Fresh or frozen embryos – which are better

1. Is Frozen Embryo Transfer better than Fresh? Bruce Shapiro MD, PhD Medical Director, Fertility Center of Las Vegas Clinical Associate Professor, University of Nevada School of Medicine

2. Disclosures Research grants: • Actavis • Merck & Co. Consulting/Speakers Bereaus: • Merck • TEVA • Glycotope GMBH

3. Learning Objectives • Review indicators of embryo- endometrium asynchrony in fresh autologous cycles • Review the effects of ovarian stimulation on perinatal outcome and maternal risks • Review the use of embryo cohort cryopreservation to circumvent such risks.

4. Early history of freezing human embryos or gametes • 1949 – First human gamete cryopreservation (sperm vitrification) • 1984 - First live birth with FET • 1985 – First pregnancies with thawed blastocysts • 1986 - First live birth with thawed oocytes Polge et al 1949, Zeilmaker et al 1984, Cohen et al 1985, Chen 1986

5. Motivation for fresh vs FET studies • In 2004 we noticed the pregnancy rates in our FET cycles were as good as those in our fresh cycles • In 2005-2006, our live birth rates with FET began to exceed those with fresh transfer.

6. Live Birth Rates at The Fertility Center of Las Vegas 2004.0 2005.0 2006.0 25 30 35 40 45 50 55 Fresh - FCLV FET - FCLV Fresh - Nat Avg FET - Nat Avg Age <35 Live birth rate per transfer (%)

7. Rationale for investigation of FET cycles and implantation potential • If supernumerary “second-best” frozen embryos implanted more readily than fresh primary embryos, then could further improvement be realized if “best” primary embryos were cryopreserved in a freeze all cycle and replaced in an FET cycle?

8. Ovarian Stimulation • Controlled ovarian stimulation (COS) with exogenous FSH promotes development of multiple ovarian follicles • Multiple follicles produce supraphysiologic levels of estradiol, progesterone, and other hormones • These hormones affect and control endometrial development, maturation, and uterine contractile activity.

9. Endometrial Changes • Mature pinopodes appear 1-2 days earlier in cycles with COS and are less numerous • Pinopode function not yet confirmed, but generally believed to have role in implantation and the endometrial receptive phase • Progesterone receptor down-regulated 1-2 days earlier in cycles with COS. Mirkin et al, 2004. Nikas et al, 1999. Develioglu et al, 1999. Horcajadas et al 2007.

10. Advanced endometrial histology Advanced endometrial histology has been correlated with premature progesterone elevation and implantation failure. Nikas et al, 1999. Kolibianakis et al, 2002.

11. Gene expression profiles • Gene expression profiles are different between natural cycles and cycles of COS consistent with dysregulation of gene expression in hyperstimulated cycles • Many genes associated with the implantation window on hCG +7 were delayed by 2 days • This is consistent with histological and biochemical discrepancies found previously in other studies. Horcajadas et al, 2007

12. Overall effect of ovarian stimulation on the endometrium • Following COS, the endometrium is “histologically advanced, biochemically different, and genomically dysregulated.” Horcajadas et al, 2007.

13. Blastocysts

14. Embryo developmental pace • There is biological variation in embryonic developmental pace • Some embryos form expanded blastocysts on day 5 of development, others on day 6 • Day 5 blastocysts implant more readily than day 6 blastocysts in fresh IVF cycles following ovarian stimulation. Shapiro et al 2001.

15. Embryo developmental pace Shapiro et al 2001. Clinical Pregnancy Implantation 0% 10% 20% 30% 40% 50% 60% 70% Day 5 Blastocysts Day 6 Blastocysts

16. Questions raised by the effect of embryo developmental pace on IVF outcome • Why do fresh day 5 blastocysts implant more readily than fresh day 6 blastocysts? • Do day 5 and day 6 blastocysts have different implantation rates in FET cycles? • If day 5 and day 6 blastocysts have similar implantations rates in FET cycles in the absence of COS, should they also have similar rates in donor oocyte cycles?

17. Studied Day 5 and Day 6 blastocyst transfers in Fresh, FET and donor oocyte cycles • Retrospective study: • 377 fresh autologous cycles • 106 autologous FET cycles • 56 fresh oocyte donation cycles Shapiro et al 2008.

