20-03-23 - Prenatal testing

Question 1

Learning outcomes

Answer 1

• 1. to be able to describe (in terms of ‘what, when & why’) the techniques of screening and testing available during the prenatal period: ultrasound, combined test, chorionic villus sampling, and amniocentesis
• 2. to summarise the ethical questions and dilemmas raised by prenatal screening and testing
• 3. to outline the process of NIPT and describe the ethical considerations around its use
• 4. to outline what preimplantation genetic diagnosis (PGD) is, and the circumstances underwhich it can currently be carried out
• 5. to discuss what tissue typing is, and the circumstances underwhich a “savior sibling” can be created
• 6. to summarise the ethical dilemmas arising from PGD, particularly those concerning what is meant by “serious” disability, late onset conditions and prefering disability,
• 7. to appreciate the ethical concerns raised around the application of CRISPR gene-editing technology to humans

Question 2

What does prenatal testing consist of?

What is the focus of prenatal testing?

Where can prenatal problems arise?

Answer 2

• Prenatal testing consists of prenatal screening and prenatal diagnosis
• The focus is on detecting problems with the pregnancy as early as possible
• The problems may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts (as in preimplantation genetic diagnosis) or as early in gestation as practicable screening for chromosomal anomalies.
• The problems might be related to mother – screening for Gestational diabetes

Question 3

What is the difference between prenatal screening and prenatal diagnosis?

What are examples of when each is used?

Answer 3

• Prenatal screening - focuses on finding problems among a large population with affordable and noninvasive methods.
• Example are – Down syndrome, Blood Borne Virus, USS
• Prenatal diagnosis - focuses on pursuing additional detailed information once a particular problem has been found, and can sometimes be more invasive.
• Example are - amniocentesis and chorionic villus sampling

Question 4

What are 4 reasons for prenatal testing?

Answer 4

• 4 reasons for prenatal testing:

1) To enable timely medical or surgical treatment of a condition before or after birth

2) To give the parents the chance to terminate the pregnancy with the diagnosed condition

3) To give parents the chance to prepare psychologically, socially, financially, and medically for a baby with a health problem or disability, or for the likelihood of a stillbirth.

4) To organise appropriate fetal surveillance

Question 5

Who is screening in pregnancy offered to in the UK?

Why is this done?

What do these tests consist of?

Are they diagnostic?

What can be done for diagnosis?

Answer 5

• Screening during pregnancy is offered to all pregnant women in the UK
• This is done to assess either woman or baby have particular health issue or disability
• Simple tests are offered – Blood test, USS or questionnaire
• Not diagnostic
• Follow on tests can be conducted for diagnosis

Question 6

What blood test cans be offered in prenatal testing?

What 4 things can this be used to detect?

Answer 6

• Full blood counts can be offered in prenatal testing
• 5 things can this be used to detect:

1) Blood group

2) Rhesus state
* Rhesus disease is a condition where antibodies in a pregnant woman’s blood destroy her baby’s blood cells

3) Haemoglobinopathies – Thalasemmia and Sickle cell disorder

4) Infectious diseases

5) Chromosomal disorders – Trisomies ( 21, 18 and 13)

Question 7

Screening for Haemoglobinopathies. How can Haemoglobinopathies be inherited?

What groups are high risk?

In what 4 cases can we screen for Haemoglobinopathies?

Describe how autosomal recessive inheritance occurs (in picture)

Answer 7

• Haemoglobinopathies can be Inherited altered haemoglobin gene disorders that are autosomal recessive
• High risk - family origins from Africa, the Caribbean, the Mediterranean, South East Asia, the Middle East and the Far East but can be found (less frequently) in all ethnic groups
• 4 cases can we screen for Haemoglobinopathies:

1) If woman is carrier then partner testing will be offered

2) If partner is positive - genetic counselling
* The giving of advice to prospective parents concerning the risks of genetic disorders in a future child.

