The document discusses infertility issues for women over 40. It notes that 15% of women now delay childbearing until after age 40. Ovarian aging leads to a decline in both egg quantity and quality with increasing female age. After age 40, evaluation should include tests of ovarian reserve like AMH, AFC, and FSH. IVF is the best treatment option for these women, though success rates decline sharply after age 43. Oocyte donation is the only effective treatment for infertility caused by declining egg quality due to age.

1. INFERTILITY
ABOVE 40
Aboubakr Elnashar
Benha University Hospital,
Egypt
ABOUBAKR ELNASHAR

2. CONTENTS
1. INTRODUCTIOM
 Magnitude of problem
 Ovarian aging
 Age associated infertility
2. EVALUATION
 When
 What
3. TREATMENT
 Pre conception counseling
 Methods
CONCLUSION
3
ABOUBAKR ELNASHAR

3. 1. INTRODUCTION
Magnitude of problem
15 %
(voluntarily or involuntarily) postponed their desire for
pregnancy requesting reproductive tt after 40
(CDC, 2011)
Number of women ≥43 y seeking IVF is increasing
25%
ICSI cycles in Europe: ≥ 40 y
10% in Egypt
(Mansour R & Abousetta 2006).
ABOUBAKR ELNASHAR

4. Risk
Poor response to ovarian stimulation
Obstetric risks:
Miscarriage
PET
IUGR
Chromosomal defects in the offspring
ABOUBAKR ELNASHAR

5. Ovarian aging
ABOUBAKR ELNASHAR

6. At birth:
1–2 million oocytes in her ovaries
As a woman ages:
absolute number of developing follicles declines at a rate that is bi-
exponential to her age.
At 37.5 y:
The rate of follicle loss (atresia) more than doubles when
reserves fall below the critical level of 25,000
As the ovarian follicular pool decreases:
Infertility
cycle shortening
cycle irregularity and finally
menopause
ABOUBAKR ELNASHAR

7. Number of primordial follicles and
Poor quality of oocytes in relation to
Female age and
Reproductive events.
ABOUBAKR ELNASHAR

8. Aneuploidy of oocytesAge (years)
20%30
30%35
60%40
85%42
≥90%45
Effect of age on aneuploidy of oocytes
ABOUBAKR ELNASHAR

9. Age associated infertility
What?
increasing age: lowered fertility.
Particularly noticeable: above 30 Y
Accelerating: between 35 and 40 Y
Reducing to almost zero: 45 Y
ABOUBAKR ELNASHAR

10. Causes
1. Decrease quality of oocytes
{Increase in the rate of oocyte aneuploidy}
Most important
2. Decrease numbers of oocytes:
Decrease ovarian reserve
3. Increase in the miscarriage rate
ABOUBAKR ELNASHAR

11. Ovarian:
Primarily related to ovarian aging and the
diminishing ovarian follicle count.
Endometrium
has the capacity to maintain a pregnancy
throughout reproductive years, even beyond (egg
donation)
Age does not affect the endometrium’s response
to hormonal stimulation.
PR from donor egg cycles confirm that the age of
the recipient does not affect PR
ABOUBAKR ELNASHAR

12. ABOUBAKR ELNASHAR

13. SOGC Clinical Practice Guideline, 2011
Reproductive-age women should be aware that
natural fertility and ART success (except with egg
donation) is significantly lower for women in their
late 30s and 40s.
(II-2A) SOGC, 2011
Above 40y:
1. Decreased oocyte quality
2. Decreased oocyte number
3. Poor endometrium
4. Medical Risk: DM, Hypertension, hypothyroidism
ABOUBAKR ELNASHAR

14. 2. EVALUATION
When?
After 40 y
Immediate evaluation in women.
35-40 Y
After 6 months of unprotected intercourse without
conception
Because of the decline in fertility and the
increased time to conception that occurs after the
age of 35, women > 35 ys of age should be
referred for infertility work-up after 6 months of
trying to conceive.
(III-B) SOGC, 2011
ABOUBAKR ELNASHAR

15. What?
I. Infertility investigation:
Semen analysis
Mid luteal P
HSG
 No specific findings: unexplained infertility
 Age related factors:
Endometriosis
Fibroids
Polyps
:Assessment of uterus
ABOUBAKR ELNASHAR

16. ABOUBAKR ELNASHAR

17. II. Ovarian reserve tests:
 A.F.C
 AMH
 FSH, E2
>39 y34–38 y24–33yParameter
1.1
(0.5–2.3)
1.6
(0.8–2.9)
2.1
(1.1–3.4)
AMH level
(ng/mL)
Median (interquartile range)
7.9
(6.2–10.6)
7.4
(6–9.4)
6.9
(5.5–8.3)
FSH level (IU/L)
Median (interquartile range)
7
(4–11)
10
(6–13)
11
(8–16)
AFC
Median (interquartile range)
(Imog et al ,2011)
ABOUBAKR ELNASHAR

18. NICE, 2013
High responseLow response
16 or more4 or lessTotal AFC
3.5 or more
25
0.8 or less
5.5
AMH
ng/ml
pmol/l
Conversion ratio:7
4 or less8.9 or moreFSH IU/L
ABOUBAKR ELNASHAR

19. Indications:
≥ 35 ys or
< 35 ys
Endometriosis
Unexplained infertility
Single ovary
Previous ovarian surgery,
Poor response to FSH,
Previous exposure to chemotherapy or
radiation
(Iii-b) SOGC, 2011
ABOUBAKR ELNASHAR

