Downs_Syndrome_Antenatal_Testing

Question 1

What guidelines were issued by NICE in 2021 regarding Down’s syndrome antenatal screening?

Answer 1

The combined test is now standard and should be done between 11 - 13+6 weeks.

Question 2

What does the combined test for Down’s syndrome include?

Answer 2

Nuchal translucency measurement + serum B-HCG + pregnancy-associated plasma protein A (PAPP-A).

Question 3

What are the markers for Down’s syndrome in the combined test?

Answer 3

Increased HCG, decreased PAPP-A, thickened nuchal translucency.

Question 4

What similar results are seen for trisomy 18 (Edward syndrome) and trisomy 13 (Patau syndrome) in the combined test?

Answer 4

Increased HCG tends to be lower in these conditions.

Question 5

What is offered to women who book later in pregnancy for Down’s syndrome screening?

Answer 5

The quadruple test between 15 - 20 weeks.

Question 6

What does the quadruple test for Down’s syndrome include?

Answer 6

Alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, and inhibin A.

Question 7

What are the typical results for Down’s syndrome in the quadruple test?

Answer 7

Decreased alpha-fetoprotein, decreased unconjugated oestriol, increased human chorionic gonadotrophin, increased inhibin A.

Question 8

What are the typical results for Edward’s syndrome in the quadruple test?

Answer 8

Decreased alpha-fetoprotein, decreased unconjugated oestriol, decreased human chorionic gonadotrophin, normal inhibin A.

Question 9

What are the typical results for neural tube defects in the quadruple test?

Answer 9

Increased alpha-fetoprotein, normal unconjugated oestriol, normal human chorionic gonadotrophin, normal inhibin A.

Question 10

What are the possible outcomes of the combined or quadruple tests?

Answer 10

Lower chance or higher chance result.

Question 11

What does a ‘lower chance’ result mean in the context of combined or quadruple tests?

Answer 11

1 in 150 chance or more e.g. 1 in 300.

Question 12

What does a ‘higher chance’ result mean in the context of combined or quadruple tests?

Answer 12

1 in 150 chance or less e.g. 1 in 100.

Question 13

What is offered to women with a ‘higher chance’ result from the combined or quadruple tests?

Answer 13

A second screening test (NIPT) or a diagnostic test (e.g. amniocentesis or chorionic villus sampling (CVS)).

Question 14

What does NIPT stand for?

Answer 14

Non-invasive prenatal screening test.

Question 15

What does NIPT analyze?

Answer 15

Small DNA fragments that circulate in the blood of a pregnant woman (cell free fetal DNA, cffDNA).

Question 16

Where does cffDNA derive from?

Answer 16

Placental cells and is usually identical to fetal DNA.

Question 17

What does the analysis of cffDNA allow for?

Answer 17

Early detection of certain chromosomal abnormalities.

Question 18

How high are the sensitivity and specificity of NIPT for trisomy 21?

Answer 18

Greater than 99%.

Question 19

At what gestation do private companies offer NIPT screening?

Answer 19

From 10 weeks gestation.

Question 20

summarise Down’s syndrome: antenatal testing

Answer 20

Down’s syndrome: antenatal testing

NICE issued updated guidelines on antenatal care in 2021 including advice on screening for Down’s syndrome
the combined test is now standard
these tests should be done between 11 - 13+6 weeks
nuchal translucency measurement + serum B-HCG + pregnancy-associated plasma protein A (PAPP-A)
Down’s syndrome is suggested by ↑ HCG, ↓ PAPP-A, thickened nuchal translucency
trisomy 18 (Edward syndrome) and 13 (Patau syndrome) give similar results but the hCG tends to lower
quadruple test
if women book later in pregnancy the quadruple test should be offered between 15 - 20 weeks
quadruple test: alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotrophin and inhibin A

Interpreting the results of quadrapule tests

Alpha-fetoprotein Unconjugated oestriol Human chorionic gonadotrophin Inhibin A
Down’s syndrome ↓ ↓ ↑ ↑
Edward’s syndrome ↓ ↓ ↓ ↔
Neural tube defects ↑ ↔ ↔ ↔

Results of combined or quadruple tests

Both the combined and quadruple tests return either a ‘lower chance’ or ‘higher chance’ result
‘lower chance’: 1 in 150 chance or more e.g. 1 in 300
‘higher chance’: 1 in 150 chance or less e.g. 1 in 100

Non-invasive prenatal screening test (NIPT)

If a woman has a ‘higher chance’ results she will be offered a second screening test (NIPT) or a diagnostic test (e.g. amniocentesis or chorionic villus sampling (CVS). Given the non-invasive nature of NIPT and extremely high sensitivity and specificity, it is likely this will be the preferred choice for the vast majority of women.