3) Amniocentesis or CVS – to see if fetus is affected

4) Newborn – blood spot screening

• how autosomal recessive inheritance occurs (in picture)

Question 8

What 3 syndromes are we screening for when screening for prenatal trisomies?

What kind of pregnancies is testing sensitive for?

What are 5 factors that affect screening for trisomies?

Answer 8

• 3 syndromes are we screening for when screening for prenatal trisomies:
  1) Down’s syndrome (trisomy 21)
  2) Edwards’ syndrome (trisomy 18)
  3) Patau’s syndrome (trisomy 13)
• The test is sensitive for singleton and twin pregnancies, not for any other higher multiple pregnancy.
• 5 factors that affect screening for tirsomies:
  1) Smoking
  2) Ethnicity
  3) BMI
  4) Age
  5) Assisted pregnancy (donor egg or frozen embryo)

Question 9

What is the commonest cause of identifiable learning disability?

What is it usually due to?

What % of those with Down’s syndrome have a congenital abnormality?

What % have profound or severe intellectual impairment?

How common is Down’s syndrome in live births?

How many people in the UK have it?

Describe the graph for Maternal age and Risk of Down’s Syndrome (in picture)

Answer 9

• Down’s syndrome (Trisomy 21) is the Commonest cause of identifiable learning disability
• It is usually due to non- disjunction at chromosome 21 at meiosis.
• 50 % those with Down’s syndrome will have a congenital abnormality
• 80% profound or severe intellectual impairment
• Natural prevalence 1:1000 live births
• There are approximately 40,000 people in the UK with the condition
• Graph for Maternal age and Risk of Down’s Syndrome (in picture)

Question 10

What is the mortality of Edwards’ syndrome (trisomy 18) and Patau’s syndrome (trisomy 13)?

Answer 10

• Most babies with Edwards’ syndrome (trisomy 18) or Patau’s syndrome (trisomy 13) will die before or shortly after birth.
• Some babies may survive to adulthood, but this is rare.

Question 11

What is the optimal time for the First trimester combined test screening for trisomy?

What are the 4 factors used for calculation?

How are results given?

What is the cut off for high and low risk?

Answer 11

• The optimal time for the First trimester combined test screening for trisomy is 11+2 weeks to 14+1 weeks of gestation
• The 4 factors used for calculation:

1) Maternal age

2) Nuchal translucency measurement (NT) ((measure the amount of fluid under the skin at the back of the baby’s neck)

3) Two biochemical markers, free beta hCG and PAPP-A

4) Gestational age calculated from the crown rump length (CRL) measurement (which corresponds to a CRL of 45.0 mm to 84.0 mm.)

• Results – are given as high or low chance
• The cut off is 1 in 150.
• This means that if your screening test results show a risk of between 1 in 2 to 1 in 150 that the baby has Down’s syndrome, this is classified as a higher risk result.
• If the results show a risk of 1 in 151 or more, this is classified as a lower risk result.
• The higher the second number gets, the lower the risk becomes (the less likely you are to have a baby with Down’s syndrome).

Question 12

What is nuchal translucency used for?

Answer 12

• Nuchal translucency is used to measure the amount of fluid under the skin at the back of the baby’s neck.

Question 13

What is the detection rate for down syndrome?

What is the false positive rate?

What is the Edwards’ syndrome detection Rate (DR)?

What is the false positive rate?

Answer 13

• Down’s syndrome detection Rate (DR) is 84%
• 84 out of 100 women carrying Down’s syndrome pregnancies will receive a screen-positive result. The remaining 16% of women carrying Down’s syndrome pregnancies will receive a screen-negative result
• False Positive Rate (FPR) is 2.2%
• This means 2.2% of women who are not carrying Down’s syndrome pregnancies will receive a screen-positive result. (97.8% of women who are not carrying Down’s syndrome pregnancies will receive a screen-negative result
• Edwards’ syndrome detection Rate (DR) is about 85% and False Positive Rate is 0.2%

Question 14

What does the Second Trimester Screening test for trisomy consist of?

