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

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Hot Topics in REI …It’s not so simple

October 18, 2019 Eleni Greenwood Jaswa, MD MSc University of California San Francisco

Disclosures

Research grant recipient (EMD Serono)

Overview AMH Egg freezing Preimplantation genetic testing (PGT)

AMH

What’s new?

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How often do you discuss AMH with patients?

A. <1 time per week
B. 1-2 times per week
C. 3-4 times per week
D. >4 times per week

< 1 t i m e p e r w e e k 1

2

t i m e s p e r w e e k 3

4

t i m e s p e r w e e k > 4 t i m e s p e r w e e k

70% 5% 8% 17%

What is antimullerian hormone (AMH)?

Dimeric glycoprotein

produced by granulosa cells

f preantral (primary and

secondary) and small antral follicles

After activation from

primordial stage

Production continues

until midantral stages (2–7 mm)

Broekmans. Trends Endocrinol Metab. 2008.

AMH and fertility

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, estradiol) 1,2

Not affected by phase of cycle
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)

1Broekmans. Endocr Rev. 2009 . 1ASRM Practice Committee. Fertil Steril. 2015. 3Steiner. Obstet Gynecol. 2011

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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%
Women with normal AMH: 75%
p=NS
1Steiner. JAMA. 2017

AMH does not predict natural fertility

1Steiner. JAMA. 2017

AMH does not predict natural fertility

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%
1Zarek. J Clin Endocrinol Metab. 2015.

AMH is not a ”fertility biomarker”

1Greenwood. Fertil Steril. 2017.

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What does AMH predict?

Response to ovarian stimulation
Menopause?

1ASRM Practice Committee. Fertil Steril. 2015.

AMH and response to ovarian stimulation

AMH and time to menopause

AMH reflects the size of the primordial follicle pool
The natural cause of menopause is depletion of these follicles

De Kat. BMC Med. 2016

Trajectory of decline?

Doetinchem Cohort Study (N= 3326)
5 visits over 20 years
Baseline age 20-59 (avg 40)
~13,000 samples by picoAMH assay
Acceleration of decline after age

40y

Large variation in AMH levels at a

given time before menopause

“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.”

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De Kat. JCEM. 2019 De Kat. JCEM. 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)
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)

Shelf life = 24 months
“Meant to be used only in conjunction with
ther clinical assessments and laboratory

findings”

Test performed “reasonably well” at

identifying women who already had their LMP versus women who were more than five 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

>0.1 ng/mL <0.01 ng/mL 0.01-0.099 ng/mL

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Measuring AMH - Caveats

It’s not so simple

AMH Caveats

AMH levels likely vary across the menstrual cycle

1Tsepelidis. Hum Reprod. 2007. 2Kissell. Hum Reprod. 2014.

VARIES DOES NOT VARY

AMH Caveats

Levels are affected by OCPs
19-50% reduction in serum AMH

after recent OCP exposure

1Dewailly. Hum Reprod Update. 2014.

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AMH Caveats

Variability between assays
Different antibodies
Different calibration techniques
Rule of thumb
<0.5: Assays vary
0.3 – 3.0: Assays agree
>4-5: Assays vary
It is not recommended to compare

absolute values from clinical studies that use different assays

1Rustamov. Hum Reprod. 2012. 2Dewailly. Hum Reprod Update. 2014.
Serum antimüllerian hormone level assessment generally

should not be ordered or used to counsel women who are not infertile about their reproductive status and future fertility potential.

The use of antimüllerian hormone levels as a predictor of the
nset of menopause is unsuitable for clinical practice at this

time.

1ACOG Committee Opinion. Obstet Gynecol. 2019.

Egg Freezing

What’s new?

What percent of women who freeze their eggs are estimated to use them?

A. 0-25%
B. 25-50%
C. 50-75%
D. 75-100%
2

5 % 2 5

5

% 5

7

5 % 7 5

1

%

50% 1% 5% 44%

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10/18/2019 8 Why should women consider egg freezing?

To preserve a woman’s current fertility and increase their chances of achieving pregnancy at a later age

Heffner, NEJM 2004

Frequency of egg freezing

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

ASRM Perspective

2012 2018

Egg freezing no longer considered experimental
Declined to recommend OC ”for the sole

purpose of circumventing reproductive aging in healthy women’’

“Data on the safety, efficacy, cost-

effectiveness, and emotional risks of elective oocyte cryopreservation are insufficient to recommend elective oocyte cryopreservation.”

