Fertility in Midlife

FERTILITY IN
MIDLIFE
SCI IVF CENTRE

 Dr Shivani Sachdev
Gour
 MD DNB MRCOG
(UK)
 Consultant Fertility
Specialist
Gynaecologist
 Director
 SCI IVF Centre New
Delhi
 DR Nupur Garg
 MS, FNB
Consultant Fertility
Specialist
Gynaecologist
 Director
SCI IVF Centre
Noida

 We are seeing celebrities with millions of
followers having babies at an older age
 Aishwarya rai at 37 Rani mukherjee 37 Neha
Dhupia 38 Kareen Kapoor 36 Farah Khan
triplets at 40 yrs of age

Age shock: misperceptions of the impact of age
on fertility before and after IVF in women who
conceived after age 40 K. Mac Dougall, Hum
Reprod. 2013 Feb
 30% of women expected their fertility to decline gradually
until menopause at around 50 years
 31% reported that they expected to get pregnant without
difficulty at the age of 40
 44% reported being ‘shocked’ and ‘alarmed’ to discover that
their understanding of the rapidity of age-related reproductive
decline was inaccurate’.
 28% advocated better fertility education earlier in life
 23% indicated that with more information about declining
fertility, they might have attempted conception at an earlier
age.
 46% of women acknowledged that even if they had
possessed better information, their life circumstances would
not have permitted them to begin childbearing earlier

Reasons for a mistaken belief in robust
fertility
 Healthy lifestyle and family history of fertility
(26%)
 Incorrect information from friends, physicians
 Misleading media reports of pregnancies in
older celebrity women (28%).

 MIDLIFE DEFINITION
 the central period of a person's life, between
around 45 and 60 years old.
OXFORD DICTIONARY

 Experiencing pregnancy in late 30s or early
40s isn't just a Hollywood thing, it's a national
trend.
 According to CDC data and statistics , From
2000 to 2014, the proportion of first birth to
women aged 30-34 yr rose by 28 per cent
(16.5-21.1%) and first births to women aged
35 yr and over rose by 23 per cent (7.4-9.1%).
 In 2013 in the U.S., there were 677 births to
women 50 and over—up from 600 in 2012

Percentage of first births, by age
of mother: USA, 2000–2014(CDC)

 Increasing Trends of midlife parenthood —
 Greater financial stability
 More emotionally prepared
 Flexibility with work schedules due to having
established careers
 In India- increase in median age of marriage,
higher school enrolment for females have
contributed.

 In-depth qualitative interviews were conducted
between 2009 and 2011 with 46 couples and 15
individual self-selected US women and men
who had used IVF to conceive their first child
when the woman was aged 40 or older at the
time of delivery.

ADVANTAGE OF FIRST TIME PARENTING OVER THE AGE OF 40
USING IVF
DISADVANTAGES OF FIRST TIME PARENTING OVER THE AGE OF 40
USING IVF

Older Age for Parenthood
 More women pursuing higher education and
careers and postponing marriage
 Availability of simple and effective
contraceptives
 Problems finding suitable partner
 Increased prosperity
 Misconception on effect of age on fertility
 Longer and healthier life span
 Increasing use of ART

Need for fertility at Midlife-
 Career oriented women
 Late marriages
 Delayed childbearing
 Increased rates of Divorces, Re-marriages
 Secondary infertility due to late planning for
second child

OVARIAN RESERVE AND AGE
•At birth- about 2 million
eggs
•Adolescence -400, 000
•37yrs- 25,000.
• 51yrs- 1000 immature
eggs and it is not just
number but quality
because pt say we can
see egggs on scan but
they are poor quality that
they shd understand

Monthly Fertility Rates By Agevan
Noord-Zaadstra et al., 302, p. 1363, 1991

DECLINE IN MARITAL FERTILITY RATES
WITH AGE
 Age of marriage and
risk of
childlessness(FERTIL
ITY RATES)
 6% at age 20 to 24
 9% at age 25 to 29
 15% at age 30 to 34
 30% at age 35 to 39
 64% at age 40 to 44
Menken J.Age and
infertility. Science
1986;233: 1389–94.