What is the optimal time for this?

What are the 2 factors used for calculations?

What is not present in the second trimester screening?

How does the quadruple test compare with that of the combined test in terms of detection rate?

What are the DRs and FPRs for Down’s syndrome and Edward’s syndrome?

When will an ultrasound examination and amniocentesis will be offered?

Answer 14

• The Second Trimester Screening for trisomy is a Quadruple test
• Optimal time is 14+2 -20 weeks
• 2 factors used for calculations:

1) Maternal age

2) Four biochemical markers -AFP, hCG (total, intact or free beta subunit), uE3 and Inhibin-A.

• There are no scans in the 2nd trimester screening
• The Quadruple test has a lower detection rate than the combined test
• Detection rate is 80% and FPR is 3.5%. for Down’s syndrome.
• Detection Rate (DR) is about 73% and FPR 0.1% for Edward’s syndrome
• If the risk of having a term pregnancy affected with Edwards’ syndrome is 1 in 100 or higher an ultrasound examination and amniocentesis will be offered

Question 15

What are the 2 potential results when screening for all trisomies?

How quickly are results given back?

Answer 15

• 2 potential results when screening for all trisomies:

1) Chance of having a baby with Down’s syndrome

2) Combined chance of having a baby with Edwards’ syndrome or Patau’s syndrome.

• If screening test returns a lower-chance result, result should be told within 2 weeks.
• If it shows a higher chance, results should be told within 3 working days of the result being available.

Question 16

What are the 3 options for women who receive a higher-chance result 1:150 from first or second trimester screening tests?

Answer 16

• 3 options for women who receive a higher-chance result 1:150 from first or second trimester screening tests:

1) No further tests

2) A new, more accurate blood screening test called non-invasive prenatal testing (NIPT)

3) Diagnostic tests: chorionic villus sampling (CVS) or amniocentesis (gives chromosomes of baby)

Question 17

What is Non-Invasive Prenatal Testing (NIPT) used for?

When can NIPT be performed?

What is another name for NIPT?

Where does most of the DNA in NIPT from?

How common is a no results” outcome?

What groups is a “no results” outcome common in? How are results given?

When are no further tests offered?

Answer 17

• Non-Invasive Prenatal Testing (NIPT) is used for screening and is not a diagnostic test
• NIPT can be performed from 10 weeks of pregnancy
• NIPT is also known as cell free DNA screening test (cfDNA) , as cell-free DNA material is extracted and analysed from maternal blood test.
• Most of the DNA comes from the mother but a small amount comes from the baby’s placenta.
• In up to 3% of the cases enough cfDNA cannot be extracted to provide the results, this is commoner in overweight women, where we have “No Result”.
• The results are given as low or high chance result
• If the results are low chance then no further test is offered.

Question 18

How accurate is a high result NIPT for different trisomies?

Which trisomy is NIPY better in detecting?

In what scenario is NIPT more accurate?

Answer 18

• Accuracy of NIPT: if the result is high chance then

1) 91 times out of 100 for Down’s syndrome

2) 84 times out of 100 for Edwards’ syndrome

3) 87 times out of 100 for Patau’s syndrome

• NIPT is better at finding babies who have Down’s syndrome than finding babies with Edwards’ syndrome or Patau’s syndrome.
• NIPT is more accurate for women, who’ve already had a higher chance result from their first screening test.

Question 19

How accurate is NIPT in twin pregnancies?

Answer 19

• NIPT can be as accurate in identical twin pregnancies as if you were pregnant with one baby.
• NIPT may be less accurate in non-identical twin pregnancies because there are two placentas releasing their own DNA.

Question 20

What are diagnostic tests used for?

Who are they offered to?

What kind of tests are they?

What is an alternative to this?

