Fertility Facts

Four common topics that may come up in your office ( and why IVF is not just a money grab )

Dr. Carol Redmond

Hannam Fertility Centre, Toronto November 2014

The Questions

1.

“Can you check my fertility?” 2.

“Can I freeze my eggs?” 3.

“I’m not getting pregnant, can I just take Clomid?” 4.

“If Clomid doesn’t work, what does help? How does IVF work?”

“Can you check my fertility?”

• History • AGE • Regular cycles • History of STI • Family history of early menopause • Symptoms of endometriosis http://whattoexpectwhenyouarenot.wordpress.com/

Endometrioma PCO occur in 1/3 of women without PCOS

Ultrasound

Submucosal Fibroid http://www.fornewyou.com/Endometrioma-Cyst http://www.medscape.com/viewarticle/491677_2 http://tatjana-mihaela.hubpages.com/hub/polycysticOS

Age

• Egg quality declines with age • Egg quality is the gate keeper to fertility • If all else is normal, egg quality decides cycle fecundity and success rates with ART http://nymag.com/news/features/mothers-over-50-2011-10/

Myths and Misconceptions

• “My cycles are regular so my fertility is fine” • “I’ve stayed fit and healthy so my fertility has been maintained” • “My day 3 FSH is good so my fertility is still fine” • “All the women in my family get pregnant easily over age 40” • “I got pregnant easily the first time so I will be fine”

Age

• Daniluk surveyed 1021 women age 20-40 (2010) • Most expected to have more than 1 child in their 3 rd or 4 th decade • 70% expected to start after age 30 • 60% wanted 2 children • 20% wanted more than 2 children • Most thought health was a better predictor of fertility than age

•

The first sign of aging of the eggs is infertility

• There are no other clinical or biochemical signs • The first clinical sign of aging is a shortening of the cycle (Lambalk, 2009)

Age

Odds of Natural Conception

Age of marriage and percentage of women not using contraception but childless (Menken, 1986) 80% 60% 40% 20% 0% 20-24 25-29 30-34 35-39 40-44

Age

60% 40% 20% 0% Estimated age-related chances of conception within 12 months resulting in live birth (Leridon, 2004) 80% 30 35

Age

40

Age

• So if eggs are the gate keeper, can we assess egg quality?

NO!

Age

• Egg quality can only be assessed at the time of IVF • What is “ovarian reserve testing” testing then?

• This is testing egg quantity • Egg quantity declines with age • If number of eggs is declining, it is a reasonable assumption that another aging process – declining egg quality – is also ongoing

Tests of Ovarian Reserve

1.

AMH 2.

AFC (Antral Follicle Count) 3.

Day 3 FSH

Tests of Ovarian Reserve

1.

AMH • Produced by pre-antral and small antral follicles • The serum level reflects the number of small follicles in the ovaries • The absolute level does not predict fertility • The ideal range is 15-30 pmol/L

Does Low AMH Level Matter?

• 1/3 of young women (age 21) will have an AMH level <12 pmol/L (Lund Kristensen, 2012) • 26% of potential egg donors showed an AMH level in the low range (Gleicher, 2010) • I surveyed 94 women presenting to HFC for donor sperm

Age

<35 35-40 >40

% with AMH <15

30% 60% 72%

Pregnancy Rate

Did not affect Did not affect Pregnancy rate 50% lower 30% with good AMH Lowest AMH level with a conception (age 42) was 3 pmol/L (3 rd try)

How Do We Use AMH Levels?

• Changes in AMH may matter • A dropping AMH level suggests declining egg numbers, which indicates ovarian aging, which suggests egg aging • AMH predicts ovarian responsiveness • AMH is a good predictor of the ability of the ovary to “superovulate”

Tests of Ovarian Reserve

2.

Antral follicle count • Also measures the reserve of small follicles, but very observer dependent 3.

FSH • This is the last thing to change as the ovary ages • Significant decline in ovarian reserve can occur in the presence of a normal FSH level • High FSH level strongly predicts an inability of the ovary to “superovulate ”

“How can I tell if I’m fertile?”

•

Try to get pregnant

• A low AMH level at any age does not preclude pregnancy • A normal AMH level does not imply normal fertility http://pregnancytips.org/getting-pregnant/how-to-get-pregnant/trying-to-get-pregnant/

“Can I freeze my eggs to be safe?”

