Reproductive tech: Screening and Testing

Question 1

Define screening test, in the context of pregnancy.

Answer 1

• Offered to all pregnant women to assess the chance of you or your baby having a particular health problem or disability.
• Usually simple tests (for example, a blood test, ultrasound scan or questionnaire).
• Do NOT provide a definite diagnosis, but help you and your midwife decide whether you need further tests to make that diagnosis

Question 2

Define diagnostic test, in the context of pregnancy.

Answer 2

• Follow-on tests that we carry out to find out whether your baby does have a particular condition.
• Offered to women who have had a ‘higher-chance’ result from screening.
• May involve chorionic villus sampling or amniocentesis, which can be associated with a slightly increased risk of miscarriage. Alternatively it may involve a detailed ultrasound scan.

Question 3

Identify possible reasons to carry out screening/testing.

Answer 3

1. To reassure parents (but not straightforward…)
2. To inform and prepare parents for the birth of an affected infant;
   a) Decision on timing, mode and place of delivery
   b) Preparing parents to cope with an affected child
   c) Introducing parents to specialist neonatal services
   d) Ensuring foetal surveillance
3. To allow in utero treatment,
4. To allow termination of an affected fetus
5. To provide information so that parents may choose between 2, 3 or 4 (key issue here = choice)

Question 4

Identify the main screening tests performed on pregnant women.

Answer 4

(for natural conception)

-Non-invasive screening, e.g. ultrasound, serum test (both of them used together in Down’s Syndrome screening)

Question 5

Identify the main diagnostic tests performed on pregnant women.

Answer 5

(for natural conception)

• Invasive prenatal diagnostic (PND) testing, e.g. chorionic villus sampling, amniocentesis
• Non-invasive prenatal genetic testing (NIPT)

(for IVF) (extra testing)
-Preimplantation genetic diagnosis (PGD)

Question 6

What is US ?

Answer 6

Uses sound waves; painless; no risk

Question 7

When and why may we use ultrasound as a screening technique in pregnancy ?

Answer 7

When is it? Two screenings offered:

1) Dating scan: 12 weeks (8 – 14)- get gestational age + viability of the pregnancy
2) Anomaly scan: 20 weeks (18 – 20 weeks and 6 days)- look for structural abnormalities

Why is it?
Anomaly: physical abnormalities, e.g. spina bifida

Question 8

Identify ethical abnormalities arising from US screening.

Answer 8

Everyone is offered anomaly scan, not everyone chooses to take it

Question 9

Describe the screening test for Down’s Syndrome.

Answer 9

♦ Combined screening test, combination of ultrasound and serum test, at 10 – 13+6 weeks (measures the chance of DS, NOT a diagnostic test (note: can also detect other trisomies))

♦ US component: Nuchal translucency (increased translucence if cardiac abnormalities, and in certain trisomies)
Serum component: Analyse markers in blood, including: pregnancy associated plasma protein-A (PAPP-A), decreased in Down’s; free ß-human chorionic gonadotrophin (free ß-hCG), increased in Down’s

Question 10

Identify any ethical issues arising from screening test of Down’s Syndrome.

Answer 10

Risk (low v high); if greater than 1:150 then option to take diagnostic test (amniocentesis or CVS).

Question 11

Down’s Syndrome

• Other names
• Cause
• proportion with congenital abnormality
• proportion with severe intellectual impairment
• prevalence

Answer 11

• Trisomy 21
• Usually due to non- disjunction at chromosome 21 at meiosis
• 50 % will have a congenital abnormality
• 80% profound or severe intellectual impairment
• Natural prevalence 1:600 live births but incidence now 6:10,000 (because often decide to terminate pregnancy)

Question 12

Describe the correlation between maternal age and risk of Down’s Syndrome.

Answer 12

25: 1 in 1500
30: 1 in 1000
40: 1 in 100

Question 13

How specific and sensitive is the combined screening test for DS ?

Answer 13

• False positives (i.e. test indicates DS, but fetus not affected)
2.2%

• False negatives (related to “detection rate”, i.e. test does not indicated DS, but fetus affected)
16%

Question 14

Which screening test is used for DN if the mother presents later than 14 weeks ?

Answer 14

QUADRUPLE TEST

• Used if women presents later (14 weeks 2 days +)
• Blood test: alpha-fetoprotein (AFP) (decreased in DS); total human chorionic gonadotrophin (hCG) (increased in DS); unconjugated oestriol (decreased in DS); inhibin-A (increased in DS)
• No Ultrasound
• If high risk, may offer diagnostic test

Question 15

How specific and sensitive is the quadruple test for DS ?

Answer 15

FP: 3.5%
FN: 20%

Question 16

Amniocentesis

• What does it consist of ?
• When is it performed ?
• Why do we perform it ?

Answer 16

AMNIOCENTESIS
-Needle inserted through the abdomen and into amniotic fluid
-15+ weeks (15 – 18)
-Why:
For karotyping if screening tests suggest aneuiploidy
DNA anaylsis if parents carrier of an identifiable gene
Enzyme assays for inborn errors of metabolism
Diagnosis of foetal infections

Question 17

Identify ethical issues associated with amniocentesis.

Answer 17

0.5-1% risk of miscarriage (also, delay in getting results); infection, injury

Question 18

How specific and sensitive is amniocentesis ?

Answer 18

FP: 0.1-0.6%
FN: 0.6%

Question 19

Chorionic Villus Sampling

• What does it consist of ?
• When is it performed ?
• Why do we perform it ?

