Early Pregnancy Screening

Question 1

What is the most common aneuploidy seen in live born infants?

Answer 1

Trisomy 21

Question 2

What is the background risk of T21 if the maternal age is

35?

40?

Answer 2

35 - 1:300

45: 1:100

Question 3

At what gestation should combined first trimester screening (CFTS) be undertaken?

Answer 3

11+0 - 13+6/40

Question 4

What four factors are used to calculate risks for CFTS

Answer 4

Maternal age
USS measurement of NT
PaPP-A (Pregnancy associated plasma protein-A)
B-HCG

Question 5

What is associated with low-PaPP-A, increasing false positives?

Answer 5

Assisted Reproductive Technology

Question 6

At what gestation can NIPT / cell-free DNA testing be performed?

Answer 6

Any gestation from 10/40

Question 7

What is the risk of test failure of NIPT for IVF compared to spontaneously conceived pregnancies?

Answer 7

IVF: 5.2%

Spontaneously conceived: 2.2%

Question 8

At what gestation can MSS2 be performed?

Answer 8

15-20/40

Question 9

At what gestation can amniocentesis be performed from?

Answer 9

15/40

If performed before, increases risk of adverse outcomes like talipes

Question 10

What is the sensitivity and specificity of MSS1?

Answer 10

Sensitivity = 85%

Specificity = 95%

Question 11

What is the sensitivity and specificity of MSS2?

Answer 11

Sensitivity = 70-75%

Specificity = 93%

Question 12

What is the sensitivity and specificity of NIPT?

Answer 12

Sensitivity = 99%

Specificity = 99%

Question 13

At what gestation can CVS be performed from?

Answer 13

11/40

Before this gestation, CVS is associated with an increased risk of transverse limb reduction defects

Question 14

What PAPP-A level is defined as low?

Answer 14

<0.4 MoM (5th centile) on first trimester screen

Question 15

What adverse outcomes is a low PAPP-A associated with

With normal chromosomes

Answer 15

Stillbirth
Infant death
IUGR
PTB
PET
Pregnancy loss <20/40

Question 16

What is an abnormal NT result?

Answer 16

=3.5mm (95th centile)

Question 17

What is an abnormal NT result associated with

With normal chromosomes

Answer 17

Miscarriage
IUFD
Specific structural abnormalities, especially cardiac
Genetic syndromes

Should be referred for tertiary anatomy scan (regardless of MSS result)

Question 18

What is PAPP-A

Answer 18

Pregnancy associated plasma protein A
Large glycoprotein produced by the placenta and decidua

Thought to have several functions including

• prevention of recognition of the fetus by the maternal immune system
• matrix mineralisation
• angiogenesis

Question 19

What is genetic carrier screening?

Answer 19

The detection of carrier status of autosomal and X-linked recessive diseases in couples or people who do NOT have an a priori increased chance of being a carrier based on their or their partners’ personal or family history

Question 20

Who should genetic carrier testing be offered to?

As per RANZCOG

Answer 20

Everyone

Not publicly funded, costs $400
Inequitable

Question 21

What conditions are tested for in Genetic Carrier Screening?

Answer 21

Thalassaemia
Cystic fibrosis
Spinal muscular dystrophy
Fragile X syndrome

Question 22

What are the two options for Genetic Carrier Screening?

Answer 22

1. Sequential
   - cheaper. If normal (majority), no need for partner to get tested
   - gives information on individual, which can inform cascade testing
2. Couple
   - quicker timeframe
   - probably for couple
   - but do not necessarily get access to individual results

Question 23

Outline your counselling points for antenatal aneuploidy screening:

Answer 23

• MSS screens for Down syndrome, Edward and Patau syndrome.
• MSS-1 and MSS-2 funded but not compulsory.
• Detects 75% of of total range of prenatal testable conditions. Negative testing does not guarantee a completely normal baby.
• Screening gives parents options to terminate pregnancy if significant abnormality or make preparations for baby.
• High risk screening requires further invasive testing to confirm diagnosis of an abnormality. Invasive testing has some inherent risks.
• Process may reveal other anomalies not expected.

Question 24

List the antenatal screening tests available including parameters tested and testing gestation etc.

Answer 24

Combined first trimester screening:

• Parameters: NT, maternal age, BhCG, PAPP-A
• Gestation 11+0 to 13+6

MSS-2:

• Parameters: maternal age, alpha-fetoprotein, oestriol, BhCG, inhibin
• Gestation: 15+0 to 20+0 weeks

NIPT/cell-free fetal DNA:
- Gestation: from 10 weeks.