• Egg freezing is now a reliable technology with the advent of egg vitrification • Most of the babies are from frozen donor eggs • A survey in 2012 of the 7 USA Commercial Egg Banks revealed that 8780 frozen eggs had generated 602 pregnancies (6.8%) (Quaas, 2013) http://retrievefreezerelax.com/egg-freezing-basics/

Egg Freezing

• We can expect a thaw rate of 86% • And a fertilization rate of 76% • So 10 eggs on average will generate 3 blastocysts • Implantation rate per embryo from fresh eggs:

Age

<35 35-37 38-40 41-42 >42

Success

37% 28% 18% 10% 4% SART data, 2012, (n=165,172 cycles)

Egg Freezing

• The success rate will depend on the quality of the eggs being frozen • This will decline with age

Age

Survival Fertilization % day 3 embryos # clinical pregnancy % eggs to LB

30-36 (n=11)

83% 70% 55% 64% 8%

37-39 (n=11)

71% 62% 40% 27% 3% Chang, 2013

Egg Freezing

• This is where AMH levels fit in • The AMH level is a reasonable predictor of egg yield with IVF AMH 6 pmol/L AmH 12 pmol/L 3-6 eggs 6-12 eggs • A 37 year old with an AMH of 7? • Maybe 3 eggs to freeze, which may make 1 embryo, if all three eggs thaw and fertilize, with IR of 27%

Egg Freezing

• Things to consider: • Effort – requires ovarian stimulation and egg retrieval • Very little data yet on thawing and pregnancy rates (CCRM has had 47 thaws of non donor frozen eggs in the past few years (personal communication, 2014) http://www.bodyconfidential.co.uk/Health/Egg-Freezing-A-21st-Century-Dilemma

Egg Freezing

• Things to consider (cont): • Cost!

•Retrieving eggs and freezing $8,000 $5,000 •Medications •Yearly storage costs $250 $2,125 •Thawing •Fertilization with ICSI $1,800 $17,175 •Total Cost

Embryo Banking

• This is a more certain option • Proceed with IVF, fertilize eggs, make embryos, screen embryos with PGS for aneuploidy • Each euploid embryo has a 60-70% chance of a live birth – independent of age at transfer http://www.biopoliticaltimes.org/article.php?id=5833

“I’m not getting pregnant, can’t I just take Clomid?”

The Miracle Drug Clomid

• First get a diagnosis • Ovulation • Semen analysis • Sonohysterogram to check uterus and tubal patency http://www.kinetic-international.net/Oral_clomid50.html

Myths and Misconceptions

• “We didn’t have sex on exactly the right day” • “I know it’s because I’ve been stressed” • “The sperm leaks out” • “I need to lie there for ½ hour” • “We are having sex too often/not often enough” • “It doesn’t matter that we smoke – all our friends do and they have kids” http://raspberrytruffles.org/trying-is-fun/

Clomid

• Estrogen receptor blocker • Can induce the development of more than 1 egg per month (40% of cycles) • 40% of women have anti-estrogenic side effects (thin endometrium, poor cervical mucus) which impede pregnancy • Nuisance side effects: headaches, visual flashes, hot flushes, moodiness

Clomid

• How well does it work?

• Not very…

Clinical Pregnancy Rate Per Cycle

CR (n=537) Dovey, 2013 (n=4100)

<35

9% 11%

36-37 38-40

9% 9% 5% 7%

>40

0% 4%

What Does Work?

Ongoing Pregnancy Rate Per Cycle

100% 80% 60% 40% 20% 0% Intercourse IUI IVF Hannam PGS CCRM

Age

<35 35-37 38-40 >40 Hannam Fertility Center, 2014

100% 80% 60% 40% 20% 0%

What Does Work?

Medicated IUI with 2-4 Follicles Pregnancy Rate Per Cycle

1 2

IUI Cycle # Age

<35 35-37 38-40 >40 3 Hannam Fertility Center, 2014

FSH Superovulation and IUI

• FSH • Daily injections for 10-13 days • Daily monitoring with blood & USS • Costly • 20% of pregnancies are twins • 1% are triplets

IVF

• Two multi-centre prospective randomized trials in a population of patients with unexplained infertility and unsuccessful Clomid and IUI looked at proceeding to FSH and IUI then IVF as needed, or straight to IVF • Both showed a higher pregnancy rate achieved in fewer cycles and at a lower cost if the patients proceeded directly to IVF • (FORT-T trial, 2014, & FASTT trial, 2010)

IVF

• 272 women COH & IUI • CLBR after 2 cycles 27% • Twins 13% • 1 triplets • 1 quadruplet • 176 women IVF • LBR after 1 cycle 39% • Twins 10% • (Chambers, 2010) http://www.co-parentmatch.com/In-Vitro-Fertilization-IVF.aspx

100% 80% 60% 40% 20% 0% 0

IVF

IVF & ICSI with 2 Embryos Transferred

1 2

Blastocysts Produced

3+

Age

<35 35-37 38-40 >40 Hannam Fertility Center, 2014

IVF

• National Health Service funded IVF • < 40 years of age, 3 IVF cycles After 1 st cycle After 2 nd cycle After 3 rd cycle 30% pregnant 53% pregnant 63% pregnant • Took less than 2 years to achieve 3 cycles ( Goswami , 2013)

