pregnancies from donor eggsolder gravidas: pregnancies from donor eggs richard j. paulson, md...

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

• 1903 First manned powered flight - (Wright Bros)

• 1905 Special Theory of Relativity - (Einstein)

• 1911 Discovery of structure of the atom (Rutherford)

• 1923 Universe extends beyond Milky Way - (Hubble)

• 1928 Penicillin identified (Fleming)

• 1947 Sound barrier broken (Yeager)

• 1953 The double helix (Watson and Crick)

• 1957 Sputnik

• 1969 1st lunar landing (Neil Armstrong, Apollo 11)

• 1978 Louise Joy Brown

JUNE 13 • 1969 • 40¢

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?

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

Elizabeth Carr Born 12-28-81

First IVF Baby in the USA

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‖

Sauer, Paulson and Lobo, NEJM 1990;323:1157

Donor eggs

under 40

Donor eggs

over 40

IVF (own eggs)

over 40

Transfers 14 8 26

Pregnancies 7/14 (50%) 6/8 (75%) 4/26 (16%)

Live births 7/14 (50%) 5/8 (63%) 2/26 (8%)

―Reversing the natural decline

in human fertility‖

Sauer, Paulson and Lobo, JAMA 1992;268:1275

Donor eggs

under 40

Donor eggs

over 40

IVF (own eggs)

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%)

―Pregnancy after age 50: application of oocyte donation to

women after natural menopause‖

Sauer, Paulson and Lobo, Lancet 1993;341:321

14 Couples

- 21 Transfers

- 8 Pregnancies (38%)

- 7 Live births (33%)

Cumulative pregnancy rates

after oocyte donation

Paulson et al, Human Reprod 1997;12:835

Number of cycles

Cumulative pregnancy rates after oocyte

donation by age of female partner

Paulson et al, Human Reprod 1997;12:835

Number of cycles

Cumulative pregnancy rates after oocyte

donation by diagnosis

Paulson et al, Human Reprod 1997;12:835 Number of cycles

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)

0

500

1000

1500

2000

2500

3000

Oral Vaginal

*p<0.005

Serum E2 levels (pg/mL)

*

Tourgeman et al, Am J Obstet Gynecol 1999;180:1480-3

Vaginal E2 administration

• Mean endometrial E2

after oral micronized

E2 2 mg bid

(13 pg/mg protein)

• Mean endometrial E2

after vaginal micronized

E2 2 mg bid

(918 pg/mg protein)

*p<0.005

Endometrial E2 levels

(pg/mg protein)

*

Tourgeman et al, Am J Obstet Gynecol 1999;180:1480-3

0

200

400

600

800

1000

1200

1400

Oral Vaginal

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

• 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?

• Danger to mother

• Decreased life expectancy of parents

• Quality of parenting

• ―Unnatural‖

How old is too old?

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 pre-

pregnancy evaluation is normal

*ASRM practice committee, FS 2006; 86:S127

Turner syndrome

• Aortic dissection may occur even if pre-

pregnancy 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 – 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

0

10

20

30

40

50

60

Ag

e (

ye

ars

)

Thirties Fifties

Female

Male

*

**

*P<0.001 **P=0.03

*

**

The Marriage

0

10

20

30

40

50

60

Ag

e (

ye

ars

)

Thirties Forties Fifties

Years Married

Physical Functioning

0

10

20

30

40

50

60

Ph

ysic

al

Co

mp

on

en

t

Sco

re (

PC

S)

Thirties Forties Fifties National

A high score

denotes high

levels of

physical

functioning.

P<0.001 P=0.26

Mental Functioning

0

10

20

30

40

50

60

Men

tal

Co

mp

on

en

t S

co

re

(MC

S)

Thirties Forties Fifties National

A high score

denotes high

levels of

mental

functioning.

* *

* P=0.02 P=0.30

Total Parenting Stress

52

54

56

58

60

62

64

66

To

tal

Pare

nti

ng

Str

ess (

TS

)

Thirties Forties Fifties

A high score

denotes

high levels

of parenting

stress.

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 age-related 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