PRENATAL GENETIC TESTING FACTS, HOPES AND CHALLENGES

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PRENATAL GENETIC TESTINGFACTS, HOPES AND
CHALLENGES

• Nancy Press, PhD
• Schools of Nursing and Medicine
• OHSU

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REPRODUCTIVE GENETIC TESTING A VERY BRIEF
OVERVIEW

• What tests exist?
• How do they work?
• What do they do?
• What changes are taking place?

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REPRODUCTIVE GENETIC TESITNG COMPRISES

• Sample collection
• Amniocentesis
• CVS
• Fetal cells in maternal serum
• Testing modalities
• Karyotyping
• PCR
• Diagnosis of specific disorders
• Both Down Syndrome and CF can be diagnosed from a
  sample obtained through amniocentesis

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INVASIVE MODES OF SAMPLE COLLECTION

• Amniocentesis
• Early amniocentesis
• Chorionic villus sampling

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AMNIOCENTESIS

• A technique for removal, via a needle puncture of
  the uterus, of amniotic fluid containing fetal
  cells
• Any genetic analysis can be performed on these
  cells
• The usefulness of amnioc is tightly linked to
• expanding knowledge about genetics
• development of techniques of fetal analysis
• changing legal and social norms.

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AMNIOCENTESIS KARYOPTYPING

• 1955
• Fluid could be removed from the amniotic sac
• Fetal cells cultured
• Total number of chromosomes, including the sex
  chromosomes could be ascertained
• The first use of karyopting was to identify male
  fetuses of women who carried serious genetic
  conditions on their X chromosome
• This was before abortion was legal

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AMNIO AND DOWN SYNDROME

• A karyotype with 3 copies chromosome 21 (trisomy
  21) was indicative of Down Syndrome
• Implications
• An important source of mental retardation
• Predicted by increasing age rather than narrow
  genetic history
• Set pattern for first establishing technique and
  then expanding indicated diseases

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INSTITUTIONALIZING OF AMNIOCENTESIS IN MID-1970S

• NICHD National Registry for Amniocentesis Study
  Group demonstrated the safety of amniocentesis
• Passage of Roe v. Wade
• Birth of genetic counseling
• Way was opened for population based use of
  amniocentesis for women of advanced maternal age.

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AGE AND AMNIOCENTESIS

• Primary medical complication is fetal loss
• Amnio is offered at the age at which there is an
  equipoise between fetal loss and age-based risk
  of Down Syndrome
• As safety of procedure increased, the age at
  which it is offered decreased
• This assumes that miscarriage and disability are
  bad and equivalent events

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EARLY AMNIOCENTESIS

• Amniocentesis performed in the 11-13th week of
  pregnancy
• Greeted enthusiastically initially
• Recent data suggest possibility of significantly
  greater fetal risks
• higher rates of pregnancy loss
• risk of fetal malformations (e.g. club foot)
• More technically difficult leading to greater
  failure rate

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CHORIONIC VILLUS SAMPLING (CVS)

• Chorionic villi are precursors of the placenta
  and a good source of fetal tissue.
• CVS can be performed safely by 10th week both
  transabdominally and transvaginally
• Risks compare well with second trimester
  amniocentesis
• Waiting period for results is shorter than with
  amniocentesis 3-8 rather than 10-14 days
• Will probably continue to gain ground as the
  early technique

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MATERNAL SERUM FETAL CELL RECOVERY

• A small number of fetal cells are sloughed off
  and cross into maternal blood circulation
• In principle, these cells can then be used for
  any fetal analysis this is the promise of the
  technique
• And it could be simple, cheap, and non-invasive
  enough to be a screen sometime in the future
• However
• Fetal cells in maternal blood are numerically
  rare
• Identification and isolation is difficult
• The type of cell most amenable to isolation is
  not ideal for chromosomal analysis

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ULTRASOUND

• A test unto itself
• Used on the basis of little data for multiple,
  routine screenings
• Shopping mall testing
• Patient demand
• But where did that demand come from?
• Being used in Europe in place of multiple marker
  screening for neural tube defects

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MULTIPLE MARKER SCREENING

• Test revolutionized prenatal diagnosis
• First screening test offered to all pregnant
  women solely to discover risk of fetal anomaly
• Developed for neural tube defects later expanded
  to chromosomal abnormalities
• Began with measure of maternal serum
  alpha-fetoprotein and added other serum markers
• Late 1980s California was first state to mandate
  offer to all pregnant women

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SCREENING VERSUS DIAGNOSIS

• Screening tests search a population of apparently
  healthy persons to isolate those few at increased
  risk.
• Screening tests should be easy, inexpensive, and
  not entail risk for screenee.
• Screening tests can be as simple as ascertaining
  a patients age or ethnicity
• Screening tests have high rates of initial
  positive results and must be followed by
  diagnostic testing.