IVF with PGS

• PGS = pre-implantation genetic screening for aneuploidy • Euploidy rate • 56% if excellent blastocyst morphology • 39% if good blastocyst morphology • 42% if average blastocyst morphology • 25% if poor blastocyst morphology • (Capalbo, 2014)

IVF & PGS Case Studies

• 39-40 year old woman with unexplained infertility • Over 4 IVF cycles she generated 106 eggs • 33 year old woman with unexplained infertility • Over 1 IVF cycle she generation 15 eggs 31 blastocysts 8 blastocysts 8 euploid 1 euploid

IVF & PGS Case Studies

• 40 year old trying for 2 years IUI X 1 Clomid & IUI X 1 FSH & IUI X 2 IVF 4 blastocysts no pregnancy (took 4 months) IVF 5 blastocysts all aneuploid Donor egg

IVF & PGS

• Recurrent implantation failure 43 Women PGS 33 Women no PGS 45 Good Prognosis 1 euploid 1-2 blastocysts 1 euploid • ( Greco , 2014) 68% 21% 70%

IVF & PGS & Miscarriage

• PGS is the answer to most miscarriage (Benner, 2012)

IVF & PGS & Miscarriage Case Study

• 40 year old TDI X 8 • IVF 5 blastocysts 9 months later, repeat IVF •No eggs 3 months later •Transfer 1  miscarriage •Transfer 1  miscarriage •Transfer 1  no pregnancy •3 embryos did not survive thawing •Day 3 FSH 19

IVF

• Women for donor sperm over age 40 TDI x 6 24%

vs.

IVF & ICSI x 3 28% • Nearly all successful IVF was in first attempt • Single IVF = 6 cycles of TDI • ( De Brucker , 2013)

Summary

1.

Age remains the best predictor of fertility 2.

3.

AMH levels do not predict fertility Serial AMH levels may have value 4.

Egg freezing is great technology (when applied to young women) 5.

If you are sub-fertile, there is no simple approach that also has a great success rate 6.

IVF, particularly with PGS, if highly effective, but not simple or natural

Questions?

You are invited to contact me anytime at [email protected]

http://www.cartoonstock.com/directory/i/infertility.asp

References

• Benner, A. 2012. Evaluation of 571 IVF cycles and 4873 embryos using 23-chromosome SNP (single nucleotid polymorphism) microarray PGS. Fertil & Steril 97(3)Supp:S23.

• Capalbo, A., Rienzi, L., Cimadomo, C, Maggiulli, R., Elliott, T., Wright, G., Nagy, Z., & Ubaldi, F. 2014. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum. Reprod 29(11):234-9. • Chambers, G., Sullivan, E., Shanahan, M., Ho, M., Priester, K., & Chapman, M. 2010. Is in vitro fertilisation more effective than stimulated intrauterine insemination as a first-line therapy for subfertility? A cohort analysis. Aust N Z J Obstet Gynaecol 50(3):280-8. • Chang , C., Elliott, T., Wright, G., Shapiro, D., Toledo, A., & Nagy, Z. 2013. Prospective controlled study to evaluate laboratory and clinical outcomes of oocyte vitrification obtained in in vitro fertilization patients aged 30 to 39 years. Fertil & Steril 99(7):1891-7. • Daniluk, J. Koert, E., & Cheung, A. 2011. Childless women’s knowledge of fertility and assisted human reproduction: identifying the gaps. Fertil & Steril 97(2):420-6.

References

• De Brucker, M., Camus, M., Haentjens, P., Verheyen, G., Collins or the low road? Repro BioMed Online 26(6):577-85.

, G., & Tournaye, H. 2013. Assisted reproduction using donor spermatozoa in women aged 40 and above: the high road • Gleicher, N. Can egg donor selection be improved - a pilot study. Reprod Biol Endocrinol 8:76.

• Goswami, M., Hyslop, L., & Murdoch, A. 2013. NHS-funded IVF: consequences of NICE implementation. Hum Fertil 16(2):121-7. • Greco, E., et al. 2014. Comparative genomic hybridization selection of blastocysts for repeated implantation failure treatment: a pilot study. Biomed Res Int. 2014:457913.

• Lambalk, C. Van Disseldorp, J., De Koning, C., & Broekmans, F. 2009. Testing ovarian reserve to predict age at menopause. Maturitas 63(4):280-91. • Leridon H. 2004. Can assisted reproductive technlogy compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 19:1548-53.

References

• Lund Kristensen, S. 2012. The association between circulating levels of AMH and follicle number, androgens, and menstrual cycle characteristics in young women. Fertil & Steril 97(3):779-785.

• Menken J., Trussell, J., & Larsen, U. 1986. Age and infertility. Science 233:1389-94.

• Quaas, A., Melamed, A., Chung, K., Bendikson, K., & Paulson, R. 2013. Egg banking in the United States: current status of commercially available cryopreserved oocytes. Fertil & Steril 99(3):827-31.