20. Significance:
Particularly important ≥40y
1. All detect the quantity rather than the quality of the
follicular pool
(Broekmans et al. 2006)
2. Poor predictive value for non pregnancy and should
be used to exclude women from tt only if levels are
significantly abnormal.
(II-2a) SOGC, 2011
3. Predict response to ovarian stimulation and
potentially, successful outcome with ART.
4. Help in determining the dose of HMG/FSH and the
protocol of stimulation to be used but they are poor
predictors of PR
(Fauser B et al 2007)
ABOUBAKR ELNASHAR

21. 3. TREATMENT
Pre-conception counseling
Risks of pregnancy above 40,
Promotion of optimal health and weight
Screening for medical condition: hypertension, DM.
(III-B) SOGC, 2011
Women should be informed that increased risk of
spontaneous pregnancy loss
chromosomal abnormalities.
Women should be counseled about and offered
appropriate prenatal screening once pregnancy is
established.
(II-2A) SOGC, 2011
ABOUBAKR ELNASHAR

22. ABOUBAKR ELNASHAR

23. Methods:
1. CC and IUI
2. GnT and IUI
3. IVF
4. Oocyte donation:
The only effective tt for age-related infertility and
declining oocyte quality
ABOUBAKR ELNASHAR

24. 1. CC and IUI
Simple, inexpensive
Aim: 2 or 3 dominant follicles of at least 18 mm.
PR/cycle
(Tsafrir et al, 2009, Dovey et al,2011)
1–4 %
38 to 40y: 7%
41 to 42 y: 4%
42: 1%
ABOUBAKR ELNASHAR

25. LBR:
40-41y: low
>42 y: No LB
(Corsan et al.1996)
CC:
PR and LBR are low.
Little or no value
Swift referral for IVF after 1 or 2 failed cycles.
ABOUBAKR ELNASHAR

26. 2. FSH and IUI
Aim:
2 or 3 dominant follicles. Ovulation induction may encourage
the recruitment of suboptimal follicles that may otherwise
have not developed.
PR/cycle
(Tsafrir et al.2009)
3%
LBR/cycle: 1 %
LBR/cycle
(Haebe et al, 2002)
40-42y: 9.8 %
>44: no live births
ABOUBAKR ELNASHAR

27. ABOUBAKR ELNASHAR

28. No significant difference in LBR between ovarian
stimulation protocols (GnRH-a and FSH, FSH,CC,
tamoxifen, CC and FSH)
(Haebe et al, 2002)
All live births happened within the 1st or 2nd cycles
PR for COS, IUI are low for women > 40 y.
Women > 40 should consider IVF if they do not
conceive within 1 to 2 cycles of COS.
(II-2B) SOGC, 2011
ABOUBAKR ELNASHAR

29. 3. ICSI
Advantage:
overcoming
most male problems
female mechanical problems which are not
uncommon in older women.
 significantly higher PR and LBR than COS IUI
But lower rates than oocyte donation.
ABOUBAKR ELNASHAR

30. Cycle cancellation and LBR women > 40
Author Initiated
cycle
Cancellation
Rate %
LBR%
Klipstein et al, 2005 2750 19.9 9.7
Tsafrir et al , 2007 1217 16.6 4.7
Serour et al, 2010 2386 16 6.7
ESHRE 2010 8.6
ABOUBAKR ELNASHAR

31. Number of oocytes collected/cycle in women aged
40 years and above.
(Seng et al, 2005)
ABOUBAKR ELNASHAR

32. Implantation rates as a function of female age
Age Implantation rate
25-29 18.2%
30-34 16.1%
35-39 15.3%
40-44 6.1%
(Hull MG et al 1996; ASRM Practice Committee, 2006)
ABOUBAKR ELNASHAR

33. PR and LBR in
infertile women
above age 40
ABOUBAKR ELNASHAR

34. LBR/cycle
6.7% (range: 10% to 0.5%).
40 to 42: 7.4%
≥ 43: 1.1%
(Sorour et al, 2014)
Miscarriage rate
40 to 42: 43.1%
≥ 43: 65.2%
Once women have attained age 43 y, alternative
methods such as oocyte donation cycles or
previously cryopreserved embryos are likely to be
more effective.
ABOUBAKR ELNASHAR

35. Upper age for allowing IVF attempts
Old studies:
41 or 42 y
Recent studies:
43 and 44 y:
CPR: 8.3%/cycle
LBR: 5.3 %/ cycle
≥45: No pregnancy.
(Mehmet et al, 2013)
Reasonable success rate up to 44 y
Most pregnancies occurred within the first 3
cycles
≥45: no benefit from ART procedures using their
own oocytes.
ABOUBAKR ELNASHAR

36. Very recently
Human Fertilization and Embryology Authority (HFEA) (2014)
LBR/cycle
38–39 y: 19.2 % /cycle
40-42: 12.7 %
43-44: 5.1 %
45 and over: 1.5 %.
ABOUBAKR ELNASHAR

37. 4. Oocyte donation
PR based on the age of the donor, not the
recipient.
Pregnancies and live births have been reported in
women into their 60s
Use of donor eggs above 50y: controversial.
Increased rates of complications:
Maternal death
Hypertension
Prematurity
Fetal and neonatal death
Operative delivery. ABOUBAKR ELNASHAR

38. CONCLUSIONS
Outcome of ART is adversely affected by
advancing maternal age
IVF is best chance for successful ongoing
pregnancy in this age group
Ovulation induction and IUI with either CC or
FSH can waste much precious time: reducing
chances of success with IVF.
Women 45 y and beyond do not benefit
from ART procedures using their own oocytes.
The only effective tt for ovarian aging is oocyte
donation.
(II-2B) SOGC, 2011
ABOUBAKR ELNASHAR

39. Thank You
ABOUBAKR ELNASHAR