arceli keh

Older Gravidas:
Pregnancies from Donor Eggs
Richard J. Paulson, MD
University of Southern California
Keck School of Medicine
Florida Society of Reproductive Endocrinology & Infertility
Orlando, Florida, August 4 2012
Learning objectives
1. To describe the development of oocyte
donation
2. To outline the appropriate workup of
women planning pregnancies after the
age of 40
3. To assess the outcomes and risks
associated with pregnancies in women
beyond the age of natural child-bearing
Oocyte donation 2009
17,697 cycles, 12% of ART
CDC-SART 2009
Historical Perspective - 20th century
Historical Perspective - 20th century
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1903
1905
1911
1923
1928
1947
1953
1957
1969
1978
First manned powered flight - (Wright Bros)
Special Theory of Relativity - (Einstein)
Discovery of structure of the atom (Rutherford)
Universe extends beyond Milky Way - (Hubble)
Penicillin identified (Fleming)
Sound barrier broken (Yeager)
The double helix (Watson and Crick)
Sputnik
1st lunar landing (Neil Armstrong, Apollo 11)
Louise Joy Brown
When new methods
of human reproduction
Become available—
Can traditional
family life survive?
Will marital infidelity increase?
Will children and parents
still love each other?
Would you be willing to have
a “test-tube” baby?
JUNE 13 • 1969 • 40¢
Howard W Jones, MD
Georgeanna Jones, MD
Professors
Department of Ob/Gyn
Johns Hopkins University
Baltimore, Maryland
Age Discrimination and Assisted
Reproduction
Professors, Department of Ob/Gyn,
Johns Hopkins, 40 year careers, shared office
Mandatory retirements
— Howard 1976
— Georgeanna 1978
7/78 relocated to Department of Ob/Gyn at
Eastern Virginia School of Medicine in Norfolk
Planned to stay 2 years to start an REI division
Their moving truck arrived in Norfolk in July
1978, just when Louise Brown born
First IVF Baby in the USA
Elizabeth Carr
Born 12-28-81
Egg retrieval – HOW?
1st pregnancy after oocyte donation
• Donor = 42 years old
– Stimulation: Clomiphene + hMG
– Monitoring: Serum E2, urinary LH (q3h)
– Laparoscopy: 23 hrs after LH surge
• 5 oocytes recovered, 1 donated
• 4 embryos transferred, no pregnancy
• Recipient = 38 years old, donor insem
– Synchronous ovulation
– 1 embryo transferred
• + preg, ―normal sac‖, Spont. AB
• 47 XX + 9
Trounson et al, Br Med J 1983;12:286
1st live birth
• Donor = 29 years old
– Bilateral tubal blockage, undergoing IVF
• 5 oocytes recovered, 1 donated
• Recipient = 25 years old, POF
– Artificial steroid replacement regimen
• Oral E2 valerate
• Vaginal Progesterone (50 mg b.i.d.)
– One 2-cell embryo transferred
• day 16 = day 2 of progesterone
• Live birth at 37 weeks by ―elective C-section‖
– 7th attempt
Lutjen et al, Nature Jan 12,1984;307:174
(received 12/9/83, accepted 12/16/83)
Ovum transfer
• Insemination of donor
• Recovery of conceptus (―ovum‖)
• Transfer of ovum to recipient
Ovum transfer
Ovum transfer
Ovum transfer
In vivo cultured blastocyst
Ovum transfer
Department of OB/GYN, Harbor-UCLA Medical Center, 1982
Ovum transfer
Ovum transfer
First US baby from
egg donation
L.A. Times, February 3, 1984
Buster et al, Lancet 1983;2:223
Follicle aspiration
• Ultrasound-guided
• Most common
method
• Conscious sedation
• Office procedure
• Made oocyte
donation possible
Egg donation: synchronization
Donor:
Ovarian stimulation
(injectable FSH)
Recipient:
Uterine preparation
(estrogen and progesterone)
―Extending reproductive potential
to women over 40‖
Donor eggs Donor eggs IVF (own eggs)
under 40
over 40
over 40
Transfers
14
8
26
Pregnancies 7/14 (50%) 6/8 (75%)
4/26 (16%)
Live births
2/26 (8%)
7/14 (50%) 5/8 (63%)
Sauer, Paulson and Lobo, NEJM 1990;323:1157
―Reversing the natural decline
in human fertility‖
Donor eggs Donor eggs IVF (own eggs)
under 40
over 40
over 40
Transfers
43
86
70
Pregnancies 14/43(33%) 34/86(40%) 8/70 (11%)
Live births
13/43(30%) 29/86(34%) 6/70 (9%)
Sauer, Paulson and Lobo, JAMA 1992;268:1275
―Pregnancy after age 50:
application of oocyte donation to
women after natural menopause‖
14 Couples
- 21 Transfers
- 8 Pregnancies (38%)
- 7 Live births (33%)
Sauer, Paulson and Lobo, Lancet 1993;341:321
Cumulative pregnancy rates
after oocyte donation
Number of cycles
Paulson et al, Human Reprod 1997;12:835
Cumulative pregnancy rates after oocyte
donation by age of female partner
