ART for women over 40 years of age.pdf

ART options for
women over the age of 40
Tevfik Yoldemir MD Bsc MA PhD
tevfik.yoldemir@marmara.edu.tr

Kaplan Meier curves for cumulative probability of pregnancy
across cycles of pregnancy attempt by age group
Fertil Steril. 2016 June ; 105(6): 1584–1588.e1. doi:10.1016/j.fertnstert.2016.02.028

Fecundability and cumulative pregnancy rates for the cohort as
calculated from survival analysis

Fecundability and cumulative pregnancy rates by history of
prior pregnancy as calculated from survival analysis

Effect of female age on the probability of natural conception
leading to ongoing pregnancy or livebirth within 12 months
Human Reproduction, Vol.35, No.8, pp. 1808–1820, 2020
<20%

20-28%
15-21%

9-13%
6-9%

5-8%
5-8%

24-33%
18-26%

11-16%
8-10%

7-10%
6-9%

Which is better for live birth prediction in patients aged over
40 with their first IVF treatment?
European Journal of Obstetrics & Gynecology and Reproductive Biology 221 (2018) 151–155

Cumulative live birth rate
of advanced-age women
more than 40
Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 201-205

Cumulative live birth rates and number of oocytes
retrieved in women of advanced age- Fresh cycles
Human Reproduction, 2018;33(11): 2010–2017
<13%

IVF in women aged 43 years and older
RBMO VOLUME 42 ISSUE 4 2021 p 768-773

Frozen cycles
<10%

Overall Cumulative pregnancy rates
(CPRs) and
cumulative live birth rates (CLBRs)

Predictive model of
CLBRs according to age
and number of oocytes
retrieved

Predicted live birth rates (with 95% CI) per
oocyte retrieval cycle, excluding freeze-all cycles
RBMO VOLUME 42 ISSUE 3 2021

Predicted live birth rates (with 95% CI) per fresh
aspiration cycle

Live birth rates (LBR) between fresh
euploid embryo transfers versus cryo-all
cycles
J Assist Reprod Genet (2016) 33:401–412

live birth rates (LBR) between fresh euploid
embryo transfers versus cryo-all cycles

Freeze-all strategy – Live birth rate
Cumulative live birth rates per women over
complete cycles of IVF
a The conservative CLBR was calculated
based on the assumption that women who did
not return for the subsequent treatment had
no chance of pregnancy and a live birth.
b The optimal estimates of the CLBR
assumed that women who did not return for
the subsequent treatment had the same
chance of pregnancy and a live birth as
those who did return.
Archives of Gynecology and Obstetrics (2022) 305:251–259
10%
15%
the analysis cohort included 20,687 women,
with 32,043 complete cycles and 13,334 live
births

The live birth rates and cumulative live birth rate

Cumulative live birth rates - Freeze-all cycles (20,687 women)
The model 1 (pretreatment model) was constructed using the patient characteristics to estimate the chance of a live
birth over a maximum of seven consecutive complete cycles for patients ready to start IVF treatment.
In the model 2 (post-first-treatment model), we using patient characteristics and treatment characteristics at first complete
cycle to estimate the cumulative probability of a live birth over consecutive complete cycles after the first attempt.
The potential predictors considered for analysis in this procedure were woman’s age, infertility type, and causes of
infertility and treatment characteristics (for model 2 only)

AMH has no role in predicting oocyte quality
in women with advanced age
H group (= > 1.1 ng/ml) L group (< 1.1 ng/ml)
H group (= > 1.1 ng/ml) L group (< 1.1
ng/ml)
Scientific Reports | (2020) 10:19750

AMH has no role in predicting oocyte quality
in women with advanced age
H group (= > 1.1 ng/ml)
L group (< 1.1 ng/ml)
Scientific Reports | (2020) 10:19750

AMH independently predicts aneuploidy but not live birth
per transfer in IVF PGT-A cycles
Reproductive Biology and Endocrinology (2023) 21:19

