG Sunday, June 27, 2015 Sunday, September 20, 2015
To promote health and alleviate the mental and physical distress of individuals and couples diagnosed with infertility through education and financial assistance
Sunday, June 27, Sunday, September 20, 2015