Number of cycles
Paulson et al, Human Reprod 1997;12:835
Cumulative pregnancy rates after oocyte
donation by diagnosis
Number of cycles
Paulson et al, Human Reprod 1997;12:835
Hormonal control of
Endometrial Receptivity
Endometrial preparation
• Estrogen
– Endometrial proliferation
– Progesterone receptors
Pregnancy without ovaries:
E2 and P4 sufficient
• Primate model
• Hodgen et al, JAMA 1983; 250:2167
• First pregnancy after ovarian failure
• Lutjen et al, Nature 1984;307:174
• Variable duration and dosage of
hormonal stimulation
• Navot et al, NEJM 1986;314:806
• Navot et al, JCEM 1989;68:485
• Krasnow et al, Fertil Steril 1996;65:332
Recipient protocol – USC 2009
Alternative routes of E2
administration
•
•
•
•
Oral
Trans-dermal
Intramuscular
Vaginal administration of estrogen
– Optimize absorption
– Target endometrial delivery
Trans-dermal estrogen
administration
Vaginal E2 administration
• Mean serum E2 after
oral micronized E2
2 mg bid
(279 pg/ml)
• Mean serum E2 after
vaginal micronized E2
2 mg bid
(2344 pg/ml)
Serum E2 levels (pg/mL)
3000
2500
2000
1500
1000
500
0
*
*p<0.005
Oral
Vaginal
Tourgeman et al, Am J Obstet Gynecol 1999;180:1480-3
Vaginal E2 administration
Endometrial E2 levels
(pg/mg protein)
• Mean endometrial E2
after oral micronized
1400
1200
E2 2 mg bid
*p<0.005
1000
(13 pg/mg protein)
800
• Mean endometrial E2
600
after vaginal micronized
400
E2 2 mg bid
200
(918 pg/mg protein)
0
Oral
*
Vaginal
Tourgeman et al, Am J Obstet Gynecol 1999;180:1480-3
Progesterone
• Luteinization
• Decidualization
• Receptivity to
Embryo Implantation
Routes of P4 administration
• Much higher levels (quantities) than E2
– Approximately 100-fold 
• Oral
– First-pass metabolism: prohibitive
• Transdermal
– Quantity: nearly prohibitive
– Skin metabolism (5 reductase)
• Intramuscular
• Vaginal
• Other (intranasal, rectal, sublingual)
Routes of P4 administration
• Much higher levels (quantities) than E2
– Approximately 100-fold 
• Oral
– First-pass metabolism: prohibitive
• Transdermal
– Quantity: nearly prohibitive
– Skin metabolism (5 reductase)
• Intramuscular
• Vaginal
• Other (intranasal, rectal, sublingual)
Obstetric outcomes after age 50
• Retrospective analysis: 1991-2001
• 77 Postmenopausal women over age
50 undergoing IVF with donor eggs
Mean + S.D.
Range
Age (years)
52.8 + 2.9
50 - 63
Prior pregnancies
1.2 + 1.7
0-6
Prior births
0.6 + 1.2
0-4
Paulson et al. JAMA 2002;288:2320
Recipient screening (>50)
• Pre-cycle screening:
– General health status
• History and physical examination, PAP
• Mammogram, blood chemistry
• Infectious disease screen
– Normal cardiovascular reserve
• Stress treadmill, EKG
– Normal uterine cavity
• Imaging studies - ultrasound, x-ray dye studies
Recipient screening
• Pre-cycle screening:
– Normal response to exogenous hormones
• Endometrial biopsy
– Psychosocial consultation
• Non-genetic parenting
• Parenthood at advanced reproductive age
– Pre-conceptual counseling
• Obstetrical issues
Recipients
• Modifications to
Endometrial Replacement protocol (if needed):
– Increase E2 (vaginal administration)
– Vaginal P4
Delivery outcomes
• 45 Live births
– 78% Caesarean delivery
• 31 Singletons
– 68% Caesarian delivery
– 6% Vacuum-assisted delivery
– 26% Spontaneous vaginal delivery
• 14 Multiple gestations
– 100% Caesarian delivery
Obstetric complications
• 20.0% gestational diabetes
– 17.5% diet controlled
– 2.5% insulin
• Comparison values
– 5% overall, increasing with age
• <20 years of age: 3.7%
• 20-30 years of age: 7.5%
• >30 years of age: 13.8%
Obstetric complications
• 35% Pre-eclampsia
(pregnancy induced hypertension)
– 25% mild
– 10% severe
• Comparison values
– 3 - 5% in young women
– 10% in women over 40
• Reasons:
– age, donated gametes
Obstetric complications
• Effect of age
Pre-eclampsia
(35%)
Diabetes
(20%)
< 54 yrs old (n=30)
26%
13%
> 55 yrs old (n=10)
60%
40%
No effect of parity upon incidence of pre-eclampsia
(34.8% vs 35.2%, primiparas vs multiparas)
Paulson et al. JAMA 2002;288:2320
Obstetric complications
• One case of rupture of membranes at 29
weeks of singleton, hospitalization for 10
days until delivery
• One case of delivery of twins at 30 weeks of
gestation for sudden onset of severe
preeclampsia
• One hysterectomy for placenta accreta
• One transfusion after cesarean delivery for
placenta previa.