Answer 20

• Diagnostic tests are the follow-on tests to find out whether fetus does have a particular condition.
• These are offered to women who have had a ‘higherchance’ result from screening.
• These are invasive tests like chorionic villus sampling or amniocentesis.
• Alternatively, a detailed ultrasound scan can be done

Question 21

What occurs in Chorionic Villi Sampling (CVS)?

When is CVS done?

How often will results not be obtained?

What is there a risk of with CVS?

What 2 types of conditions does CVS test for?

Why do ethical issues arise?

What is the false positive and false negative rate of CVS?

Answer 21

• In Chorionic Villi Sampling (CVS), a fine needle inserted through abdomen and into uterus; or through cervix, & small piece of developing placenta removed
• CVS is done from 11 weeks on wards
• In 2% of cases, no results will be obtained
• There is a risk of miscarriage with CVS
• 2 types of conditions CVS tests for:

1) Inherited disorders (cystic fibrosis, sickle cell, thalassemias, muscular dystrophy) and

2) Chromosomal disorders

• Ethical issues arise due to 2% risk of miscarriage (also, delay in getting results) infection, heavy bleeding
• CVS has a false-positive rate of 1-2%, and a false-negative rate of 2%

Question 22

What occurs during Amniocentesis? In what 3 cases can amniocentesis be used for?

When is amniocentesis done?

What is amniotic fluid aspirated?

What is the risk of miscarriage?

Why do ethical issues arise?

What is the false positive and negative rate of amniocentesis?

Answer 22

• During amniocentesis, a needle is inserted through the abdomen and into amniotic fluid
• 3 cases can amniocentesis be used for:

1) For karotyping if screening tests suggest aneuiploidy

2) DNA analysis if parents carrier of an identifiable gene

3) Enzyme assays for inborn errors of metabolism

• Amniocentesis is Done after 15 weeks
• Amniotic fluid is aspirated to study fetal chromosomes
• Ethical issues arising around amniocentesis due to risk of miscarriage (also, delay in getting results); infection, injury
• False-positive rate of 0.1-0.6%, and a false-negative rate of 0.6%

Question 23

What does ultrasound screening use?

What are 2 positives of ultrasound screening?

What are the 2 times ultrasound screening is carried out?

What kind of abnormalities is it used to identify?

Why do ethical issues arise around ultrasound scanning?

Answer 23

• Ultrasound screening uses sound waves
• 2 positives of ultrasound screening:
  1) Painless
  2) No risk
• 2 times ultrasound screening is carried out:

1) Dating scan: 12 weeks (10 – 14) , number of pregnancies, viability, gestational weeks, NT thickness, Neural tube defects Anomaly scan:

2) 20 weeks (18 – 20 weeks & 6 days)

• Ultrasound Screening is used to find physical abnormalities, e.g. spina bifida, placental position
• Ethical issues arise around ultrasound scanning as everyone is offered anomaly scan, not everyone chooses to take it

Question 24

Who is Preimplantation Genetic Diagnosis (PGD) offered to?

What does PGD involve?

How common and expensive is PGD?

What 2 types of disorders is PGD acceptable for (HFE Act 2008)?

Answer 24

• Preimplantation Genetic Diagnosis (PGD) is offered to couples who are at risk of passing on a genetic disorder
• It involves removing 1 cell from the early embryo (4-8 cell embryo)
• PGD is not common and it’s expensive
• 2 types of disorders PGD is acceptable for (HFE Act 2008):

1) A disorder that may affect capacity for live birth – Risk of child being born with or developing a serious disability (genetic, chromosomal, mitochondrial)

2) If gender-related disorder, can use to select gender – 100+ conditions listed on HFEA site

Question 25

What 6 factors from the Code of Practice can be used to define ‘serious’?

Answer 25

• 6 factors from the Code of Practice can be used to define ‘serious’:
  1) Consider the views of those seeking treatment
  2) Likely degree of suffering
  3) Availability of effective treatment
  4) Speed of degeneration
  5) Extent of intellectual impairment – Social support available
  6) Family circumstances

Question 26

What are the 5 most common genetic conditions in the Caucasian population that PGD can be used to detect?