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SCREENING VERSUS DIAGNOSIS (contd)

• Diagnostic tests are offered to individuals known
  to be at increased risk of a condition
• Some sort of screening process must have been
  used to identify them
• Diagnostic tests answer the question, does this
  person have this disease?
• Diagnostic tests are more complicated and
  expensive to perform and may entail risk.
• Diagnostic tests are expected to do a much better
  job at identifying all (sensitivity) and only
  (specificity) cases of the disorder.

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CURRENT SCREENING PRACTICES FOR SOME POPULATION
SEGMENTS
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CURRENT SCREENING PRACTICES FOR GENERAL POPULATION
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MUST PREGNANT WOMEN BE DIVIDED BY AGE???

• For 25 years maternal age has been used as a
  screen
• Currently there is debate about these guidelines
• This seems based largely on the trend toward
  women bearing children at later ages
• a 2.7-fold increase from 1974 to 1997 in US
• a dramatic increase in number of amnios, meaning
  more fetal loss and economic costs
• The most radical suggestion for changing the
  current routine is to screen women of all ages in
  an identical manner

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SUGGESTED ONE-AGE SCREENING PROTOCOL
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PROS AND CONS OF ONE-STAGE APPROACH

• Advantages
• Believed to have 80-90 detection rate for
  trisomy 21 and other chromosomal abnormalities
• Decrease the number of amniocenteses in older
  women
• Increase the detection rate in younger women
  and, of course , in terms of raw numbers, younger
  women have the greatest number of DS babies

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PROS AND CONS OF ONE-STAGE APPROACH

• DISADVANTAGES
• Gives up universal amnio screening of women 35
  some women would now bear a child with Down
  syndrome who wouldnt have before
• Is it ethicaly acceptable to deny/ withdraw
  accepted medical service a form of health care
  rationing for older pregnant women
• One-age screening detects DS, but not NTDs
• Would not solve problem of multiple screenings
  and multiple chances for initial positive results
  and anxiety.

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PRENATAL SCREENING AND THE EXPERIENCE OF
PREGNANCY

• A 30 year old Southeast Asian
• Offered standard blood work revealing anemia
• Couple offered thalassemia carrier testing and
  are
• Carrier couple offered CVS and are negative
• Later offered multiple marker screening and woman
  is
• Offered amniocentesis
• Outcome Healthy baby and a disastrously
  upsetting and expensive pregnancy.
• There appear to be no empirical data on the
  frequency of such experiences. However,
  variations on this theme are frequently reported
  by obstetric providers.

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ETHICAL ISSUES IN PRENATAL TESTING

• Different parts of the population see very
  different things
• Religious issues
• Disability rights
• The therapeutic gap and genetic optimism
• The missing abortion conversation

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RELIGIOUS OBJECTIONS TO TESTING

• Conservative religious positions may object to
  abortion under all circumstances
• The link of prenatal testing and abortion is
  crystal clear to them
• Offering ? testing is deeply objectionable
• Clear and simple and most ? from this tradition
  know precisely what they think when they begin
  pregnancy

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THE DISABILITY CRITIQUEA POWERFUL CRITIQUE OF
PRENATAL TESTING

• Based on the claim that using, or even offering
  tests to detect fetal anomalies has an expressive
  character that is rejecting and hurtful to those
  who live with disability.
• The choice to abort an otherwise desired fetus on
  the basis of one trait or characteristic, sends
  the message
• that the lives of those with disability are not
  valuable
• that the disability makes the child unacceptable

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THE THERAPEUTIC GAPAND GENETIC OPTIMISM

• Therapeutic gap describes the reality of
  genetic testing today
• This gap has existed for some decades now
• Huntington disease
• Cystic fibrosis
• Gap implies something small
• Genetic optimism keeps the gap metaphor from
  being called into question

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THE MISSING ABORTION CONNECTION

• Discussion of abortion is strangely missing from
  most published work on prenatal testing, as well
  as from most discussions by providers
• Perhaps mentioned at end of a laundry list of
  benefits
• Stated in fairly coded way as giving the benefit
  of reproductive choice

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WHY IS ABORTION SO ABSENT FROM THE PUBLISHED
CONVERSATION??