Question 25

List the confounding factors for CFTS:

Answer 25

- IVF conception - Maternal weight - Smoking

Question 26

What is the fetal loss rates for CVS and amniocentesis?

Answer 26

0.5-1% but does not vary between procedures in meta-analysis with experienced operators.

Question 27

Outline the issues with invasive diagnostic testing:

Answer 27

- Can have maternal cell contamination - Failure of cell culture to grow - Rapid FISH analysis can only test limited number of chromosomes, not full karyotype. - Some karyotype abnormalities do not predict the phenotype.

Question 28

What complications are associated with CVS and amniocentesis? What risks are associated specifically with CVS?

Answer 28

- Bleeding - Miscarriage - Amniotic fluid loss - Infection - Rh sensitisation. CVS-specific risks: - Technical failure - Risk of mosaicism.

Question 29

What are the relative contraindications for amniocentesis?

Answer 29

- Active PV bleeding - Unfused amniotic chorionic membranes - Intercurrent maternal febrile illness (defer for 1 week).

Question 30

List the three major ways chromosomes can be assessed:

Answer 30

- Conventional (G-banded) karyotype - Rapid aneuploidy test e.g. FISH analysis - Chromosomal microarray analysis

Question 31

Can MSS and cfDNA be used in triplets and higher order pregnancies?

Answer 31

No

Question 32

What is the altered performance of screening tests in twin pregnancies?

Answer 32

CFTS sensitivity 72-80%; improved to 89% when assessing nasal bones. cfDNA: increased failure rate and less performance data. Higher unreportable rate >5%

Question 33

What are benefits and limitations of CFTS (compared with NIPT)?

Answer 33

Benefits: - Fully funded Limitations: - Positive predictive value 7-10% - Limited gestation of use 11+0 to 13+6 - Lower sensitivity (85%) and specificity (95%)

Question 34

What are benefits and limitations of NIPT (compared with CFTS)?

Answer 34

Benefits: - High sensitivity 99% and specificity 99% - Positive predictive value 45% - A low risk test reduces need for invasive diagnostic testing and fetal loss. - Assesses sex chromosome abnormalities, fetal sex. Limitations: - Not funded and expensive $500-$1000. - Does not provide information on structural abnormalities.

Question 35

Explain the underlying principles of the currently available non-invasive prenatal tests (NIPT) used to detect Trisomy 21: (5 marks)

Answer 35

• Cell-free DNA testing involves taking a maternal blood sample and collecting maternal and fetal DNA fragments (fetal DNA fragments are placental in origin) and comparing them against a reference genome to determine its chromosome of origin and then counting the number of DNA fragments from each chromosome. • Done from 10 weeks as needs sufficient fetal DNA fragments in maternal plasma to analyse. • 99% sensitivity and specificity for Trisomy-21. An appropriate screening tool particularly for trisomy 21 • Is not a diagnostic test; if she has an abnormal test result she should be offered diagnostic testing. Can assess risk of autosomal aneuploidy, sex chromosome aneuploidy and some other conditions and fetal sex

Question 36

Discuss the epidemiology of having a baby with cystic fibrosis (CF) in Australia and New Zealand (5 marks): 

Answer 36

- Most common life-threatening inherited disorder in NZ. - CF affects 1 in 3,500 newborns. - CF most common amongst Northern Europeans and Ashkenazi Jews. Carrier status incidence 1:25. - Less common amongst Africans, Maori and Pacific Islanders.

Question 37

Discuss the genetic basis of cystic fibrosis:

Answer 37

- Cystic fibrosis results from an abnormality in the cystic fibrosis transmembrane conductance regulator protein (CFTR). The CFTR gene is a single large gene encoded on chromosome 7. - Inheritance is autosomal recessive i.e. need two CFTR gene defects. Can be homozygous (same CFTR gene defect) or heterozygous (different CFTR gene defects) with variable disease phenotype. - Most common mutation type is F508del-CTR (75%). - A couple who are both carriers of CFTR gene mutation have a 1 in 4 chance of having a child with cystic fibrosis.

Question 38

A Caucasian couple with a 2 year old child with CF are referred to you by their general practitioner for pre-pregnancy planning. BOTH parents are carriers with an identified CF mutation.  List 4 screening or treatment options available for this couple to avoid having another child affected with CF and provide 1 limitation for each:

Answer 38

1. Preimplantation genetic diagnosis: - Limitation: requires IVF. 2. Non-carrier donor gamete: - Limitation: donor may have unidentified gene mutation. 3. Antenatal amniocentesis: - Limitation: risk of miscarriage; termination if CF affected. 4. cell-free fetal DNA (cfDNA): - Limitation: expensive ($500-$1000) and not funded; still requires invasive diagnostic testing if abnormal.