“Marketing this technology for the purpose of

deferring childbearing may give women false hope and encourage women to delay childbearing.”

Terminology changed to “Planned OC”
“Elective,” “social,” “nonmedical” terms are

trivializing and insufficiently respectful of the fact that the treatment is being undertaken to avert infertility that, if it arises, will in fact be a medical condition (infertility)

“An emerging but ethically permissible

procedure that may help women avoid future infertility”

Emotional implications

Decision regret in 1/6 women
Risk factors
Low number of eggs
Low predicted chance of live birth

with eggs

Inadequate emotional support
Inadequate information
1Greenwood. Fertil Steril. 2018.

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ASRM 2018 Guideline

Patients may wish to consult with an independent mental health professional before choosing planned OC, to further explore their expectations, motivations, and any concerns surrounding the procedure (Greenwood et al). Recent research suggests that some women experience decisional regret over having cryopreserved oocytes, a development that needs to be better understood and addressed (Greenwood et al).

1ASRM Ethics Committee. Fertil Steril. 2018. 2Greenwood. Fertil Steril. 2018.

Optimal Timing?

Age 37
Greatest improvement in chances
f live birth
Most cost-effective
Age 34
Highest chances of live birth
Age 25-30
Little benefit
1Mesen. Fertil Steril. 2015.

Optimal timing for egg freezing?

Personal

circumstances

Biologic

circumstances

1Franasiak. Fertil Steril. 2014.

*UCSF Unpublished data

How many eggs to freeze?

Overall, estimates ~6% live birth per
ocyte

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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

1Cobo. Fertil Steril. 2015.

How many eggs to freeze?

1Goldman. Hum Reprod. 2017.

How many eggs to freeze?

1Goldman. Hum Reprod. 2017.
1Doyle. Fert Steril. 2016.

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Success rates after Planned OC

1,468 women underwent planned OC
Mean age = 37
9% returned to use them about 2y later

(N=137)

85% survived thaw
Live birth per transfer = 31.6%
Live birth per patient (40 babies)
< 35y = 50%
>35y = 23%
At least 8-10 mature eggs should be frozen
Encourage women to come at younger ages
1Cobo. Fertil Steril. 2016.

How many women will use their eggs?

9% (Cobo 2016, IVI Spain)
6% (Hammarberg 2017, Melbourne IVF)
6% (Greenwood 2018, UCSF)
…<<50% (expert predictions)

Egg Freezing + AMH

AMH can predict response to ovarian

stimulation

Counseling tool for number of cycles required

to meet a certain goal

Preimplantation Genetic Testing (PGT)

What’s new?

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Which of the following best summarizes the evidence regarding the role of preimplantation genetic testing (PGT-A) in IVF?

A. PGT-A improves IVF pregnancy outcomes
B. PGT-A does not improve IVF pregnancy outcomes
C. Something else

P G T

A

i m p r

v

e s I V F p r e g n a . . . P G T

A

d

e

s n

t

i m p r

v

e I V F . . . S

m

e t h i n g e l s e

29% 30% 42%

Terminology – International Glossary on Infertility and Fertility Care 2017

PGS (preimplantation genetic screening)  PGT (preimplantation genetic testing) PGS  PGT-A (PGT for aneuploidies) PGD  PGT-M (PGT for monogenic/single gene defects) PGT-SR (PGT for chromosomal structural rearrangements)

1Zegers-Hochschild. Fertil Steril. 2017.

FISH based PGT-A

Day 3 (cleavage stage) biopsy
Initial impression of improvement in live birth

after IVF

Meta-analysis of 9 RCTs:
No benefit for live birth after IVF
Harmful in women of advanced maternal age
1Mastenbroek. Hum Reprod Update. 2011.

Evolution of PGT

FISH…
aCGH
SNP
qPCR
NGS
1Rosen. Y&J.

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Blastocyst biopsy with newer PGT platforms?

1Dahdouh. Fertil Steril. 2015.

