INFERTILITY

ABOVE 40

Aboubakr Elnashar Benha University Hospital,

Egypt

ABOUBAKR ELNASHAR

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

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).

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Risk Poor response to ovarian stimulation

Obstetric risks:

Miscarriage

PET

IUGR

Chromosomal defects in the offspring

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Ovarian aging

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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

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Number of primordial follicles and

Poor quality of oocytes in relation to

Female age and

Reproductive events.

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Aneuploidy of oocytes Age (years)

20% 30

30% 35

60% 40

85% 42

≥90% 45

Effect of age on aneuploidy of oocytes

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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

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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

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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

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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

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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

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What?

I. Infertility investigation:

Semen analysis

Mid luteal P

HSG

No specific findings: unexplained infertility

Age related factors:

Endometriosis

Fibroids

Polyps

:Assessment of uterus

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II. Ovarian reserve tests:

A.F.C

AMH

FSH, E2

>39 y 34–38 y 24–33y Parameter

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

NICE, 2013

High response Low response

16 or more 4 or less Total AFC

3.5 or more

25

0.8 or less

5.5

AMH

ng/ml

pmol/l

Conversion ratio:7

4 or less 8.9 or more FSH IU/L

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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

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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)

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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

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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

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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%

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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.

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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

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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

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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.

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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

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Number of oocytes collected/cycle in women aged

40 years and above. (Seng et al, 2005)

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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)

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PR and LBR in

infertile women

above age 40

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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.

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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.

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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 %.

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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

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

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Thank You

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