Answer 19

Chorionic Villus Sampling
-Fine needle inserted through abdomen and into uterus; or through cervix, and small piece of developing placenta removed

-11 weeks (11-14 weeks)

-Why:
Tests for inherited disorders (cystic fibrosis, sickle cell, thalassemias, muscular dystrophy) and chromosomal disorders ; (sex) – allows you to test earlier in pregnancy

Question 20

How specific and sensitive is chorionic villus sampling ?

Answer 20

FP: 1-2%
FN: 2%

Question 21

Identify ethical issues associated with chorionic villus sampling.

Answer 21

1%risk of miscarriage (also, delay in getting results); infection; heavy bleeding

Question 22

Identify examples of diseases for which DNA tests are available.

Answer 22

• Cystic fibrosis
• Phenylketonuria
• Tay-Sachs
• Duchenne Muscular dystrophy
• Huntington’s disease (adult onset)
• Inherited breast and ovarian cancers

Question 23

Non-invasive prenatal genetic testing/diagnosis (NIPT/D)

• what does it consist of ?
• when ?
• why ?

Answer 23

Non-invasive prenatal genetic testing (NIPT)
-Cell-free foetal DNA (DNA from placenta, v similar to DNA from foetus)
-9— 10 weeks
-Why:
• Risk of chromosomal abnormalities with more accuracy than other non-invasive methods (invasive still required for definitive result)
• Definitive diagnosis of some conditions (e.g. cystic fibrosis, achrondroplasia)
• Can determine gender

Question 24

What are the main reasons for a prenatal genetic diagnosis ?

Answer 24

If the baby is found to be affected, people can use this information to:

• prepare for the birth of a child with a genetic disorder (there are some conditions, such as spina bifida, where advance warning of the disease may be relevant to the method of delivery and care of the newborn)
• terminate the pregnancy

Question 25

What proportion of parents with prenatal diagnosis of DS decide to terminate the pregnancy ?

Answer 25

In the UK 89-95% of those receiving positive test for DS terminate pregnancy

Question 26

Preimplantation genetic diagnosis (PGD) - What does it consist of ? - Who is it offered to ? - Cons of use

Answer 26

Preimplantation genetic diagnosis -What does it consist of ? It involves removing 1 cell from the early embryo (4-8 cell embryo) (in IVF) - Who is it offered to ? Offered to couples who are at risk of passing on a genetic disorder - Cons: expensive (but may be cheaper in the long term?)

Question 27

Is NIPT offered in the NHS ?

Answer 27

No, but can be obtained privately

Question 28

What disorders may PGD used for ?

Answer 28

- A disorder that may affect capacity for live birth - Risk of child being born with or developing a "serious" disability (genetic, chromosomal, mitochondrial) - If gender-related disorder, can use to select gender - 100+ conditions listed on HFEA site ``` To determine what a "serious" disability is: ○ Take into consider the views of those seeking treatment ○ Likely degree of suffering ○ Availability of effective treatment ○ Speed of degeneration ○ Extent of intellectual impairment ○ Social support available ○ Family circumstances ```

Question 29

Identify adult onset conditions.

Answer 29

Huntington’s, cancers

Question 30

What type of disease is Huntington's ? What age does it manifest at ?

Answer 30

Inherited, late onset, degenerative condition | Manifests ~ 30-50 yrs

Question 31

What probably do you have to inherit Huntington's from your parents if one parent has it ?

Answer 31

50/50 (non sex linked dominant inheritance pattern)

Question 32

Identify the main issues associated with testing for Huntington's disease.

Answer 32

1) Prenatal genetic testing for HD - If seek testing, do so on understanding that they will terminate if test positive - Why? Testing is only available to adults, and not all at risk choose to take it; prenatal testing means that the parents know something about the child’s future that the child has not elected to know 2) PGD for HD - Thus select an embryo that does not carry the inherited HD gene

Question 33

Identify the main issues that arise with genetic testing.

Answer 33

1) Adult onset conditions e. g. Huntington’s, cancers 2) Carriers (fetus may not suffer from disease but may be a carrier, does that change how we deal with this) 3) Preference FOR disabled embryos (in IVF) - The case of Tomato Lichy and Paula Garfield (did not want to positively select but said it should be a choice by the parents rather than having to choose able one)

Question 34

Describe what is meant by savior sibling. Is this allowed ?

Answer 34

♠ Create an embryo (using PGD) that will be a tissue match (“tissue typing”) (including HLA match) for an existing child who has a condition that requires e.g. bone marrow transplant ♠ Initially (2001): this was approved for removal of cord blood cells (source of stem cells) AND the embryo had to be at risk of inheriting the same disorder But in 2004 both of these conditions were removed, hence bone marrow transplant now possible (although solid organ donation is prohibited)

Question 35

Identify examples of savior siblings, the condition involved and the ruling of each.

Answer 35

1) Hashmi family (2002) Beta-thalassaemia, inherited UK (HFEA) granted permission 2) Whittaker family (2002) Diamond Blackfan anaemia, not inherited UK (HFEA) refused; US granted 3) Fletcher family (2004) Diamond Blackfan anaemia, not inherited UK (HFEA) granted approval (change of regulation in 2004)

Question 36

Explain the ethical issues associated with savior siblings.

Answer 36

• Is the saviour sibling being “used” as a means (to help the other child) rather than an end in themselves (just for being them)? BUT people have children for all kinds of reasons • What is the psychological effect on the saviour sibling (and the existing child) and their resultant relationship? BUT then, what of the impact of bereavement on a family? One way or the other, need to consider 4 principles of medical ethics for parents, existing child, and for savior sibling child.

Question 37

Consider the following questions: 1) Do you think, with the advent of NIPD, that genetic screening should be available to all pregnant women? If so, for which conditions? 2) Do you think that PGD should be allowed, if so, for which conditions? 3) What concerns do you have over the creation of “savior siblings”?

Answer 37

OK