PGT-A (trophectoderm biopsy, day 5-6) increases implantation rates, thus improving embryo selection

2013 2017

Trends over time

1SART. 2National Vital Statistics Reports. 2018.
Increased single embryo transfers
IVF twin rates stable
IVF triplet and higher order multiple rates have

decreased by 50%

STAR Trial

Single-Embryo Transfer of Euploid Embryo

PGT-A did not improve pregnancy outcomes

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STAR Trial

Largest ever RCT for PGT
NGS
Women 25-40y (N=661) randomized to
PGT-A (plus morphology)
Morphology only
SET
No difference in pregnancy rates per

embryo transfer

50%
46%

Mosaicism:

More than one chromosomal makeup within the cells of an embryo

Prevalence: 4 to 20+%
Lower implantation, higher SAB

rates vs euploid

Healthy children have been born
Scoring systems to (de)prioritize

embryos for transfer

1Grati. Reprod Biomed Online. 2018.

On the horizon

Non-invasive PGT-A (niPGT-A)?
Based on sequencing DNA released into the culture

medium from the embryo

1Huang. PNAS. 2019.

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Summary

AMH Egg freezing Preimplantation genetic testing (PGT)

Thanks!

AMH and time to menopause

Nested case-control study

within Nurses Health Study (N=654)

Premenopausal blood sample

assayed for AMH (32-44yo; avg 40)

Followed for 15y
Strong associations between

lower AMH levels and higher risk of early menopause (<45yo)

1Bertone-Johnson. Hum Reprod. 2018.

References

1. Devine K, Mumford SL, Wu M, DeCherney AH, Hill MJ, Propst A. Diminished ovarian reserve in the United States assisted reproductive technology population: diagnostic trends among 181,536 cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Fertil Steril. 2015;104(3):612-19.e3. 2. Silberstein T, MacLaughlin DT, Shai I, Trimarchi JR, Lambert-Messerlian G, Seifer DB, et al. Mullerian inhibiting substance levels at the time of HCG administration in IVF cycles predict both ovarian reserve and embryo morphology. Hum

Reprod. 2006;21(1):159-63.

3. Haadsma ML, Mooij TM, Groen H, Burger CW, Lambalk CB, Broekmans FJ, et al. A reduced size of the ovarian follicle pool is associated with an increased risk of a trisomic pregnancy in IVF-treated women. Hum Reprod. 2010;25(2):552- 8. 4. van der Stroom EM, Konig TE, van Dulmen-den Broeder E, Elzinga WS, van Montfrans JM, Haadsma ML, et al. Early menopause in mothers of children with Down syndrome? Fertil Steril. 2011;96(4):985-90. 5. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30(5):465-93. 6. Thum MY, Abdalla HI, Taylor D. Relationship between women's age and basal follicle-stimulating hormone levels with aneuploidy risk in in vitro fertilization treatment. Fertil Steril. 2008;90(2):315-21. 7. Smeenk JM, Sweep FC, Zielhuis GA, Kremer JA, Thomas CM, Braat DD. Antimullerian hormone predicts ovarian responsiveness, but not embryo quality or pregnancy, after in vitro fertilization or intracyoplasmic sperm injection. Fertil

Steril. 2007;87(1):223-6.

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References

8. Riggs R, Kimble T, Oehninger S, Bocca S, Zhao Y, Leader B, et al. Anti-Mullerian hormone serum levels predict response to controlled ovarian hyperstimulation but not embryo quality or pregnancy outcome in oocyte donation. Fertil

Steril. 2011;95(1):410-2.

9. Greenwood EA, Cedars MI, Santoro N, Eisenberg E, Kao CN, Haisenleder DJ, et al. Antimullerian hormone levels and antral follicle counts are not reduced compared with community controls in patients with rigorously defined unexplained

infertility. Fertil Steril. 2017;108(6):1070-7.

10. Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, et al. Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age. Jama. 2017;318(14):1367-76. 11. de Kat AC, van der Schouw YT, Eijkemans MJ, Herber-Gast GC, Visser JA, Verschuren WM, et al. Back to the basics

f ovarian aging: a population-based study on longitudinal anti-Mullerian hormone decline. BMC medicine. 2016;14(1):151.

12. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2015;103(3):e9-e17. 13. Morin SJ, Patounakis G, Juneau CR, Neal SA, Scott RT, Jr., Seli E. Diminished ovarian reserve and poor response to stimulation in patients <38 years old: a quantitative but not qualitative reduction in performance. Hum Reprod. 2018. 14. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616-24. 15. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

References

16. Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Human reproduction update. 2011;17(4):454-66. 17. Dahdouh EM, Balayla J, Garcia-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril. 2015;104(6):1503-12. 18. Grati FR, Gallazzi G, Branca L, Maggi F, Simoni G, Yaron Y. An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening. Reprod Biomed Online. 2018;36(4):442-9.

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