1. 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

2. The Questions “Can you check my fertility?” “Can I freeze my eggs?”
“I’m not getting pregnant, can I just take Clomid?”
“If Clomid doesn’t work, what does help? How does IVF work?”

3. “Can you check my fertility?”
History
AGE
Regular cycles
History of STI
Family history of early menopause
Symptoms of endometriosis

4. Ultrasound Endometrioma Submucosal Fibroid
PCO occur in 1/3 of women without PCOS

5. 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

6. 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”

7. Age Daniluk surveyed 1021 women age 20-40 (2010)
Most expected to have more than 1 child in their 3rd or 4th 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

8. 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)

9. Odds of Natural Conception
Age of marriage and percentage of women not using contraception but childless (Menken, 1986)
Estimated age-related chances of conception within 12 months resulting in live birth (Leridon, 2004)
Age
Age

10. Age
So if eggs are the gate keeper, can we assess egg quality?
NO!

11. 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

12. Tests of Ovarian Reserve
AMH
AFC (Antral Follicle Count)
Day 3 FSH

13. Tests of Ovarian Reserve
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 pmol/L

14. 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
% with AMH <15
Pregnancy Rate
<35
30%
Did not affect
35-40
60%
>40
72%
Pregnancy rate 50% lower
30% with good AMH
Lowest AMH level with a conception (age 42) was 3 pmol/L (3rd try)

15. 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”

16. Tests of Ovarian Reserve
Antral follicle count
Also measures the reserve of small follicles, but very observer dependent
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”

17. “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
(70% of women over 40 coming for donor sperm with good AMH levels did not conceive)

18. “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)

19. 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
Success
<35
37%
35-37
28%
38-40
18%
41-42
10%
>42 4%
SART data, 2012, (n=165,172 cycles)

20. Egg Freezing
The success rate will depend on the quality of the eggs being frozen
This will decline with age
Age
30-36 (n=11)
37-39 (n=11)
Survival
83%
71%
Fertilization
70%
62%
% day 3 embryos
55%
40%
# clinical pregnancy
64%
27%
% eggs to LB 8% 3%
Chang, 2013

21. Egg Freezing This is where AMH levels fit in
The AMH level is a reasonable predictor of egg yield with IVF
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%
AMH 6 pmol/L
3-6 eggs
AmH 12 pmol/L
6-12 eggs

22. 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)

23. Egg Freezing Things to consider (cont): Cost! $8,000 $5,000 $250
Retrieving eggs and freezing
$8,000
Medications
$5,000
Yearly storage costs
$250
Thawing
$2,125
Fertilization with ICSI
$1,800
Total Cost
$17,175

24. 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

25. “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
Don’t know how I feel about this image??

26. 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”

27. 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

28. Clinical Pregnancy Rate Per Cycle
Clomid
How well does it work?
Not very…
Clinical Pregnancy Rate Per Cycle
<35
36-37
38-40
>40
CR (n=537) 9% 5% 0%
Dovey, 2013 (n=4100)
11% 7% 4%

29. What Does Work?
Hannam Fertility Center, 2014

30. What Does Work?
Age
IUI Cycle #
Hannam Fertility Center, 2014

31. FSH Superovulation and IUI
Daily injections for days
Daily monitoring with blood & USS
Costly
20% of pregnancies are twins
1% are triplets
Boring slide??

32. 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)

33. IVF 272 women COH & IUI 176 women IVF CLBR after 2 cycles 27%
Twins 13%
1 triplets
1 quadruplet
176 women IVF
LBR after 1 cycle 39%
Twins 10%
(Chambers, 2010)

34. IVF Hannam Fertility Center, 2014
IVF allows an assessment of egg quality
HFC # blastocyst charts
Hannam Fertility Center, 2014

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

36. 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)
Human Reprod 2014 June;29(6): )

37. IVF & PGS Case Studies
39-40 year old woman with unexplained infertility
Over 4 IVF cycles she generated
33 year old woman with unexplained infertility
Over 1 IVF cycle she generation
106 eggs
31 blastocysts
8 euploid
15 eggs
8 blastocysts
1 euploid

38. 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

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

40. IVF & PGS & Miscarriage PGS is the answer to most miscarriage
Site!!
(Benner, 2012)

41. IVF & PGS & Miscarriage Case Study
40 year old TDI X 8
IVF
5 blastocysts
Transfer 1  miscarriage
Transfer 1  no pregnancy
3 embryos did not survive thawing
9 months later, repeat IVF
No eggs
3 months later
Day 3 FSH 19

42. IVF Women for donor sperm over age 40
Nearly all successful IVF was in first attempt
Single IVF = 6 cycles of TDI
(De Brucker, 2013)
TDI x 6
vs.
IVF & ICSI x 3
24%
28%

43. Summary Age remains the best predictor of fertility
AMH levels do not predict fertility
Serial AMH levels may have value
Egg freezing is great technology (when applied to young women)
If you are sub-fertile, there is no simple approach that also has a great success rate
IVF, particularly with PGS, if highly effective, but not simple or natural

44. Questions?
You are invited to contact me anytime at

45. References
Benner, A 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 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 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 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):
Daniluk, J. Koert, E., & Cheung, A Childless women’s knowledge of fertility and assisted human reproduction: identifying the gaps. Fertil & Steril 97(2):420-6.

46. References
De Brucker, M., Camus, M., Haentjens, P., Verheyen, G., Collins, G., & Tournaye, H Assisted reproduction using donor spermatozoa in women aged 40 and above: the high road or the low road? Repro BioMed Online 26(6):
Gleicher, N. Can egg donor selection be improved - a pilot study. Reprod Biol Endocrinol 8:76.
Goswami, M., Hyslop, L., & Murdoch, A NHS-funded IVF: consequences of NICE implementation. Hum Fertil 16(2):121-7.
Greco, E., et al Comparative genomic hybridization selection of blastocysts for repeated implantation failure treatment: a pilot study. Biomed Res Int. 2014:
Lambalk, C. Van Disseldorp, J., De Koning, C., & Broekmans, F Testing ovarian reserve to predict age at menopause. Maturitas 63(4):
Leridon H Can assisted reproductive technlogy compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 19:

47. References
Lund Kristensen, S The association between circulating levels of AMH and follicle number, androgens, and menstrual cycle characteristics in young women. Fertil & Steril 97(3):
Menken J., Trussell, J., & Larsen, U Age and infertility. Science 233:
Quaas, A., Melamed, A., Chung, K., Bendikson, K., & Paulson, R Egg banking in the United States: current status of commercially available cryopreserved oocytes. Fertil & Steril 99(3):