Hot Topics in REI Its not so simple October 18, 2019 Eleni - PowerPoint PPT Presentation

10/18/2019 Disclosures • Research grant recipient (EMD Serono) Hot Topics in REI … It’s not so simple October 18, 2019 Eleni Greenwood Jaswa, MD MSc University of California San Francisco 1 2 AMH Egg freezing Overview AMH Preimplantation genetic What’s new? testing (PGT) 3 4 1

10/18/2019 How often do you discuss AMH with patients? What is antimullerian hormone (AMH)? 70% A. <1 time per week • Dimeric glycoprotein B. 1-2 times per week produced by granulosa cells of preantral (primary and C. 3-4 times per week secondary) and small antral follicles D. >4 times per week • After activation from primordial stage 17% • Production continues 8% 5% until midantral stages (2–7 mm) k k k k e e e e e e e e w w w w r r r r e e e e p p p p e s s s m e e e m m m i t i i t t t i 1 < 2 4 4 - - > 1 3 Broekmans. Trends Endocrinol Metab. 2008. 5 6 • AMH correlates with the size of the remaining primordial pool of follicles (ovarian reserve) 1 • Heralded as the ultimate “fertility biomarker” given relative advantages over other, older measures (FSH, AMH and estradiol) 1,2 • Not affected by phase of cycle fertility • Not affected by birth control • Early study showed an association with natural fertility in the general population (n=100) 3 • AMH <0.7 ng/mL: reduced fecundability by 62% (fecundability ratio 0.38; 95% CI 0.08-0.91) 1 Broekmans. Endocr Rev. 2009 . 1 ASRM Practice Committee. Fertil Steril. 2015. 3 Steiner. Obstet Gynecol. 2011 7 8 2

10/18/2019 Update • Time-to-pregnancy cohort study of women 30 to 44 years without a history of infertility (N=750) • Cumulative probability of conception by 12 cycles: • Women with low AMH: 84% AMH does not predict natural fertility • Women with normal AMH: 75% • p=NS 1 Steiner. JAMA. 2017 1 Steiner. JAMA. 2017 9 10 AMH does not predict natural fertility AMH is not a ”fertility biomarker” • EAGeR Trial • N=1202 • Lower and higher AMH values were not associated with fecundability • <1.0: 66.1% • 1.0-3.5: 65.2% • >3.5: 65.2% 1 Zarek. J Clin Endocrinol Metab. 2015. 1 Greenwood. Fertil Steril. 2017. 11 12 3

10/18/2019 AMH and response to ovarian stimulation What does AMH predict? • Response to ovarian stimulation • Menopause? 1 ASRM Practice Committee. Fertil Steril. 2015. 13 14 Trajectory of decline? • Doetinchem Cohort Study (N= 3326) • 5 visits over 20 years • Baseline age 20-59 (avg 40) AMH and • ~13,000 samples by picoAMH assay time to menopause • Acceleration of decline after age 40y • Large variation in AMH levels at a given time before menopause • AMH reflects the size of the primordial follicle pool • The natural cause of menopause is depletion of these follicles “Although age-specific AMH levels remain consistently high or low with increasing age, the converging trajectories and variance of AMH levels .. shed doubt on the added value of AMH to represent individualized reproductive age.” De Kat. BMC Med. 2016 15 16 4

10/18/2019 • Knowing the AMH decline rate does not improve the prediction of menopause • Except for between 20-25 (marginal improvement: C-stat 0.64  0.69) • Risk of early menopause (<45) is underestimated (esp. at young ages) De Kat. JCEM. 2019 De Kat. JCEM. 2019 17 18 • In October 2018 the PicoAMH ELISA test (Ansh Labs) became FDA cleared as a diagnostic aid in the determination of menopausal status in women 42 - 62 years old • Assay technology • Sensitive: limit of detection = 2 pg/mL (0.002 ng/mL) >0.1 ng/mL • Shelf life = 24 months • “Meant to be used only in conjunction with other clinical assessments and laboratory <0.01 ng/mL findings” • Test performed “reasonably well” at identifying women who already had their LMP versus women who were more than five 0.01-0.099 ng/mL years away from their last menstrual period • 690 women, aged 42 to 62 multi-center, longitudinal Study of Women’s Health Across the Nation (SWAN) Personal correspondence with Ansh Labs PhD . 2019 19 20 5

10/18/2019 Measuring AMH - It’s not so simple Caveats 21 22 VARIES DOES NOT AMH Caveats VARY • Levels are affected by OCPs • 19-50% reduction in serum AMH after recent OCP exposure AMH Caveats AMH levels likely vary across the menstrual cycle 1 Tsepelidis. Hum Reprod. 2007. 2 Kissell. Hum Reprod. 2014. 1 Dewailly. Hum Reprod Update. 2014. 23 24 6