Low anti-Müllerian hormone
increased risk of embryonic aneuploidy in women
of advanced age
R E P R O D U C T I V E B I O M E D I C I N E O N L I N E 3 7 ( 2 0 1 8 ) 1 7 8 – 1 8 3
Number of cycles: total population: N = 422, 107 versus 210 versus 105;
women <35 years: N = 228, 40 versus 116 versus 72;
women ≥35 years: N = 194, 67 versus 94 versus 33

The nature of aneuploidy with increasing age of
the female partner
Fertil Steril 2014:101:656-63
<40%

The number of aneuploid chromosomes in a given
trophectoderm sample
Fertil Steril 2014:101:656-63

The nature of aneuploidy with increasing age of the
female partner: a review of 15,169 consecutive
trophectoderm biopsies
Fertil Steril 2014;101(3):656-663.e1
% aneuploid
% no euploid blast
>60%
>15%

Percentage of live births per cycle
with and without PGTA
Journal of Assisted Reproduction and Genetics (2021) 38:3277–3285

Percentage of live births per embryo transferred
with and without PGTA

Percentage of cycles which had no embryos
transferred vs embryo transfer for PGTA and
non-PGTA by age group
top bar=transfer;
bottom bar=no transfer

Clinical outcomes
among age subgroups
in two groups (PGT-A
and non- PGT-A )
the PGT-A group
the non-PGT-A group

Age-related downward trends for singleton
live birth rate for total and the two groups

Age-related downward trends for
singleton live birth rate

Comparison of clinical outcomes between
two groups in different age groups

Age-related downward trends for high-
quality embryos rate
p-value*** determines the differences between the non-PGT and the PGT groups among five age groups.

Age-related downward trends for high-
quality embryos rate

Preimplantation genetic testing for aneuploidy in
patients with low embryo number
Journal of Assisted Reproduction and
Genetics (2022) 39:2027–2033
A retrospective matched cohort study examining records
for first or second-cycle IVF patients with 1 to 3
blastocysts

Subgroup analysis analyzing outcomes for
women 38 years and older & women under 38
Journal of Assisted Reproduction and Genetics
(2022) 39:2027–2033
blastocysts

Subgroup analysis analyzing outcomes by number
of blastocysts obtained
Journal of Assisted Reproduction and Genetics
(2022) 39:2027–2033
blastocysts

Preimplantation genetic testing for aneuploidy in poor
ovarian responders with four or fewer oocytes retrieved
The live birth rate per retrieval did not differ between the PGT-A and non-PGT groups (6.6% vs
5.4%).

PGT-A is associated with reduced
cumulative live birth rate
%Adjusted for diagnosis (tubal, diminished reserve, male infertility,
PCOS, uterine, tubal endometrial, other/unexplained diagnosis)

Early pregnancy loss rate at < 13 weeks
gestation, by patient age and PGT use (%)

Amongst the youngest patients (age < 35), not only does there appear to be no benefit to PGT-A, but
there appears to be a considerable reduction in CLBR per cycle start.
For those aged > 42, a slightly higher CLBR is seen in PGT-A cycles, although this was not statistically
significant.
The increased CLBR in older patients using PGT-A may be related to patients with greater ovarian
reserve electing to have PGT-A testing instead of ET, leading to a greater number of blastocysts
available for biopsy and a greater probability of having euploid embryos available for ET.
PGT-A is associated with a reduced incidence of multiple gestations, early pregnancy loss, and LBW and
VLBW infants, compared with non-PGTA cycles.
The cumulative live birth rate per cycle vs. first transfer live birth rate should be recommended as the
most appropriate patient-centered outcome measure for determining the utility of PGT-A.

Aneuploidies (PGT-A) cycle outcomes and
blastocyst quality on day 5
Journal of Assisted Reproduction
and Genetics (2023) 40:1467–1477

Aneuploidies (PGT-A) cycle outcomes and
blastocyst quality on day 5

Age dependent IVF success rates
https://www.hfea.gov.uk/media/2894/fertilitytreatment-2017-trends-and-figures-may-2019.pdf.

