Antenatal screening

Question 1

What options for antenatal screening exist in NZ/Australia?

Answer 1

• MSS1 / first trimester combined screening - MA & USS NT & blood test (bHCG and PAPP-A)
• MSS2 / second trimester maternal serum screening - MA & blood test (Estriol E3, AFP, inhibin, bHCG)
• NIPT - blood test for cell free fetal DNA in maternal circulation
• Monogenic carrier screening - for common recessive / x-linked conditions can be done in the private sector (e.g. cystic fibrosis, spinal muscular atrophy and fragile X syndrome)
• All women should have a FBC to screen for thalassemia and high risk ethnic groups should be considered for more detailed carrier status

Question 2

What gestation can each screening test be used?

Answer 2

MSS1/combined test - 11-13+6 weeks

MSS2/serum test - 15-20 weeks

NIPT - any time after 10 weeks

Question 3

What are the pros and cons of combined screening?

Answer 3

Pros:

• early detection from 11 wks
• sensitivity 85%; specificity 95%
• Includes PAPP-A (also helpful for predicting risk of PET and SGA)
• Includes late 1st trimester scan which can confirm chronicity, abnormal placentation, major anatomical abnormalities (incl. turners syndrome)

Cons:

• Needs to be done at a specific timeframe
• Not as sensitive of specific as NIPT, thus resulting in more anxiety and possible unnecessary invasive testing, and missing more true positive cases
• Serum screening markers can be affected by smoking, obesity and IVF conception

Question 4

What are the pros and cons of NIPT?

Answer 4

Pros:

• Most sensitive (99%) and specific (99%) screening modality
• Can be used at any time after 10 weeks
• Can detect other genetic abnormalities including X-linked and point mutations (e.g. fragile X)

Cons:

• Only available privately - causing health inequity
• In 1-6% cases unable to provide result - NB women with a ‘no call’ result are at higher risk of having a chromosomal abnormality and should be offered USS and either repeat NIPT or routine combined screening
• Obesity can affect the result
• Does not routinely involve USS which can detect other anatomical abnormalities
• May detect genetic imbalances which may have health consequences for the mother and should be included in counselling

Question 5

How does NIPT work?

Answer 5

• Capture fetal Cell free DNA in maternal blood stream which is analysed using real-time PCR (FISH can be used but less accurate)

Question 6

What is the accuracy of each screening test?

Answer 6

First trimester combined - 85%, 95%

second trimester serum - 70-75%, 93%

NIPT - 99%, 99%

Question 7

What would the maternal serum screening be for trisomy 21, 18, 13 and neural tube defects?

Answer 7

T21 - bHCG and inhibin A = high; uE3 and AFP = low

T18 - bHCG, AFP, uE3 = low

T13 - bHCG = low

Open spina bifida- AFP = high, rest normal

Anencephaly - AFP = high, rest low

Question 8

Counsel a woman on amniocentesis.

Answer 8

• Diagnostic test for chromosomal abnormalities
• Undertaken after 15 weeks (prior to this increases risk of limb defects like talipes).
• Day case procedure. Under US guidance a needle is used to remove a sample of amniotic fluid which is sent for genetic testing
• Results take around 2 weeks
• Risks: - 1/100 to 1/1000 risk if miscarriage due to procedure (i.e. above background risk)
• bleeding - infection (chorioamnionitis) 1:1000
• Amniotic fluid leak
• Rhesus isoimunisation
• Limb defects (if <15 weeks)

Question 9

Counsel a woman on CVS.

Answer 9

• It is a diagnositc test for chromosmal abnormalities
• Day case procedure. Under US guidance a needle is used to take a sample of the chorionic villi in the placenta for genetic testing. Can be done transabdoinally or transvaginally, depending on placental location.
• Undertaken after 11 weeks (prior to this increases risk of transverse limb defects), and ususally before 14 weeks.
• Full results take around 2 weeks

Risks:

• 1/100 - 1/500 risk miscarriage due to procedure (i.e. above background risk)
• bleeding
• infection (chorioamnionitis)
• Amniotic fluid leak
• Rhesus isoimunisation
• Limb defects (if <11 weeks)

Question 10

What genetic tests can be conducted on CVS or amniocentesis sample?

Answer 10

• Rapid aneuploidy tests: FISH, quantitive fluorescent PCR (results within 3 days). Looks for specific known abnormalities -for T13/T18/T21 and X/Y.
• G-banded karyotype (traditional method - number length and banding pattern of chromosomes are visually assessed by cytogenetisist)
• Chromosomal microarray / molecular karyotype - assesses microscopic DNA differences (<5-10Mb mutations) across whole genome, and compares it to a normal control genome. More detailed assessment and more sensitive than traditional G-banded karyotype, detecting 10% more significant chromosomal defects. BUT will not detect balanced chromosome rearrangements. Can also detect small mutations of uncertain clinical significance - this needs to be carefully discussed during genetic counselling. (results take 2 weeks or more)

Question 11

Who is offered amniocentesis/CVS?

Answer 11

• High risk of T21, T13 or T18 on combined screening, maternal serum screening or NIPT
• Age >35 years as carries higher risk chromosomal abnormality
• Previous child with chromosomal abnormality
• Family history of certain heritable disease incl.: CF, SMA, haemophilia

Question 12

What is reproductive carrier screening and what are the two options?

Answer 12

• Genetic screening for autosomal recessive or X-linked genetic conditions
• Paired couple screening OR sequential screening (screening the female partner first, then only screenig the male partner if she is a carrier for autosomal recessive or X-linked condition)

Question 13

If both members of a couple are found to carry an autosomal recessive condition, or the woman found to have an x-linked condition, what are their options?

Answer 13

1. Having a child naturally and testing after birth to see if the child is affected.
2. Conceiving naturally and having diagnostic testing during pregnancy to determine if the fetus is affected. This is usually performed with an invasive test (amniocentesis or chorionic villus sampling).
3. Conceiving the pregnancy by in vitro fertilisation (IVF) and testing embryos by preimplantation genetic diagnosis (PGD). Unaffected embryos would then be selected for achieving pregnancy.
4. Using donor sperm, egg or embryo from unaffected individuals.
5. Adoption.
6. Not having children

Question 14

What are the options for aneuploidy screening in twin pregnancies? Evaluate their performance.

Answer 14

Combined first trimester screening

• all serum markers are affected by multiple pregancy and become less accurate
• sensitivity 72-80% (can be improved by USS assesment of nasal bones)
• The serum markers and scans must be obtained within 1-2 days of each other to run the algorithm

NIPT

• Not very comprehensive data on this yet
• Evidence that 100% sensitive for detecting T21
• Higher ‘no-call’ result >5% compared with singeltons, potentially requirirng other screening

Second trimester serum screening

• can be offered but sensitivity and specificity signifcanlty reduced

Question 15

What are the options for aneuploidy screening in triplets and higher order pregnancies?

Answer 15

• serum markers are not validated
• NIPT not validated
• USS assessmeent of NT and nasal bones should be offered at 11-13 weeks

Question 16

What is the risk of downs syndrome at age 35? Age 40? Age 50?

Answer 16

35 = 1 in 350

40 = 1 in 100

50 = > 1 in 10