18. Contrasting patterns of clinical pregnancy rates in fresh and FET Shapiro et al 2008.

19. Day 5 vs Day 6 Blastocysts • Similar aneuploidy rates • Similar implantation potential in frozen- thawed cycles • Frozen-thawed day 6 blastocysts transferred in cycles without ovarian stimulation implant more readily than fresh day 6 blastocysts in cycles with ovarian stimulation. Kroener et al 2012. Murata et al 2005. Richter et al 2006. Shapiro et al 2008.

20. Day 5 vs Day 6 Blastocysts • Conclusion: The different implantation potential between day 5 and day 6 blastocysts is consistent with advanced endometrial development in cycles of ovarian stimulation, so that slower embryos are less likely to implant because the endometrial receptive phase ends prematurely. Richter et al 2006. Shapiro et al 2008.

21. Study: Are there degrees of asynchrony? • Retrospective analysis • 361 fresh blastocyst transfers • 25 independent variables potentially affecting IVF success • Outcome measure of clinical pregnancy • Multiple logistic regression modeling • Validated against a second set of 219 blastocyst transfers Shapiro et al 2008.

22. Model of synchrony factors in fresh autologous cycles Day of Blastulatio n P4 Leve l Blastocys t Diameter Fres h Mode l 5 Low Large 80% 5 Low Small 54% 5 High Large 62% 5 High Small 33% 6 Low Large 68% 6 Low Small 38% 6 High Large 46% 6 High Small 20% Shapiro et al 2008

23. Comparison of FET Results with Fresh Transfer Model Day of Blastulatio n P4 Leve l Blastocys t Diameter Fres h Mode l FET Results 5 Low Large 80% 88% 5 Low Small 54% 76% 5 High Large 62% 87% 5 High Small 33% 85% 6 Low Large 68% 78% 6 Low Small 38% 69% 6 High Large 46% 77% 6 High Small 20% 73% Shapiro et al 2008, Shapiro et al 2013

24. Fresh versus frozen in cycles with “premature luteinization” • If premature elevation of progesterone at the time of the hCG trigger is associated with decreased implantation rates, could we improve implantation rates if we cryopreserved all embryos and transferred them in FET cycles? Bosch et al 2003, Shapiro et al 2010.

25. Retrospective study of fresh versus frozen in cycles with “premature luteinization” • 118 fresh transfers matched to 118 freeze- all cycles, all in cycles with P4>1.0 on day of trigger • Matched on maternal age and number of bipronuclear oocytes produced • Similar numbers of transferred blastocysts Shapiro et al 2010.

26. Retrospective study of fresh versus frozen in cycles with “premature luteinization” Results • Cancellation rate greater with FET • Pregnancy, implantation, ongoing pregnancy per transfer, and ongoing pregnancy per retrieval all greater with FET • Pregnancy loss rate lower after FET. Shapiro et al 2010.

27. Cryopreservation rescues cycles with “premature luteinization” Shapiro et al 2010, comparing 236 matched cycles with elevated P4. Cancellation Rate Loss/Pregnancy Ongoing/Retrieval 0 10 20 30 40 50 60 70 80 90 Frozen-Thawed Fresh

28. Can FET in young patients be comparable to fresh donor cycles? • One advantage of donor oocyte cycles is the transfer of healthy embryos derived from young donors • Another advantage is the absence of an endometrium exposed to supraphysiolgic hormone levels resulting from COS • Therefore, shouldn’t the implantation and pregnancy rates of young patients in FET cycles rival those of donor oocyte cycles? Shapiro et al 2010.

29. How does FET in young patients compare to fresh donor cycles using young donors? • Compared 205 autologous FET and fresh oocyte donation cycles • Autologous patients and oocyte donors <35 years of age in oocyte retrieval cycle Shapiro et al 2010.

30. How does FET in young patients compare to fresh donor cycles using young donors? Results • Similar implantation rates (65.9% vs 62.1%) • Similar ongoing pregnancy rates (79.7% vs 75.0%) Shapiro et al 2010.