AGE IN YEARS DECREASE IN
FECUNDABILITY
34-35 14%
36-37 19%
38-39 30%
40-41 53%
42-44 59%
 Fecundability did not differ between women aged 30–31
years and 32–33 years
 At any age >30 years, women who have never
conceived have a lower probability of achieving a
pregnancy compared to women with prior fertility. FERT

IUI:effect of age and number of cycle of
Insemination on Pregnancy RatesVan Noord
Zaadstra et al BMJ 1991

Impact of Age on IVF- LBR
Outcome
 The percentage of IVF cycle started resulting
in live births
 Centers for Disease Control and Prevention, ASRM for
Assisted Reproductive Technology. 2010 assisted
reproductive technology: fertility clinic success rates
report. Atlanta (GA):CDC; 2012
AGE in
YRS
<35yrs 35-37 38-40 41-42 43-44 >44 EGG
DONO
R
LBR 41.5 31.9 21.1 12.4 5 1 51%

<35 42 43 44 45 46 47
Clinical preg/cycle 24.1 7.7 5.4 1.9 0 0
Spont
abortion/clinical preg
12.8 34.6 37.5 66.7
 A total of 843 IVF retrievals in 459 patients 42 years old were
assessed.
 Only one IVF cycle in patients aged 44 years resulted in delivery.
 None of the 54 cycles performed in women of 45 years or older
resulted in a pregnancy
 A marked decline in clinical pregnancy accompanied by an
increase in spontaneous abortion rates, was found in patients 42
years old.

Age related Rates of
Miscarriages
 Centers for Disease Control and Prevention, American
Society for Reproductive Medicine Society for Assisted
Reproductive Technology. 2010 assisted reproductive
technology: fertility clinic success rates report. Atlanta
(GA):CDC; 2012
AGE in YRS 33-34 35-37 38-40 41-42 >42
MISCARRIA
GE RATES%
11.4 13.7 19.8 29.9 36.6

Medical Risk of Pregnancy At An Advanced
Age
Risks to women-
 Gestational diabetes
 Preeclampsia
 Cesarean delivery
 Preterm delivery of a baby with low birth
weight.
 Ectopic Pregnancy

 Age increases the risks of other disorders that
may adversely affect fertility
 leiomyomas
 tubal disease
 Endometriosis
 Endometrial Polyp

Ethnic differences in ovarian aging between
Caucasian and Indian women
 Ovaries from Indian women seem to age at an
earlier stage than Caucasian.
 Similar ovarian reserve markers and ovarian
response was observed in women with a 6-year
difference in favour of Caucasian, which suggest
ethnic differences in ovarian aging. M. Banker Fert
Stert 2013
 Despite similar ages, AMH levels, ovarian
stimulation duration and gonadotropin doses,
Asian women have decreased AFCs and a lower
yield of total and mature oocytes compared to
their Caucasian counterparts
 A.G. Kelly Sep 2017 Fert Stert

Who are at increased Risk?
history of
 prior ovarian surgery
 chemotherapy
 radiation therapy
 severe endometriosis
 smoking
 pelvic infection
 strong family history of early menopause

Correct Age For Planning?
 In order to have a ≥90% chance of achieving
 one-child female partner is ≤35yr
 two-child ≤31yr
 three-child ≤28 years
if IVF is an acceptable option.
If IVF is not acceptable, couples should start no
later than 32, 27 and 23 years if they desire a
one-, two- or three-child family, respectively

How long should women try before
calling their doctors?
 Under the age of 35 = at least a year
 Over the age of 35 = six months
 At either point, women should talk to their
doctors about a fertility evaluation.
 Men should also talk to their doctors if this much
time has passed

PATH TO SHORTEN TIME TO
SUCCESSFULL SINGLETON
HEALTHY PREGNANCY

Women<40yr
max 6 single
ET
DUO-STIM in
POR Patient
PGT-A with
CCS to shorten
TTP and
increase CPR
No effect of
Patients AGE on
Oocyte
Donation Cycles
Agonist trigger
to cycle
cancellation
due to OHSS
Immediate
FET after
Failed Fresh
IVF
GnRH
Antagonist
Protocol to
shorten TTP
Cumulative
LBR with
Oocyte
numberDELPHI
CONSENSU
S
STATEMENT
Timely
management of
fertility treatment
to avoids over- or
under-treatment

Advance Maternal Age In IVF: Present and
Future Treatment
PREVENT
REDUCESOLVE
COMPENSAT
E
Ubaldi Frontiers in Endocrinology Feb 2019

PREVENT
 Freezing of Oocytes-Reproductive
Insurance
 Reduces the incidence of oocyte donation
(OD) and the burden of ineffective fertility
treatment at older ages.
 Education and Counselling-

Fertility preservation-Non Medical
Reasons


Facebook, Apple
now cover egg
freezing costs for
female employees
 The policy is meant
to give employees
more freedom to
pursue family
planning according
to their own
timeline ..

