Transcript TE Chicago (v3)

Choosing children
Practical and Moral Choices in the
Practice of Preimplantation Genetic Testing
Mr Tarek El-Toukhy
Department of Women’s Health
Guy’s, King’s and St Thomas’
School of Medicine,
King’s College London
Centre for Preimplantation Genetic Diagnosis
Preimplantation Genetic Testing
Detection of genetic information in an
embryo made by examining a
representative sample taken at a
preimplantation stage of development
Centre for Preimplantation Genetic Diagnosis
Centre for Preimplantation Genetic Diagnosis
PGD principle
Biopsy
affected
affected
Test
transfer only unaffected embryos back to the patient
Fertilisation in vitro
(IVF or ICSI)
Appropriate
Genetic
Counselling
Accurate
genetic
diagnosis
Embryo biopsy
Diagnosis
by
FISH
PCR
DENATURING
Transfer
2 unaffected
embryos
Steps to PGD
ANNEALING
TAQ
PRIMER
TAQ
EXTENSION
Prenatal diagnosis and
termination of pregnancy
Chorion
Villus
Sampling
Types of genetic disorders
Single Gene disorders
(PCR)
Chromosome
• Spinal Muscular Atrophy
rearrangements (FISH)
•
•
•
•
Cystic Fibrosis
Huntingdon’s Disease
Sickle cell disease
EB
64 Reciprocal translocations
14 Robertsonian
6 Inversions
Sex Linked disorders
(FISH)
e.g. OTC, Hunter’s, ALD etc
Centre for Preimplantation Genetic Diagnosis
Types and Use of
Preimplantation Genetic Testing
Preimplantation genetic diagnosis (PGD)
Reducing recurrent genetic risk
Preimplantation genetic screening (PGS)
Reducing sporadic genetic risk to improve IVF outcome
Preimplantation HLA testing (with PGD)
Reducing genetic risk and helping sibling
Preimplantation HLA testing (without PGD)
IVF Biopsy & HLA test to provide tissue matched sibling
Centre for Preimplantation Genetic Diagnosis
PGD at GSTT
ESHRE
Reports 1-7
Report 8
GSTT
1997- October
2008
Cycles started
Not reported
Not reported
695
Cycles to OR
5107
1128
606
Cycles to ET
3719 (73%)
816 (72%)
470 (68%)
CPR per OR
18%
17%
28%
CPR per ET
25%
24%
35%
Genuinely difficult practical
issues to confront
• Rights and duties of a doctor
• Rights wishes and expectations of parent
– For themselves
– For their as yet unborn (potential) offspring
• Rights of, and effects upon child once born
All influenced by society mores,
and sanctity and beginning of life arguments
Different values for sanctity of
life and start of personhood
Moral Status of the Embryo
Moral Status of the Embryo
Inconsistency of Protective
Legislation
Embryos in vivo receive less respect than those in vitro
Ethical concerns regarding PGD
• Different views of moral status of the embryo
at preimplantation stages
• Fear and concern about manipulating humans
genetically – choosing our offspring
• Use of the embryo (or the person) as a
commodity
• Worry where it will all lead; getting out of
control (slippery slope)
Where will it all end?
Genuinely difficult practical
issues to confront
• Rights and duties of a doctor
• Rights wishes and expectations of parent
– For themselves
– For their as yet unborn (potential) offspring
• Rights of, and effects upon child once born
All influenced by society mores,
and sanctity and beginning of life arguments
Rights and duties of a doctor
• Welfare of the Child:
Limiting a child’s right to an open future
• Long term safety of embryo biopsy
• Lack of, or disputed efficacy of PGD
or PGS
• Restricted access to (expensive)
technology
What might parents want?