10/18/2019 AMH Caveats • Variability between assays • Different antibodies • Serum antimüllerian hormone level assessment generally • Different calibration techniques should not be ordered or used to counsel women who are not infertile about their reproductive status and future fertility • Rule of thumb potential. • <0.5: Assays vary • 0.3 – 3.0: Assays agree • >4-5: Assays vary • The use of antimüllerian hormone levels as a predictor of the onset of menopause is unsuitable for clinical practice at this • It is not recommended to compare time. absolute values from clinical studies that use different assays 1 Rustamov. Hum Reprod. 2012. 2 Dewailly. Hum Reprod Update. 2014. 1 ACOG Committee Opinion. Obstet Gynecol. 2019. 25 26 What percent of women who freeze their eggs are estimated to use them? 50% A. 0-25% 44% B. 25-50% C. 50-75% D. 75-100% Egg Freezing 5% What’s new? 1% % % % % 5 0 5 0 2 5 7 0 - - - 5 0 1 0 - 2 5 5 7 27 28 7

10/18/2019 Why should women consider egg freezing? Frequency of To preserve a woman’s current fertility and egg freezing increase their chances of achieving pregnancy at a later age • 2600% rise in egg or embryo freezing cycles in the U.S. from 2009-2016 • 2016: ~9,000 egg freezing cycles • 2019: 17,000 cycles estimated Heffner, NEJM 2004 29 30 ASRM Perspective Emotional implications 2012 2018 • Decision regret in 1/6 women • Risk factors • Low number of eggs • Egg freezing no longer considered experimental • Low predicted chance of live birth • Declined to recommend OC ”for the sole with eggs purpose of circumventing reproductive aging in • Inadequate emotional support • Terminology changed to “ Planned OC ” healthy women’’ • • “Elective,” “social,” “nonmedical” terms are “Data on the safety, efficacy, cost- • Inadequate information trivializing and insufficiently respectful of the fact that effectiveness, and emotional risks of the treatment is being undertaken to avert infertility elective oocyte cryopreservation are that, if it arises, will in fact be a medical condition insufficient to recommend elective oocyte (infertility) cryopreservation.” • “An emerging but ethically permissible • “Marketing this technology for the purpose of procedure that may help women avoid future deferring childbearing may give women false infertility” hope and encourage women to delay childbearing.” 1 Greenwood. Fertil Steril. 2018. 31 32 8

10/18/2019 ASRM 2018 Guideline Optimal Timing? • Age 37 • Greatest improvement in chances Patients may wish to consult with an of live birth independent mental health professional before choosing planned OC, to further • Most cost-effective explore their expectations, motivations, Recent research suggests that some women and any concerns surrounding the experience decisional regret over having • Age 34 procedure (Greenwood et al). cryopreserved oocytes, a development that • Highest chances of live birth needs to be better understood and addressed (Greenwood et al). • Age 25-30 • Little benefit 1 ASRM Ethics Committee. Fertil Steril. 2018. 2 Greenwood. Fertil Steril. 2018. 1 Mesen. Fertil Steril. 2015. 33 34 Optimal timing for How many eggs to freeze? egg freezing? • Overall, estimates ~6% live birth per • Personal oocyte circumstances • Biologic circumstances 1 Franasiak. Fertil Steril. 2014. *UCSF Unpublished data 35 36 9

10/18/2019 How many eggs to freeze? Oocyte vitrification in donor egg cycles • Oocyte survival = 90% • 8-15 eggs warmed per recipient • Live birth per thawed oocyte = 6.5% • 1.4% of thaw cycles had unpredictable, zero survival and cancellation 1 Cobo. Fertil Steril. 2015. 1 Goldman. Hum Reprod. 2017. 37 38 How many eggs to freeze? 1 Goldman. Hum Reprod. 2017. 1 Doyle. Fert Steril. 2016. 39 40 10

10/18/2019 Success rates after Planned OC • 1,468 women underwent planned OC How many women • Mean age = 37 will use their eggs? • 9% returned to use them about 2y later (N=137) • 85% survived thaw • Live birth per transfer = 31.6% • 9% (Cobo 2016, IVI Spain) • Live birth per patient (40 babies) • < 35y = 50% • 6% (Hammarberg 2017, Melbourne IVF) • >35y = 23% • 6% (Greenwood 2018, UCSF) • At least 8-10 mature eggs should be frozen • …<<50% (expert predictions) • Encourage women to come at younger ages 1 Cobo. Fertil Steril. 2016. 41 42 Preimplantation • AMH can predict response to ovarian Egg Freezing + stimulation Genetic Testing • Counseling tool for number of cycles required AMH to meet a certain goal (PGT) What’s new? 43 44 11