1. © Fertility Centers of Illinois1 How to best implement and advertise a strong fertility preservation program Eve Feinberg, MD Fertility Centers of Illinois

2. © Fertility Centers of Illinois2 Fertility preservation Cancer Gynecologic conditions –endometriosis Diseases associated with ovarian failure –Turner mosaic –Autoimmune polyglandular syndrome –Fragile X premutation carriers BRCA mutation carriers Delayed motherhood

3. © Fertility Centers of Illinois3 Implementation of a program Starts in your own laboratory Proof of concept: can you successfully vitrify and warm oocytes? –Not all labs are the same –Anyone can freeze an oocyte Sibling oocyte study –10 patients using donor oocytes –Vitrified half of the cohort x 2 hours then warmed, ICSI and cultured –Preferentially transferred from vit group –Excellent pregnancy rates and fertilization, blast development rates are the same

4. © Fertility Centers of Illinois4 Implementation of a program QA/QC measures on an ongoing basis Issues of storage –Store on site vs. off site –Payment/collections –Future use for oocyte donation, need for FDA testing Program setup –Rapid appointments –Continuous IVF, no series

5. © Fertility Centers of Illinois5 Implementation of a program Mucowski et al, USC. Survey study of 62 fertility clinics offering elective oocyte cryopreservation Low utilization = storage issues

6. © Fertility Centers of Illinois6 Implementation Who is a candidate to freeze eggs? FCI SOP –Age < 43 –FSH < 20 –AFC >4 –AMH detectable

7. © Fertility Centers of Illinois7 Implementation Careful counseling NO guarantee of future pregnancy How many 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

8. © Fertility Centers of Illinois8 How many eggs does one need? Outcomes compared between patients 30-36 and 37-39 Chang et al., Fertil Steril 2013 n=12n=29

9. © Fertility Centers of Illinois9 Study limitations Infertile population At least one prior IVF cycle Likely an over-estimation of numbers needed NYU data  8 oocytes equivalent live birth rates to fresh IVF Devine K et al., Fertil Steril 2015

10. © Fertility Centers of Illinois10 How many eggs does one get? Devine K et al., Fertil Steril 2015

11. © Fertility Centers of Illinois11 Vitrification—Effect on Aneuploidy Rates? Age 8 MIIs Sibling oocyte study, half oocytes vitrified then warmed after 15 minutes Microarray-based CCS on all blasts Single best blast from each group transferred, if available, vs. best two DNA fingerprinting used to determine which embryo implanted in monozygotic gestations @ 9 weeks (maternal serum) or neonatal buccal swab Forman EL, et al: Fertil Steril 98:644-649, 2012

12. © Fertility Centers of Illinois12 No differences in aneuploidy Forman EL, et al: Fertil Steril 98:644-649, 2012

13. © Fertility Centers of Illinois13 Long term vitrification and aneuploidy Compared outcomes of 24 chromosome PGS from cryopreserved thawed oocytes to outcomes using fresh oocytes = no differences in aneuploidy rates Goldman K, et al, Fertil Steril 2015 Oocytes cryopreserved median 3.5 years, range 0-6.5 years

14. © Fertility Centers of Illinois14 10 studies, 2,265 thaw cycles, 1,805 patients Oocytes were cryopreserved because embryo freezing was illegal or patient request (infertile population) Calculated age specific probability of live birth 1,957 vitrified oocytes

15. slow freezing vitrification

16. © Fertility Centers of Illinois16 Implementation of egg freezing program: track your own data

17. © Fertility Centers of Illinois17 Success rates of vitrified oocytes Success rates lower after 40 but not significantly different between 40 and 42

18. © Fertility Centers of Illinois18 Careful counseling - data driven

19. © Fertility Centers of Illinois19 Establishing expertise Cancer Gynecologic conditions –endometriosis Diseases associated with ovarian failure –Turner mosaic –Autoimmune polyglandular syndrome (APS) –Fragile X premutation carriers BRCA mutation carriers Delayed motherhood