• Child survival and health in the face
of a lethal dominant or recessive
disorder
• Prevention of transmission of late
onset disease
• Reducing risk of pregnancy loss
• Avoiding termination of pregnancy
Parent choices that might conflict
•
•
•
•
•
•
Reducing risk of disease - better health
Eliminating disease from blood line
Being of a preferred sex
Attaining a physical or mental advantage
Attaining health for a sibling
Just being more like them – even
selecting for disease trait
Transfer of carrier embryos
(Alport’s disease: Sex selection against males)
Transfer of carrier embryos
(recessive disorder: CF)
Normal Phenotype
Impact of affected child
on parental choice
• Carrier of X linked
muscular dystrophy
• Boys will die in late teens
early 20s
• Miscarriage after PND
• Want to “complete” family
• Requests sexing for
females
Impact of affected child
on parental choice
• Carrier of X-linked
haemophiiia
• George has haemophilia and
loves football which he will be
stopped playing at age 10
• Wants sexing for female so
as not to compete with
George
• Refused use of test which
would identify normal males
Non-medical Sex Selection
• Either sex as an alternative to previous
child - ‘family balancing’
• Preference for a particular sex when
male child has genetic disease
• Sex is revealed as part of process for
something else being tested
• Males as cultural preferred gender
Late onset disease
(example: HD autosomal dominant)
?
?
HD family dynamics
She at risk of HD gene, but no
symptoms yet
Progressive degenerative
disorder
Will develop symptoms age
35-45 years old
Her mother dying of the
disorder
Brother is normal and has
family
Wants a family but the child
could inherit the disease
What should she do?
Difficulties of late onset disease
Example: Huntington’s disease
• Many years of disease free life
• Knowledge of genetic status changes
personal and reproductive prospects
• Desire not to know HD status has
implications for testing and children born
• Termination not undertaken after PND
changes child’s freedom not to know status
Current options for patients
with HD risk
•
•
•
•
•
•
Reproduce at 50% risk
Prenatal diagnosis & TOP
Remain childless
Gamete donation
Adoption (unlikely)
PGD
To know, or not to know,
HD status
Decision to reproduce but
Against Termination of Pregnancy
Know - affected
Don’t wish to know
On knowing that one has the HD
gene
When we had the result that I had the gene it was
still a shock. We had feelings which were similar to a
bereavement: firstly we knew I would get HD, and
secondly the loss of not having a child…..
We both felt more at peace now we knew I had the
gene. I’m sure fear can build up around something
that might or might not happen and sometimes it is
better to know.
Sue Wright in “The Troubled Helix”; Marteau and Richards 1996
On not wanting to know
“What’s the point of predictive testing if there’s no cure
for the disease.
No thanks, I’m just not brave enough. I have always
been so active. I always want to be doing something.
I can’t just sit around, and to end up in some
wheelchair without a life is not very appealing.
From the age of 19 or 20 I made a conscious decision
not to have a life into which men, marriage and babies
came; especially the last two.”
Julia in “The Troubled Helix”; Marteau and Richards 1996
To know, or not to know,
HD status & PGD
Decision to reproduce but
Against Termination of Pregnancy
Know - affected
Direct testing of
embryos for HD
expansion
Don’t wish to know
Direct testing of
embryos for HD
expansion
BUT result NOT
to be revealed
Direct Testing for Huntington’s
Disease
(patient knows their HD status)
H
D
Affected
unaffected
unaffected
Affected
Affected
unaffected
Affected
Non-disclosure Direct Testing
of Embryos for Huntington’s -1
(patient does NOT wish to know HD status)
?
unaffected
unaffected
Affected
Unknown
Affected
unaffected
Affected
Non-disclosure Direct Testing
of Embryos for Huntington’s -2
(patient does NOT wish to know HD status
but lab and ART centre know!)
H
D
Affected
unaffected
unaffected
Affected
Affected
unaffected
Affected
Non-disclosure Direct Testing
of Embryos for Huntington’s -3
(patient does NOT wish to know HD status
but lab and ART centre know!)
H
D
Affected
unaffected
Affected
Affected
Affected
Affected
Affected
Non-disclosure Direct Testing
of Embryos for Huntington’s -4
(patient does NOT wish to know HD status
but lab and ART centre know!)
unaffected
unaffected
unaffected
unaffected
unaffected
unaffected
To know, or not to know,
HD status & PGD
Decision to reproduce but
Against Termination of Pregnancy
Know - affected
Direct testing of
embryos for HD
expansion
Don’t wish to know
Direct testing of
embryos for HD
expansion
BUT result NOT
to be revealed
Testing of embryos
using linkage to
grandparental alleles
Exclusion of Huntington’s using
Linkage testing of Embryos
bb
aa
Affected
Unaffected
?