Education and Counselling-
 Women in their 20s and 30s should be
counselled about the age-related risk of
infertility as part of their primary well-woman
care.
 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
Advanced reproductive age and fertility. Liu KJ
Obstet Gynaecol Can. 2011

SOGC GUIDELINES
 Ovarian reserve testing (ORT) may be considered for
women aged ≥35 or for women <35 with risk factors
such as a single ovary, previous ovarian surgery, poor
response to FSH, previous exposure to CT or RT, or
unexplained infertility
 ORT prior to ART has a poor predictive value for non-
pregnancy and should be used to exclude women from
treatment only if levels are significantly abnormal

 Pregnancy rates for IUI and superovulation are
low for women aged >40.
 Women >40 should consider in vitro
fertilization if they do not conceive within 1 to 2
cycles of IUI
 A woman with decreased ovarian reserve
should be offered oocyte donation as an option
because pregnancy rates are significantly
higher than those associated with IVF with
own eggs .

COMPENSATE
 Maximisation of Ovarian Response to
Stimulation
 Improvement of Oocyte Competence-oocyte
rejuvenation

 915 PGS cycles (2610
blastocysts, 24 chr
analysis, one Centre),
mean female age 39.2
years
 Euploidy rate is
consistent across the
number of MII oocytes
retrieved
 Colamaria, Ubaldi oral
presentation, ESHRE 2015
More oocytes means more euploid
blastocysts

Cumulative Pregnancy Rates-
Indicator of IVF Success
 High ovarian
response does not
jeopardize
ongoing
pregnancy rates
and increases
cumulative
pregnancy rates in
a GnRH-
antagonist
protocol
 Human
Reproduction
2013 Fatemi

Total number of transferred embryos
required to achieve a pregnancy
categorized by the age.
 Use of
Cumulative
Live Birth Rate
per Total
Number of
Embryos to
Calculate the
Success of IVF
in Consecutive
IVF Cycles in
Women Aged
≥35 Years
 Zheng 2019
Hindawi

Posieden criteria(Patient-Oriented
Strategies Encompassing Individualized Oocyte
Number)

5 Main Strategies-To increase the
number of oocytes(POSEIDON)
 Use of recombinant FSH in preference over
urinary gonadotropin preparations
 FSH dose increase
 rec-LH supplementation
 Dehydroepiandrosterone supplementation
before OS
 Combination of follicular and luteal phase
stimulation in the same ovarian cycle-Duo
Stim

AUGMENT-Autologous Mitochondrial
transfer

 Aged oocytes have significantly reduced
amounts of mitochondria
 the energy factories of cells, leading to lower
fertilization rates and poor embryonic
development.
 Various techniques have tried to use
heterologous or autologous sources of
mitochondria to reestablish oocyte health by
providing more energy

SOLVE
 Oocyte Donation
 Generation of new gametes in vitro

THIRD PARTY
REPRODUCTION
 In patients with a clear depletion of the ovarian
reserve
 In presence of recurrent IVF failures,
especially after several (euploid) ETs, the only
options left are adoption or OD

 Physicians should obtain a complete medical
evaluation before deciding to attempt transfer of
embryos to any woman over age 50.
 Embryo transfer should be strongly discouraged or
denied to any woman over age 50 with underlying
issues that could increase or further obstetrical risks
and discouraged in women over age 55 without such
issues.