What guidance is given if a genetic disorder is found using PGD?

Answer 26

• 5 most common genetic conditions in the Caucasian population that PGD can be used to detect:
  1) Cystic fibrosis
  2) Fragile X syndrome
  3) Blood disorders such as sickle cell disease, Hemophilia, VWD
  4) Tay-Sachs disease
  5) Spinal muscular atrophy
• If a genetic disorder is found, professional genetic counseling is usually recommended owing to the host of ethical considerations related to subsequent decisions for the partners and potential impact on their extended families.

Question 27

What type of disease is Huntington’s disease?

When does it manifest?

What are the chances of inheriting HD from an affected parent?

What 3 ethical issues arise around use of PGD for detection of HD?

Answer 27

• Huntington’s disease is an Inherited, late onset, degenerative condition
• It manifests at ~ 30-50 years of age
• 3 ethical issues arise around use of PGD for detection of HD:

1) Prenatal genetic testing for HD - If seek testing, do so on understanding that they will terminate if test positive

2) Prenatal testing means that the parents know something about the child’s future that the child has not elected to know

3) PGD for HD – Thus select an embryo that does not carry the inherited HD gene

Question 28

What is a saviour sibling?

How is the saviour sibling conceived?

What are fertilised zygotes tested for?

Which zygotes re implanted?

What else are zygotes tested for?

What 4 conditions are tested for in the zygote?

Answer 28

• A saviour baby or saviour sibling is a child who is born to provide an organ or cell transplant to a sibling that is affected with a fatal disease, such as cancer or Fanconi anemia, that can best be treated by hematopoietic stem cell transplantation.
• The saviour sibling is conceived through in vitro fertilization.
• Fertilized zygotes are tested for genetic compatibility (human leukocyte antigen (HLA) typing), using preimplantation genetic diagnosis (PGD)
• Only zygotes that are compatible with the existing child are implanted
• Zygotes are also tested to make sure they are free of the original genetic disease.
• 4 conditions are tested for in the zygote:
  1) Fanconi anaemia
  2) Diamond-Blackfan anaemia
  3) B –Thalasemmia
  4) Leukemia

Question 29

What are the 2 ethical complications around saviour siblings?

What is HFEAs stance on saviour siblings?

Answer 29

• 2 Ethical complications around saviour siblings:

1) Potential adverse psychological effects on a child born not for itself but to save another

2) Commodification and welfare of the donor child

• In the United Kingdom, the Human Fertilisation and Embryology Authority (HFEA) has ruled that it is lawful to use modern reproductive techniques to create a saviour sibling

Question 30

What are CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)?

What is CRISPR gene editing?

What can it be used to do?

What are 4 applications of CRISPR gene editing?

Answer 30

• CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) are the hallmark of a bacterial defence system that forms the basis for CRISPR-Cas9 genome
• CRISPR gene editing is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified.
• The technique is considered highly significant in biotechnology and medicine as it allows for the genomes to be edited in vivo with extremely high precision, cheaply and with ease.
• It can be used in the creation of new medicines
• 4 applications of CRISPR gene editing:
  1) Disease models
  2) Biomedicine
  3) Treatment of infection
  4) Cancer.

Question 31

What can be done if the baby is found to be affected in Prenatal genetic diagnosis?

What is an argument against Prenatal genetic diagnosis?

In the UK, what % of those receiving positive test for DS terminate the pregnancy?

Answer 31

• In Prenatal genetic diagnosis, if the baby is found to be affected, people can use this information either to prepare for the birth of a child with a genetic disorder or to terminate the pregnancy
• 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, in practice “in most cases, the reason for prenatal diagnosis is to the prevent the birth of a child with a disability
• “Some argue that babies may now be seen as consumer goods and that health and fertility services have an obligation to monitor the quality of their ‘products’”
• In the UK 89-95% of those receiving positive test for DS terminate pregnancy (Nuffield NIPT report summary, 2017)