50% risk
Unaffected
a
50% risk
a
50% risk
b
unaffected
b
unaffected
Other “late onset” disorders
Suitable for PGD?
• Muscular dystrophies
• Spinal Muscular Atrophy type
II or III
• Familial cancer predisposition
The Slippery Slope:
Significant risk and seriousness
Is there a limit as
to what we should test for?
And if so, who should decide?
Significant Risk:
Predisposition and penetrance
Familial Adenomatous Polyposis Coli [100%]
Retinoblastoma [90%]
Li Fraumeni syndrome [90%]
HNPCC [70-90%]
Breast malignancy (BRCA1, BRCA2) [50-80%]
Von Hippel Lindau disease [40%]
Hypercholestrolaemia
Short stature
Is Seriousness important
as an indicator for PGD?
• Should criteria for PGD be aligned to
criteria for PND?
• Is seriousness an appropriate indicator
which embryos should be discarded or not?
• What does undertaking PGD say about the
disabled?
“Discrimination against disabled people is
still socially acceptable and people think
they mean well when they support
genetic testing and the elimination of
disease.
As a disabled person, I find it threatening
to have the quality of my life judged to
be not worth living.”
Public consultation
Screening in vs screening
out disorders?
Dwarf
Dwarf
Aa
Aa
Normal Normal
aa
aa
Curing Sibling Genetic Disease
PGD and HLA typing
• Fertile couple with serious genetic
risk undergoes ICSI to produce embryos
in vitro
• Embryos are biopsied and screened for
genetic defect as well as HLA match to
affected sibling chance
• Embryo (s) transferred to produce child
who can be a bone marrow match for
affected sibling
3:4 unaffected / carrier embryo
1:4 embryo HLA matches sibling
= 3:16 chance of both matching
Curing sibling non genetic
disease - HLA typing embryos
• Fertile couple without substantial
genetic risk undergoes ICSI to
produce embryos in vitro
• Embryos are biopsied and screened
for HLA match to affected sibling
(1:4) chance
• Embryo (s) transferred to produce
child who can be a bone marrow or
tissue match for affected sibling
IVF undertaken and embryos created and
good
parent?
biopsied to alleviate disease in a sibling
uncle friend?
or- aunt?
Undertaking PGT where
efficacy doubtful and safety
unknown
1. Conception spontaneously may be equally
efficacious or likely
2. In infertility where IVF is needed, and
embryos are removed from the cohort,
following preimplantation screening
How effective is PGD for translocations?
Guy’s SGD
Guy’s Trans.
ESHRE Recip
ESHRE Rob
Egg
Collection
Biopsy
135
148
592
347
125
125
555
329
ET
113
93
397
260
Clin Preg
38
30
73
66
(%/ET/biop/EC)
(33 / 30 / 28) (32 / 26/ 18) (18 / 13/ 12)
Livebirth
33
(%/ET/biop/EC)
(29 / 26 / 24) (27 /20 /17)
25
(25/ 20/ 19)
• 55
• 50
(13/ 10/ 9)
(19/ 15/ 14)
SGD = single gene defects; rearr.=reciprocal and Robertsonian translocations;
• Assume 75% continue
Spontaneous livebirth rate in women
after previous miscarriage
(Based on > 6000 patients from the St Mary’s Miscarriage Clinic)
Courtesy of Prof Lesley Regan & Mr Raj Rai Imperial College London
Outcome in recurrent miscarriers (>3)
with translocations
Rai, Backos, El-Gaddal, Regan
SGI abstract 889 (2004)
Outcome in next pregnancy in 52 couples (APC negative)
Livebirth
miscarriage
LBR (%)
Recip
12
11
52
Robert
2
2
50
Female
28/52 (54%)
Male
Recip
7
8
47
Robert
7
3
70
Background outcome APC negative with normal karyotype 65% (808/1253)
Is PGD for translocations worth it?
It all depends on why couples want to
embark on PGD
• Previous affected child with high liveborn risk
• Infertility and translocation (e.g. Rob 13;14)
• Feel unable to cope with further pregnancy loss
A child has a
right to an open
future
“Choosing between Possible Lives”
Rosamund Scott
Centre for Preimplantation Genetic Diagnosis