31. How does FET in young patients compare to fresh donor cycles using young donors? Shapiro et al 2010. Comparing 205 PTEC and donor cycles, egg sources <35 years of age, double blastocyst transfer. Pregnancy/Transfer Ongoing/Transfer 0 10 20 30 40 50 60 70 80 90 100 Autologous FET Fresh Donor

32. How does FET in young patients compare to fresh donor cycles using young donors? • Conclusion: In the absence of cryodamage, FET embryos can implant as readily as those from fresh oocyte donor cycles. Shapiro et al 2010.

33. Could there be a embryo screening effect in FET cycles? • If we controlled for embryo morphology, would fresh and FET implantation rates still differ? • Could the difference in implantation and pregnancy rates between fresh and FET cycles be due to a screening effect so that only the morphologically best appearing embryos remain after thaw for transfer? Shapiro et al 2013.

34. What is the nature of the reduced endometrial receptivity following ovarian stimulation? • A matched-cohort study compared 93 fresh and 93 frozen-thawed single-blastocyst transfers, matched for patient age, embryo morphology, and day of blastulation. • Fresh transfers had significantly lower ongoing pregnancy rate than FET with day 6 blastocysts, but not with day 5 blastocysts. Shapiro et al 2013.

35. Comparison of demographics and potential confounders in matched fresh and freeze-thaw transfers. Fresh FET P value Transfers 93 93 Patient age (y) * 33.8 33.8 NS Age range (y) 23–45 22–45 NS Day 5 blastulation * 23 (24.7) 23 (24.7) NS Blast diameter (mm) * 192.5 192.6 NS ICM (mm2) 4,047 3,939 NS Troph cells 13.8 14.0 NS eSET 23 19 NS Genetic screening * 4 4 NS Endometrium (mm) 10.1 9.1 0.0050 * Matching criterion Shapiro et al 2013.

36. Comparison of matched fresh and freeze-thaw transfers.

37. What is the impact of reduced endometrial receptivity following ovarian stimulation? Shapiro et al, 2013. Comparing 186 cycles matched on maternal age, embryo morphology, and day of blastulation.

38. Is the reduced endometrial receptivity following ovarian stimulation associated with embryo developmental pace? Shapiro et al, 2013. Comparing 186 cycles matched on maternal age, embryo morphology, and day of blastulation.

39. What is the nature of the reduced endometrial receptivity following ovarian stimulation? • Conclusion: COS reduces implantation of slowly-developing embryos, consistent with the embryo-endometrium asynchrony hypothesis. Shapiro et al 2013.

40. LH surge Ovulation Blastulation Embryo implantation window Endometrial Implantation window Oocyte/embryo development timeline In natural menstrual cycle P4 exposure Follicular phase

41. Trigger injection Oocyte collection Blastulation Embryo implantation window Endometrial implantation window Oocyte/embryo development timeline Following ovarian stimulation P4 exposure Ovarian stimulation

42. Randomized Trial: Fresh vs Frozen in High Responders • Randomized trial comparing fresh and frozen embryo transfers in 101 HIGH responders (>15 antral follicles) age 18-40 years. Shapiro et al 2011.

43. Randomized Trial: Fresh vs Frozen in High Responders • 65% clinical pregnancy rate in fresh transfers • 80% clinical pregnancy rate in frozen transfers • Difference not statistically significant (P=0.1109). Shapiro et al 2011.

44. Results Fresh FET P-value Transfers 52 49 # Transferred 2.0 ± 0.1 1.9 ± 0.3 NS Implantation rate 57% 65% NS Clinical pregnancies per transfer 65% 80% NS Multiple preg rate (per clinical preg) a 73.5% 59.0% NS a Study halted for excessive multiple pregnancy rate

45. Randomized Trial: Fresh vs Frozen in High Responders • However, significantly worse embryo morphology was observed in the frozen embryo transfer group. • Post-hoc analysis showed superior ongoing pregnancy rate after frozen-thawed embryo transfer when controlling for embryo morphology. Shapiro et al 2011.

46. Clinical Pregnancy Rate According to Presence of Supernumerary Embryos Supernumerar y blastocysts Fresh clinical pregnancy rate FET clinical pregnancy rate Present 33/43 (77%) 23/24 (96%) Not Present 1/9 (11%) 16/25 (64%) P<0.0001 when comparing fresh and FET in logistic regression, while adjusting for presence of supernumerary embryos as a marker of embryo quality

47. Randomized Trial: Fresh vs Frozen in Normal Responders • Randomized trial comparing fresh and frozen embryo transfers in 103 NORMAL responders (8- 15 antral follicles) age 18-40 years Shapiro et al 2011.