20. © Fertility Centers of Illinois20 Establishing expertise in cancer Gain familiarity with the different types of cancers that affect reproductive age women –Breast cancer 25% of breast cancer patients <45 –Gynecologic malignancies –Hodgkin disease Understand the impact that cancer treatment has on fertility potential Foster relationships with local oncologists –Meet in person, call when you see their patients

21. © Fertility Centers of Illinois21 Establish a fertility preservation program Develop a system where cancer patients can be seen rapidly and egg retrieval can be performed within a matter of 1-2 weeks Financial counseling/low cost care/familiarity with programs such as Livestrong and compassionate care –Kevin J. Lederer Life Foundation Patient navigator or single contact RN

22. © Fertility Centers of Illinois22 Cancer treatment and reproductive impairment Acute ovarian failure Early menopause –Risk has largely been underestimated Infertility Temporary amenorrhea –Likely recovery

23. © Fertility Centers of Illinois23 Age and ovarian failure Letorneau et al, Cancer 2012

24. © Fertility Centers of Illinois24 Infertility after chemotherapy Letorneau et al, Cancer 2012

25. © Fertility Centers of Illinois25 Know your options Ovarian tissue cryopreservation Ovarian transposition GnRH analogues Fertility sparing surgery –Unilateral oophorectomy –Trachelectomy Embryo cryopreservation Oocyte vitrification Future use of donor gametes

26. © Fertility Centers of Illinois26 Breast cancer - clinical case 33 y/o single G0 with stage III invasive ductal carcinoma presents prior to receiving neo- adjuvant chemotherapy –ER/PR + –BRCA positive –Nodal involvement –Needs to start chemotherapy 2 weeks –Day 16 of her cycle

27. © Fertility Centers of Illinois27 Clinical considerations Oocyte vitrification – best option Random start stimulation Adjuvant treatment with letrozole –Titrate to keep E2 below 500ng/mL –Can titrate up to 10mg, start 2.5mg PGD in future, needs higher number oocytes Start stimulation same day –Can start follicular or luteal phase –GA with lead follicle >14mm –Lupron trigger Back to back stimulation if time “Shanghai protocol” Kuang Y, et al Reprod Biomed Online 2014

28. © Fertility Centers of Illinois28 Shanghai protocol Kuang Y, et al Reprod Biomed Online 2014

29. © Fertility Centers of Illinois29 Establishing expertise Fertility preservation not just for cancer but conditions known to impact future fertility –Endometriosis –Turner Mosaic –Fragile X premutation carriers –Polyglandular autoimmune syndrome Education and outreach is key –Pediatricians –Peds Endocrine –Internal medicine

30. © Fertility Centers of Illinois30 Fertility preservation Cancer Gynecologic conditions –endometriosis Diseases associated with ovarian failure –Turner mosaic –Autoimmune polyglandular syndrome (APS) –Fragile X premutation carriers BRCA mutation carriers Delayed motherhood

31. © Fertility Centers of Illinois31 Fertility preservation - Endometriosis Progressive disease Can cause decline in ovarian reserve –Intrinsic to disease –Surgical intervention Association with infertility and need for future IVF Consider banking at young age with first diagnosis

32. © Fertility Centers of Illinois32 Fertility preservation - Turner mosaic 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 PGS in future –Careful cardiac screening, consider GC Oktay K., Fertil Steril 2010

33. © Fertility Centers of Illinois33 Fertility preservation – Endocrine disorders Autoimmune polyglandular syndrome –APS -1: Addison’s, chronic candidiasis, hypoparathyroidism –40.8% likely to develop ovarian failure –Consider screening and oocyte vitrification for young women who are affected Reato G. et al, J Clin Endocrinol Metab 2011 Consider oocyte vitrification at a younger age