• I have analyzed two types of goals stated in the
  literature about prenatal testing.
• Societally approved goals
• Controversial goals

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WHAT ARE THE SOCIETALLY APPROVED GOALS?

• Offering reassurance
• Providing information to the health care provider
  about the state of the pregnancy
• Allowing time for parents to prepare
  psychologically
• Permitting special medical preparation for birth
• Possibility of in utero treatment

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WHAT THE SOCIETALLY APPROVED GOALS SHARE

• Focus on benefit to woman or couple rather than
  to the society
• Focus on joint good to mother and fetus
• Are, in broadest sense, "for life"
• However, they are ultimately ancillary goals

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WHAT ARE THE CONTROVERSIAL GOALS?

• The ability to terminate pregnancies where the
  fetus is found to have an anomaly
• The concomitant cost-savings to society trough
  births averted.

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WHAT THE CONTROVERSIAL GOALS SHARE

• They imply that not all life is worthwhile
• That the interests of society may be in conflict
  with those of the fetus
• They raise the specter of eugenics in regard to
  prenatal diagnosis.
• All of these are things which make Americans
  uncomfortable
• The discourse in Europe is different AND makes
  the work of providers easier

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WHAT ARE THESE TENSIONS LIKE EMPIRICALLY?

• The MSAFP Screening Program in California data
  from the beginnings of the program

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PRESS AND BROWNER WORK ON MSAFP TESTING IN
CALIFORNIA

• Interviewed 250 pregnant ? of different race/
  ethnicity and social class
• Interviewed before and after offer of MSAFP
• Observed their prenatal intake appointment
• Interviewed health care providers who offered
  screening (nurses)
• Performed chart review of 1000 pregnant ? (re
  false positive stats)

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FINDINGS

• Very high level of test acceptance (85)
• Very low comprehension of purposes of testing by
  pregnant women
• Great emphasis by HMO on getting test offered
• Effect of making nurses feel pressured and of
  making test seem important
• Language of test offer all on how to get test
  done almost nothing on purpose of test

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FINDINGS

• Test viewed by ? as routine acceptable just as
  its meaning purpose was obscured.
• Test became imbued with the same meanings and
  perceived purposes as routine prenatal care
• Responsible maternal actions
• Providing useful information
• Reassurance
• Protecting the fetus
• Obscuring real purpose of MSAFP screening
• To find cases of untreatable birth defects in
  order to allow women and couples the opportunity
  to terminate a pregnancy

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RELUCTANT ACCEPTORS

• I went back and forth about taking the
  test... 'I should do this I don't know why I'm
  going to do this....What if I get a positive
  result and then you're panicked because you
  think that there is some kind of problem... and
  if there is no problem you feel better but
  there's been a lot of undue stress. But if
  there is a problem, well -- you're already 24
  weeks pregnant. So then you have to make a
  choice and I can't make that choice. For me the
  choice has already been made. We're going to
  have this child.... So now I've gone through all
  of this to find out something is wrong but I'm
  not going to do anything about it anyhow. So
  then I figure, why am I taking this test? I
  don't know, and then I say to myself I'm not
  going to take it and then I come for my
  appointment and I go, 'Fine, here's my arm, take
  my blood'.... In the end it was a matter of
  needing to know everything you can and do
  everything you can."

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SO WHATS A MIDWIFE TO DO?

• Be aware of whole spectrum of possible tests,
  rates of initial positives, waiting periods,
  etc., rather than offering testing on a piecemeal
  basis
• Have systems in place, whenever possible, that
  allows the patient access to varied information
  about life with the disability in question and
  not merely medical information
• Make completely clear the choices available to
  the patient that is the cases where abortion is
  the only intervention possible

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SO WHATS A MIDWIFE TO DO?

• Recognize that prenatal testing poses questions
  about parenting goals and values not primarily
  medical decisions
• Help your patient think through her/their goals
  and values in this regard
• Be truly supportive of whichever choice the
  patient makes
• But dont abandon them in thinking through this
  complicated information
• Be aware of peer pressures moving couples toward
  testing but dont treat those forces as
  illegitimate