48. Results Randomized Trial: Fresh vs Frozen in Normal Responders • 54.7% clinical pregnancy rate in fresh transfers • 84.0% clinical pregnancy rate in frozen transfers • Statistically significant difference (P=0.0013). Shapiro et al 2011.

49. Results Fresh Cryo P-value Implantation rate 37/95 = 38.9% 63/89 = 70.8% <0.0001 Clinical pregnancy rate per transfer * 29/53 = 54.7% 42/50 = 84.0% 0.0013 Ongoing pregnancy rate per transfer 27/53 = 50.9% 39/50 = 78.0% 0.0072 * The study was halted at this interim stopping point because the P-value was less than 0.03, per the pre- defined stopping rule.

50. Results

51. Fresh versus Frozen Risk Comparison IVF Outcomes When compared to fresh transfer, embryo cohort cryopreservation followed by frozen- thawed transfer has been associated with: • Reduced risk of implantation failure in normal responders • Reduced risk of implantation failure following premature progesterone elevation • Reduced risk of IVF failure per retrieval Shapiro et al 2011, Shapiro et al 2010, Roque et al 2012

52. Fresh versus Frozen Risk Comparison Maternal Risks When compared to fresh transfer, frozen- thawed transfer has been associated with: • Reduced risk of late-onset OHSS • Reduced risk of ectopic pregnancy • Reduced risk of pre-eclampsia. ASRM Practice Committee 2008, Ng et al, 1998. Ishihara et al, 2011. Shapiro et al, 2012. Maheshwari et al 2012, Imudia 2013.

53. Fresh versus Frozen Risk Comparison Perinatal Risks related to Birthweight When compared to fresh transfer, frozen- thawed transfer has been associated with: • Greater mean birthweight • Reduced risk of low birthweight • Reduced risk of small for gestational age. Maheshwari et al (2012)

54. Fresh versus Frozen Risk Comparison Perinatal Risk of Pre-Term Delivery When compared to fresh transfer, frozen-thawed transfer has been associated with: • Reduced risk of pre- term birth • Reduced risk of pre- term low birthweight Maheshwari et al 2012, Kalra et al 2011, Sullivan et al 2013, Pinborg et al 2013

55. Risks Associated with Pre-Term Delivery • Inability to regulate body temperature • Respiratory distress or apnea • Visual issues, including retinopathy • Feeding problems, digestive issues • Prolonged hospitalization • Intellectual disabilities • Low birthweight • Hearing loss • Jaundice • Bleeding in the brain • Infection • Cerebral palsy •

56. Fresh versus Frozen Risk Comparison Other Perinatal Risks When compared to fresh transfer, frozen- thawed transfer has been associated with: • Reduced risk of antepartum hemorrhage • Reduced risk of placenta previa • Reduced risk of placental abruption • Reduced risk of perinatal mortality Maheshwari et al 2012, Sullivan et al 2013

57. Trends in Fresh and FET outcomes • SART registry • 2006-2011 • Standard age groups

59. Trends in US National Average Live Birth Rates

64. Ratio of FET cycles to fresh cycle starts, 2006-2012

65. Trends in numbers of live births

66. Increasing asynchronous transfers in fresh cycles with age Retrospective study showing asynchrony factors increasing with age Shapiro et al, 2013

67. Live Birth Rates at The Fertility Center of Las Vegas 2006.0 2007.0 2008.0 2009.0 2010.0 2011.0 2012.0 30 35 40 45 50 55 60 65 70 Fresh - FCLV FET - FCLV Fresh Nat Avg FET - Nat Avg Age <35 Live birth rate per transfer (%)

68. Average Ongoing Pregnancy Rates at Fertility Center of Las Vegas

69. Conclusions • Ovarian stimulation impairs endometrial receptivity, particularly through embryo- endometrium asynchrony • Embryo cohort cryopreservation circumvents the compromised endometrium • Frozen-thawed embryo transfer may be associated with certain reduced maternal and perinatal risks, when compared to fresh autologous transfers.

70. Thank you!

Fresh or frozen embryos – which are better

Fresh or frozen embryos – which are better

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