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Zaher Merhi, M.D.

Universal Embryo Cryopreservation: Frozen versus Fresh Transfer

Disclosure: None

1.5% children in US are born through ART

1.1 million children since 2006

Fewer complications with IVF

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

Motivation for Fresh vs FET studies

Frozen is better

Shapiro et al. Fertil Steril 2011

In 2016 N=1508 Day 3 ET

Data collection by SART

Most likely due to eSET since implantation rates are higher

1) More physiologic endometrium 2) PGS

Fertility and Sterility 2014 102, 3-9DOI: (10.1016/j.fertnstert.2014.04.018)

Copyright © 2014 American Society for Reproductive Medicine Terms and Conditions

http://www.elsevier.com/termsandconditions


Transfer of an embryo into a more “physiologic environment” would result in greater pregnancy rates and potentially decrease both maternal and perinatal morbidity.

Rationale for the trend in frozen embryo transfer?

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

1. Simply related to estradiol (E2) levels? 1. What E2 cutoff makes it

“supraphysiologic”? 1. Any use of gonadotropins (at any dose)?

What is the definition of supraphysiologic environment?

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 GnRHa who did not get pregnant

glands

blood vessels

Infertile women treated with GnRH antagonist

* edematous stroma

secretions

Infertile women treated with GnRHa who became pregnant

Closest to control

Evans et al. PLOS ONE. 2012

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

1. Advanced histology (glandular changes)

2. Advanced down-regulation of the P receptor

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

Endometrium after COH

Advanced receptive phase Embryo–endometrium asynchrony

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.

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

Fresh transfer after COH

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

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

Why more cryopreservation?


Vitrification vs. slow-freeze

Wong et al. Fertil Steril 2014

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

Justifications for freeze all embryo strategy


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

Freeze-all embryo policy in normal responders?

Advantage for day 6 blastocysts

Shapiro et al, 2013. Comparing 186 cycles matched on maternal age, embryo morphology, and day of blastulation.

slower embryos are less likely to implant because the endometrial receptive phase ends prematurely

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).

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

Disadvantages of cryopreservation

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.”

www.dailymail.com

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)

1.Patients’ attitude studies?

2.Restrictive health care funding?

3.Governmental regulation?

Are we there yet?

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.

THANK YOU

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

Dr. Anja Pinborg

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.

• "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."

Professor at Hvidovre (Denmark) Hospital

Dr. Richard J. Paulson


"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.“

Professor at University of Southern 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…”

Dr. Markus S. Kupka

Palo Alto, California

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