34. © Fertility Centers of Illinois34 Fertility preservation – FMR1 Consider oocyte vitrification in known premutation carriers Fully expanded form of mutation leads to Fragile X –CGG triple repeats determine disease status Premutation 55-199 repeats and 13-26% of women will have POF/POI Risk increases with increasing repeat numbers 55-99 –High normal repeat numbers (35-54) not associated with decreased reserve Wittenberger et al, Fertil Steril 2007 Schufreider et al, ASRM 2014

35. © Fertility Centers of Illinois35 Fertility preservation - BRCA Recommendation to have oophorectomy age 40 or sooner Many will elect to do PGD for BRCA Association between BRCA and DOR Encourage childbearing at a younger age or oocyte/embryo vitrification Pavone ME et al., Reprod Sci 2014 Titus S et al., Sci Transl Med 2013

36. © Fertility Centers of Illinois36 Fertility preservation Cancer Gynecologic conditions –endometriosis Diseases associated with ovarian failure –Turner mosaic –Autoimmune polyglandular syndrome (APS) –Fragile X premutation carriers BRCA mutation carriers Delayed motherhood

37. © Fertility Centers of Illinois37 Why egg freezing? Changing role of women –Delayed childbearing for educational, professional and personal pursuits Average age of first live birth has risen steadily since the 1970s Universal truth that fertility declines sharply with advancing age Unintended childlessness is often the consequence of delayed childbearing

38. © Fertility Centers of Illinois38 Egg freezing has become mainstream

39. © Fertility Centers of Illinois39 Delayed motherhood

41. © Fertility Centers of Illinois41

42. © Fertility Centers of Illinois42 Mean age of women at first childbirth Average age in USA is 25 www.oecd.org/social/family/database

43. © Fertility Centers of Illinois43 First Births by Age of the Mother, U.S. 1970-2006 www.oecd.org/social/family/database Increase in the proportion of first births to women after the age of 35

44. © Fertility Centers of Illinois44 How old is too old?

45. © Fertility Centers of Illinois45 Why worry about age? Decline in quantity of oocytes Decline in quality of oocytes Decreased fecundability Increased infertility Increases in aneuploidy rates Increases in SAB rates Obstetric and perinatal outcomes

46. © Fertility Centers of Illinois46 Natural Fertility 35 years old Homan GF et al, Human Reproduction Update, 2007.

47. © Fertility Centers of Illinois47 ART canNOT overcome age Success of ART is dependent on age In woman with DOR and/or advanced age donor egg is often necessary Autologous oocytes Donor oocytes

48. © Fertility Centers of Illinois48 Implementation of egg freezing program Education is key –Patient education events –Referring MD education Psychological support Must tailor program to specific population –Paperwork –Consents

49. © Fertility Centers of Illinois49 Marketing Direct to patient –Fertility Awareness program –Use of Social Media –PR, News Marketing/Education to referring physicians

50. © Fertility Centers of Illinois50

51. © Fertility Centers of Illinois51 Fertility Awareness Program $90 Baseline ultrasound, AFC, FSH, E2 Semen analysis Nurse call to review results Follow up consultation offered with FCI MD

52. © Fertility Centers of Illinois52 Fertility Awareness Program CBS News

53. © Fertility Centers of Illinois53 FCI Ladies Night Out

54. © Fertility Centers of Illinois54 Partner with other entities: Egg Banxx egg freezing parties

55. © Fertility Centers of Illinois55 Controversy re: egg freezing parties Critics say delaying motherhood is nothing to party about Focus on creating work-life balance Creating better policies to support parents in the workforce. Best to avoid alcohol at a medical sponsored event

56. © Fertility Centers of Illinois56 Summary: building, implementation & advertising a fertility preservation program Establish success in own laboratory Track your program data Become an expert in fertility preservation for all indications Educate your community and colleagues Careful counseling

57. To promote health and alleviate the mental and physical distress of individuals and couples diagnosed with infertility through education and financial assistance www.lifefindsaway.org