Cumulative live birth rates with autologous oocytes

Panel A shows number of oocytes retrieved from each ART treatment cycle.
Panel B shows number of embryos formed from each ART cycle.
Panel C shows total number of embryos transferred from each ART cycle.
Panel D shows the percentage of cycles in which a blastocyst was transferred.
Panel E shows the percentage of cycles that used ICSI.
Panel F shows the percentage of cycles that used PGT Reproductive Biology and Endocrinology (2023) 21:94

Among women older than 42 years, PGT use was associated with decreased odds of live birth.
This may be due to the observed lower utilization of PGT in older age groups and the limited
availability of embryos for testing.
After adjusting for age, race/ ethnicity, BMI, nulliparity, etiology of infertility, number of oocytes
retrieved, embryos transferred, blastocyst transfer, use of ICSI, PGT, and ART treatment cycle
number, there was no association between markers of ovarian reserve (day 3 FSH and random
AMH levels) and live birth.

Women aged 43–45: who should be referred
for ovum donation?

Fresh donor oocyte IVF cycles
Fertil Steril 2014;101:1331–6

Age and Uterine Receptiveness - Oocyte Donation
The Journal of Clinical Endocrinology & Metabolism 2005; 90(7):4399–4404
Donor Eggs

Recipient age and pulsatility index – Oocyte donation
Reproductive BioMedicine Online
Vol 17. No 1. 2008 94-100
Ultrasound measurement of all patients
was performed about 2 h before embryo
transfer .
Flow velocity waveforms were obtained
from the ascending main branch of the
uterine artery on the cervix before it
entered the uterus in a longitudinal
plane.
of the uterine arteries (Average R&L)
Donor Eggs

All fresh donor oocyte IVF cycles
reported to SART between 2008 and 2010
Fertil Steril2014;101:1331–6
27,959 fresh donor oocyte
in vitro fertilization cycles
Donor Eggs

Live birth rates in donor oocytes
reported to SART between 2016 and 2018
Fertil Steril2022;117:339–48
19,128 cycles
Donor Eggs

Expectant Management Before IVF compared to
Immediate Treatment in Women Aged 39 or Above
Reproductive Sciences (2022) 29:1232–1240
The cLBR for the ‘waiting before IVF’ and the ‘immediate’ strategies were similar

Live birth rate per started cycle
<7%

Cycle cancellation per initiated cycle
Clin Exp Reprod Med 2017;44(2):111-117
https://doi.org/10.5653/cerm.2017.44.2.111
>30%

Predictors of live birth and pregnancy
success
in infertile women aged 40 and over
Doi:10.5653/cerm.2017.44.2.111
<12%
<15%
<8%

Predictors of live birth and pregnancy success
in infertile women aged 40 and over
Doi:10.5653/cerm.2017.44.2.111

Decision to Continue or to Cancel IVF Cycles in
Patients with One or Two Large Follicles
<4%

Decision to Continue or to Cancel IVF Cycles in
Patients with One or Two Large Follicles

1-year increase in age reduces the likelihood of live birth by 11% (p < 0.05)
One-unit increase in AFC count leads to a 9% increase in the odds of a live birth (p < 0.05).
<10%
<5%

Advanced age patients with five or fewer oocytes
retrieved- IVF or ICSI
Conventional IVF exhibits advantages over the ICSI method in non-male factor infertility for advanced
age patients with five or fewer oocytes retrieved.

Elective single versus double blastocyst-
stage embryo transfer women older than 36
Human Fertility, 2023

ASRM 2017 Guideline
J Evid Based Med. 2019 May;12(2):167-184

NICE Guideline

3 natural modified IVF (ICSI) cycles
Study group: All transferable embryos electively vitrified until the 3rd oocyte retrieval (OR), followed by transfer of one or more
embryos until successful pregnancy or all embryos were utilized
Control group: Couples who intended to undergo a single NM cycle with fresh ET
Facts Views Vis Obgyn, 2019, 11 (1): 77-84

