Universal Embryo Cryopreservation: Frozen versus Fresh Transfer. Zaher Merhi, M.D.

Universal Embryo Cryopreservation: Frozen versus Fresh Transfer Zaher Merhi, M.D.

Disclosure: None

Fewer complications with IVF 1.5% children in US are born through ART 1.1 million children since 2006

Motivation for Fresh vs FET studies In 2011: Randomized trial comparing fresh and frozen embryo transfers in 103 NORMAL responders (8-15 antral follicles) age 18-40 years

Frozen is better Shapiro et al. Fertil Steril 2011

2014

In 2016 N=1508 Day 3 ET

Data collection by SART

1) More physiologic endometrium 2) PGS Most likely due to eset since implantation rates are higher

Rationale for the trend in frozen embryo transfer? Transfer of an embryo into a more physiologic environment would result in greater pregnancy rates and potentially decrease both maternal and perinatal morbidity.

Ovarian stimulation Controlled ovarian hyperstimulation (COH) with exogenous FSH/LH promotes development of multiple ovarian follicles High E2, P4 and others Affect and control endometrial development, maturation, and uterine contractile activity

What is the definition of supraphysiologic environment? 1. Simply related to estradiol (E2) levels? 1. What E2 cutoff makes it supraphysiologic? 1. Any use of gonadotropins (at any dose)?

Evans et al. Hum Reprod Update. 2014

Endometrial histology is disturbed in IVF Control women of known fertility (unstimulated cycle) Donor women treated with GnRHa Infertile women treated with GnRH antagonist glands * edematous stroma blood vessels secretions Evans et al. PLOS ONE. 2012 Infertile women treated with GnRHa who did not get pregnant Infertile women treated with GnRHa who became pregnant Closest to control

Endometrial histology is disturbed in IVF Control women of known fertility (unstimulated cycle) Donor women treated with GnRHa Infertile women treated with GnRH antagonist Infertile women treated with GnRHa who did not get pregnant Infertile women treated with GnRHa who became pregnant Evans et al. PLOS ONE. 2012

J Mol Endo, 2017

Endometrium after COH 1. Advanced histology (glandular changes) 2. Advanced down-regulation of the P receptor Advanced receptive phase Embryo endometrium asynchrony 1. Lowers the expression of integrins 2. Mature pinopodes appear 1-2 days earlier in cycles with COH and are less numerous 3. Alters the immune environment of the endometrium (Natural Killer cells) 4. High VEGF during COH abnormal trophoblast invasion Weinerman et al. Fertil Steril 2014

Overall effect of ovarian stimulation on the endometrium Following COH, the endometrium is 1. histologically advanced 2. biochemically different 3. genomically dysregulated Horcajadas et al, 2007.

Fresh transfer after COH 1. Pre-eclampsia 2. Low birth weight (LBW) 3. Small for gestational age (SGA) 4. Prematurity 5. Antepartum hemorrhage 6. Placental abruption 7. Perinatal death Wong et al. Fertil Steril 2014

Risks associated with preterm 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 Neonatal death

Why more cryopreservation? 1. Improved cryopreservation techniques 2. GnRH agonist trigger in high responders: associated with abrupt termination of the luteal phase complete and irreversible luteolysis reduced live birth rates 3. Increased use of genetic screening 4. Steady decrease in national average # of embryos transferred more embryos for cryopreservation and FET Shapiro et al. Fertil Steril 2014

Vitrification vs. slow-freeze Wong et al. Fertil Steril 2014

Justifications for freeze all embryo strategy 1. Decreasing the risk of OHSS 2. Decreasing the risk of perinatal morbidity, and maternal morbidity 3. Possibility of PGD/PGS 4. Separation of embryo transfer from the stress and rigors of ovarian stimulation 5. Seems to be particularly successful in older women who undergo several episodes of ovarian stimulation before attempting an ET of thawed pooled embryos Shapiro et al. Fertil Steril 2014

Freeze-all embryo policy in normal responders? Advantages: 1.Cost per live birth may be substantially lower given that clinical pregnancy rates appear to be higher after frozen embryo transfer 2.Recent registry analyses: infants conceived from frozen embryos may have a significantly lower incidence of preterm birth compared to infants conceived from fresh embryos Freeze-all policy may substantially reduce the costs for healthcare systems

Advantage for day 6 blastocysts slower embryos are less likely to implant because the endometrial receptive phase ends prematurely Shapiro et al, 2013. Comparing 186 cycles matched on maternal age, embryo morphology, and day of blastulation.

Advantage in premature luteinization If premature elevation of P4 on the day of hcg trigger is associated with decreased implantation rates, can we improve implantation rates if we cryopreserved all embryos and transferred them in FET cycles?

Cryopreservation rescues cycles with premature luteinization Shapiro et al 2010, comparing 236 matched cycles with elevated P4 (>1 ng/ml).

Disadvantages of cryopreservation 1. Psychological burden for the patient: Waiting 2. Convenience 3.? altered embryo competence and subsequent implantation and/or development 4. Macrosomia (large babies) 5. Not all centers have good cryopreservation programs could be detrimental 6. Increase workload for fertility units? 7. SART reporting problems Barnhart. Fertil Steril 2014

Less ectopic pregnancy with FET?

Embryo transfers in cycles without ovarian hyperstimulation, such as frozen or donor cycles, were associated with lower rates of ectopic pregnancy compared with fresh autologous cycles, suggesting that a difference in the tubal-uterine environment contributes to abnormal implantation after IVF.

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Forest plot of pooled estimate of being born with birthweight of >4500 g in singletons conceived after FET versus those conceived after Fresh embryo transfer Pinborg et al. Hum. Reprod. 2014;29:618-627

Forest plot of pooled estimate of being born with birthweight of >4500 g in singletons conceived after FET versus naturally conceived (NC) singletons Pinborg et al. Hum. Reprod. 2014;29:618-627

Frozen Embryos Produce More Sociable Children Than Fresh Ones (For Some Reason)

Are we there yet? 1.Patients attitude studies? 2.Restrictive health care funding? 3.Governmental regulation?

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

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High-quality RCT should be performed to determine which cryopreservation protocol is best and whether a freeze-all strategy is truly justified in future IVF treatments

Expert Analysis: ESHRE 2014 Embryo vitrification offers the unique advantage over fresh embryos of easier coordination between the IVF process and subsequent transfer to the woman who will carry the pregnancy. Dr. Anja Pinborg Professor at Hvidovre (Denmark) Hospital "It is now possible to freeze embryos with a 90% survival rate.. Most clinicians still use the approach of placing an embryo during the same cycle when the oocyte was harvested, "the way it s always been done, but at many clinics now they see that with vitrification they can get pregnancy rates that are similar to or even better than fresh embryo transfer. I think they will go more and more to frozen embryos."

Expert Analysis: ESHRE 2014 Dr. Richard J. Paulson Professor at University of Southern California "Vitrification is so good and embryos come out of it so well that the benefit from improved endometrial receptivity outweighs any change in embryo quality. The timing coordinates so much better.

Expert Analysis: ESHRE 2014 Dr. Markus S. Kupka Palo Alto, California The most recent worldwide and European data on patterns of assisted reproductive technology show increases in frozen embryo use and decreases in triplets or greater multiples. Worldwide, frozen embryo transfers in all IVF procedures grew from 10% in 1991 to 28% in 2010. Transfers of one or two embryos grew from 20% of all IVF procedures done in North America in 1998 to 68% in 2010. "The trend is for more frozen transfers, and for reducing multiple rates