• No neonatal or maternal deaths
Summary
• Birth weight similar to that of younger
mothers
• 2x  in gestational diabetes
• 3x  in pregnancy induced hypertension
– As compared to rates in 40 yr old women
• Unusually high operative delivery rate
How old is too old?
• Is 55 a ―physiological limit‖?
– Marked increase in pre-eclampsia
– Increase in diabetes
• Possible change over time
– Increased longevity
– Better health
How old is too old?
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Danger to mother
Decreased life expectancy of parents
Quality of parenting
―Unnatural‖
Turner syndrome – OB outcome
• Case of IUP with aortic dissection
– 33 yo G1, Turner syndrome, HTN
– Singleton IUP with egg donation
– N/V, epigastric pain at 24 weeks gestation
– Echocardiogram: aortic dissection
– Emergency surgery
• Hemopericardium, repair of aortic aneurism
• Circulatory arrest, life support
– Viable infant delivered at 27 weeks
– Maternal demise
Garvey et al, Obstet Gynecol 1998;91:864
Turner syndrome
• Risk of aortic dissection  2%
– Risk of death  100-fold
• Relative contraindication to pregnancy*
– Cardiology consultation, screening
– Any abnormality = absolute contraindication
• Aortic dissection may occur even if prepregnancy evaluation is normal
*ASRM practice committee, FS 2006; 86:S127
Turner syndrome
• Aortic dissection may occur even if prepregnancy evaluation is normal
• Cardiovascular evaluation is not 100%
predictive
• Estimated mortality during pregnancy?
– 0.5% – 2.0% (?)*
• Indication for gestational surrogacy?
Reindollar, personal communication
Motherhood After Age Fifty:
An Evaluation of Parenting Stress
and Physical Functioning
Anne Z. Steiner, MD, MPH
Richard J. Paulson, MD
Steiner & Paulson, Fertil Steril 2007;87:1327
The Cohort
• Study Group
– All women conceiving via oocyte donation
after age 50 (N=49)
– 1992-2004
• Controls
– Women conceiving via oocyte donation
in their 30’s (N=49) and 40’s (N=49)
– Matched for date of embryo transfer and
gestational order
Measures
Parenting Stress Index
Short Form
• Degree of parenting
stress
• Validated
• Scores
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–
–
–
Defensive Responding
Parental distress
Parent-child dysfunction
Total stress (TS)
• Derivative of the PSI
SF-36 Health Survey
• Health profile and
quality of life
• 36 questions, 8-scales
• Overall scores
– Mental component score
(MCS)
– Physical component
score (PCS)
• Validated
• Normative data
available
Paternal Component
**
60
*
50
Age (years)
**
*
40
30
Female
Male
20
10
0
Thirties
Fifties
*P<0.001
**P=0.03
The Marriage
Age (years)
60
Years Married
50
40
30
20
10
0
Thirties Forties
Fifties
Physical Functioning
P=0.26
P<0.001
Physical Component
Score (PCS)
60
50
A high score
denotes high
levels of
physical
functioning.
40
30
20
10
0
Thirties Forties
Fifties National
Mental Functioning
Mental Component Score
(MCS)
P=0.30
60
* P=0.02
*
*
50
A high score
denotes high
levels of
mental
functioning.
40
30
20
10
0
Thirties Forties
Fifties National
Total Parenting Stress (TS)
Total Parenting Stress
66
64
A high score
denotes
high levels
of parenting
stress.
62
60
58
56
54
52
Thirties
Forties
Fifties
P=0.38
Summary
• Women conceiving in their fifties
were significantly older than their
husbands.
• Women in this group married their
current spouse at a later age
compared to the younger groups.
Summary
• They did not differ in physical or
mental functioning compared to the
younger women.
• They did not suffer from greater
parenting stress.
Conclusions
• Older parents adapt to parenting in a similar
fashion as their younger counterparts.
• The paternal contribution to childrearing
among these couples should be further
explored.
• The physical and mental capacity of these
women should not be considered an early
impediment to childrearing.
• Postmenopausal reproduction should not be
restricted based on concerns of parenting
stress.
Long-term follow-up
Arceli Keh
• World’s oldest mom
at 63 in 1997
• Lied about her age
• Treated in US
• Alive and well
Carmela Bousada
• Oldest mom at 67 in
2007
• Lied about her age
• Treated in US
• Died in 2009 of
cancer
Omkari Panwar
World’s oldest mom at 70
Wanted male child
Twins (boy-girl)
at 32 weeks by
emergency C-section
Severe pre-eclampsia
Rewinding the biological clock
• Parallels societal changes
– Perception of aging
– Expectation of aging
– Individual rights and autonomy
– Reproductive choice
Oocyte donation
• Most successful of
ARTs
• Overcomes agerelated decline in
fertility
• Pregnancy possible
in virtually any
woman with a uterus
Aging in perspective
Do not go gentle into that good night,
Old age should burn
and rave at close of day;
Rage, rage against
the dying of the light.
Dylan Thomas