Revolutionary technique to correct defective
sperm and oocyte before formation or resulting
defective embryo can be corrected using
bacterial enzyme CAS9,which binds to double
starnded DNA cut it allowing new DNA to be
inserted

PGT-A
 Minimizing the Reproductive Risks of AMA
 Avoid the transfer of aneuploid embryos
 Increase the pregnancy rate per transfer
especially when performing SET
 Less burden and complications (i.e.,
miscarriage and multiple gestation)
 Shorter time to achieve a pregnancy

PGD-A NON PGD-A
No: of ETs 68% 90.5%
Miscarriage Rates 2.7% 39%
Delivery Rate/transfer 52.9% 24.2%
Mean no. Of ETs/LB 1.8 3.7
Time to Pregnancy in
weeks
7.7 14.9
Decreases miscarriage rates and shortens the time to pregnancy

EMBRYO DIAGNOSTICS-(PGT-A)
A non selection study where all the embryo were biopsied for DNA
fingerprinting and aneuploidy assessment and were transferred prior
to performing analysis
 The clinical error rate of an aneuploidy designation (normal
designated abnormal) was FOUND very low (4%). Aneuploidy
predictive value was found 96%
 24-chromosome aneuploidy screening system , was found as
more comprehensive and accurate approach to improve outcome of
PGT-AFert Stert 2012

Effect of Advanced Paternal
Age
The trend of older parenthood is true also for males
Advanced paternal age is associated with-
 Decreased testicular volume
 Reduction in testosterone levels
 Erectile dysfunction
 Increased incidence of MAGI
 Decrease in semen volume.
 Increased DNA fragmentation
Advanced paternal age and reproductive outcome
Zofnat Wiener-Megnazi.Asian J Androl. 2012

Effect of Advanced Paternal
Age
 Increased risk of sperm germ line mutations
and Autosomal Dominant disorders
 Diseases of multifactorial origin, including
neurocognitive and psychiatric disorders,
malignancy and autism
Advanced paternal age and reproductive
outcome Zofnat Wiener-Megnazi.Asian J
Androl. 2012

Pre Conception Counselling
 Risk of spontaneous pregnancy loss
and chromosomal abnormalities
increases with age.
 Appropriate prenatal screening once
pregnancy is established.
 Risks of pregnancy with advanced
maternal age
 Promotion of optimal health and weight

Pre Conception Counselling
 Screening for concurrent medical conditions
such as hypertension and diabetes for
women aged 40
 Advanced paternal age appears to be
associated with an increased risk of
spontaneous abortion and increased
frequency of some autosomal dominant
conditions, autism spectrum disorders, and
schizophrenia.
 Men >40 and their partners should be
counselled about these potential risks when
they are seeking pregnancy, although the

ASRM Recommendations
 Education and enhanced awareness of the effect
of age on fertility is essential in counseling the
patient who desires pregnancy.
 Women older than 35 years should receive
expedited evaluation and treatment after 6 months
of failed attempts to conceive or earlier, if clinically
indicated.
 In women older than 40 years, immediate
evaluation and treatment are warranted.
Female age-related fertility decline. Committee
Opinion No. 589

Should There Be an Age Limit in Fertility
Treatment? The Debate
 Age is a fluid concept.
 One person is old, both physically and
mentally at 35, while someone else is the
proverbial “young at heart” and flexible at body
well into their 60s
 Healthy women can live well into their 80s and
longer
 Many cultures have more shared and
collectivised approaches to raising and
nurturing children
 In many countries children are raised primarily
by their grandparents.

Debate
 The state-funded Indian Council of Medical
Research (ICMR) advises an upper age limit of
50 years.
 There is fear that women’s bodies at older ages
cannot cope multiple hormonal intervention of
IVF as well as support childbirth.
 Risk of bereavement of children born at
advanced age
 Risk of psychological, social and financial
burden on children.

Need For Policy Making
 Designation of an appropriate Authority
 Age limits according to life expectancy
 Appropriate assessment of home situation of the
concerned couple
 Psychological assesment
 Legal undertaking by a responsible family
member for financial and social legal guardianship
and protection to the children born through ART to
mothers of AMA.
 This undertaking should be legally binding in case
of bereavement

Conclusion
 A woman’s right to have a baby should be based
on medical fact—not social judgment
 Patients should be carefully selected and
managed to ensure safe pregnancy
 Rigorous health campaigns and awareness
programs are needed highlighting the issue of
midlife fertility
 Need for proper guidelines
 A complete backup or insurance plan should be in
place for child’s future

Older parents owe their children “thoughtfulness and care
of parental plans for sheltering the child within a
capricious world.”
Susan Drummond

Fertility in Midlife

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Fertility in Midlife