Highly Individualized Egg Retrieval
Very early retrieval (VER) was defined
as 13.5–15.5 mm, n = 17;
ER, as 16.0–18.0 mm, n = 24; and
standard retrieval (SR) as 18.5 mm-
20.5 mm, n = 15.
Journal of Ovarian Research 2018;16 (11):23
Fifty-six women ≥43, and 37 POA patients underwent IVF
cycles

Effect of Intra-Ovarian Androgen Priming
• rHCG 260 IU subcutaneously (SC) every second day in addition to letrozole
2.5 mg daily for 8 weeks.
• GnRH agonist (GnRHa) started (depot injection of triptorelin 3.75 mg); a
second depot dose of triptorelin was given 28 days later
Doi: 10.1016/j.rbmo.2019.11.005

Clinical and Cost-effectiveness
women aged 35–45 following 6–12 months of
infertility
(i) Preimplantation genetic testing for aneuploidy (PGTA);
(ii) autologous ART from age 40 using oocytes cryopreserved at
age 32 (social freezing);
(iii) ART using donated oocytes (donor ART);
(iv) standard autologous ART treatment (standard care)
BMC Health Services Research (2022) 22:1197

Women aged 35–45
BMC Health Services Research (2022) 22:1197
12-24%
35-45%
25-35%

A Chinese practice guideline of the assisted
reproductive technology strategies for women with
advanced age
• For infertile women with DOR, dehydroepiandrosterone (DHEA) may improve the
ovarian response, the quality of the oocyte and embryo, the number of retrieved
oocytes as well as the clinical pregnancy rate. However, there is insufficient evidence.
(2C)
• Growth hormone (GH) might improve the ovarian response and live birth rate for
women with DOR or poor ovarian response, with insufficient evidence. (2C)
• For women ≥35 years old and receiving the downregulation protocol for COH,
recombinant LH (rLH) supplementation, particularly in the middle or late follicular phase
if LH <2 mlU/ml, is recommended. It may improve pregnancy outcomes such as
embryo implantation rate and clinical pregnancy rate. (1C)
• For women ≥35 years old who receiving the antagonist protocol for COH, there is no
evidence regarding the effectiveness of the supplementation of LH/rLH in benefiting the
pregnancy outcomes.(2B) J Evid Based Med. 2019 May;12(2):167-184

A Chinese practice guideline of the assisted reproductive
technology strategies for women with advanced age
• For women with advanced age and receiving ART, preimplantation genetic
screening (PGS) (e.g. Comperative Genomic Hybridization -CGH) may improve the
embryo implantation rate and ongoing pregnancy rate. But meanwhile, it may be
accompanied with a certain risk of misdiagnosis and embryo impairment. (2C)
• We suggest women greater than 38 years old, or with a history of recurrent
implantation failure/recurrent spontaneous abortion consider PGS. (2C)
 For women >37 years old or with a poor prognosis, we suggest double embryos
transfer. But the patients must be informed of the risk of multi pregnancy and
maternal and fetal complications. (2B)

Optimal individualization of patient-oriented
ovarian stimulation
J. Obstet. Gynaecol. Res. 2022 Mar;48(3):521-532

Ideal mild ovarian stimulation
at first cycle
Classification of infertile patients depending
on their ovarian reserve
ovarian stimulation

Ideal conventional ovarian hyperstimulation at first cycle
Advantages and disadvantages of
mild ovarian stimulation
ovarian stimulation

Estimated mean number of metaphase II oocytes
required to obtain at least one euploid blastocyst
Curr Opin Obstet Gynecol 2018, 30:000–000
DOI:10.1097/GCO.0000000000000452

Human Reproduction Update 2016:22(3): 306-19
doi:10.1093/humupd/dmw001

Human Reproduction Update, 2016:22(3): 306-19
doi:10.1093/humupd/dmw001

Endometrial preparation methods prior to frozen
embryo transfer

Estrogen valerate pretreatment with
the antagonist protocol

Dikkatiniz için teşekkür ederim
Tevfik Yoldemir MD Bsc MA PhD
tevfik.yoldemir@marmara.edu.tr

ART for women over 40 years of age.pdf

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