NIPT
analyses small DNA fragments that circulate in the blood of a pregnant woman (cell free fetal DNA, cffDNA)
cffDNA derives from placental cells and is usually identical to fetal DNA
analysis of cffDNA allows for the early detection of certain chromosomal abnormalities
sensitivity and specificity are very high for trisomy 21 (>99%) and similarly high for other chromosomal abnormalities
private companies (e.g. Harmony) offer NIPT screening from 10 weeks gestation

Question 21

A 34-year-old woman presents to the antenatal clinic. She is 16 weeks pregnant and she discovered her pregnancy just last week, as it was unexpected for her. She has already been pregnant three times but she had three spontaneous abortions.

The midwife offers her a quadruple test due to her late discovery of her pregnancy, which shows the following:

Alpha-fetoprotein (AFP) ↓
Unconjugated oestriol (uE3) ↓
Total human chorionic gonadotrophin (hCG) ↓
inhibin-A ↔

What is the most likely diagnosis?

Autosomal recessive polycystic kidney disease (ARPKD)
Down’s syndrome
Edward’s syndrome
Neural tube defects
Turner’s syndrome

Answer 21

Edward’s syndrome

Edward’s syndrome: quadruple test result
↓ AFP
↓ oestriol
↓ hCG
↔ inhibin A

Edward’s syndrome is the correct answer. The quadruple test is a screening test used to find patients with a higher chance of having pregnancies where the fetus is affected by Down’s syndrome, Edwards’ syndrome, Patau’s syndrome, or neural tube defects. It is usually offered to patients who discovered their pregnancy late and are not suitable anymore for the combined test. In this case, the results indicate Edward’s syndrome, caused by trisomy 18. It would present with micrognathia, low-set ears, rocker bottom feet and overlapping fingers.

Autosomal recessive polycystic kidney disease (ARPKD) is a condition which can be diagnosed prenatally with an ultrasound but not with a quadruple test.

Down’s syndrome would present with low AFP, low unconjugated oestriol, but high hCG and inhibin A.

Neural tube defects would present with isolated high AFP and normal oestriol, hCG and inhibin A.

Turner’s syndrome is a genetic syndrome characterised by only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. It is not screened using the quadruple tests.

Question 22

Due to her age, a 42-year-old pregnant woman is screened for chromosomal abnormalities. If her baby has trisomy 21 (Down’s syndrome), which of the following results would be expected?

High alpha fetoprotein (AFP)
High oestriol
Low human chorionic gonadotrophin beta-subunit (-HCG)
Low pregnancy-associated plasma protein A (PAPP-A)
Reduced nuchal translucency

Answer 22

Low pregnancy-associated plasma protein A (PAPP-A)

The following results would be expected in a trisomy 21 (Down’s syndrome) pregnancy:
Low alpha fetoprotein (AFP)
Low oestriol
High human chorionic gonadotrophin beta-subunit (-HCG)
Low pregnancy-associated plasma protein A (PAPP-A)
Thickened nuchal translucency

In the UK, all pregnant women are offered the ‘combined test’ at 11-13+6 weeks to screen for autosomal trisomies. This involves PAPP-A and -HCG blood tests along with nuchal translucency measurement by ultrasound. It has a 75% sensitivity and 3% false positive rate.

The ‘triple test’ may be used at 16 weeks but is less accurate than the ‘combined test’ and so should only be used when trisomy screening is performed after 14 weeks. It consists of AFP, -HCG and oestriol blood tests.

Question 23

A 25-year-old female patient, 12 weeks pregnant, attends for a routine scan. She agrees for her baby to be screened for chromosomal disorders using the ‘combined test’, which is explained to her. The scan is undertaken, as is a blood test.

After a few days, she is told that the result shows a higher chance of her baby having Down’s syndrome and invited to the hospital to discuss the results and next steps.

What combination of results from her combined test would have indicated a higher chance of Down’s syndrome?

Reduced nuchal translucency, increased B-HCG, increased alpha-fetoprotein (AFP)
Reduced nuchal translucency, increased B-HCG, reduced PAPP-A
Reduced nuchal translucency, reduced B-HCG, reduced alpha-fetoprotein (AFP)
Thickened nuchal translucency, increased B-HCG, reduced PAPP-A
Thickened nuchal translucency, reduced B-HCG, reduced PAPP-A

Answer 23

Thickened nuchal translucency, increased B-HCG, reduced PAPP-A

Down’s syndrome is suggested by ↑ HCG, ↓ PAPP-A, thickened nuchal translucency

The combined test for Down’s syndrome consists of assessment of nuchal translucency on the 12-week scan, and blood tests for B-HCG and PAPP-A. This can only be performed between 11 and 13+6 weeks. The chance of Down’s syndrome is raised when nuchal translucency is demonstrated to be thickened, B-HCG is raised, and PAPP-A is low.

The other options are therefore incorrect.

If women book in too late for the combined test, the triple or quadruple test should be offered between 15-20 weeks. AFP, mentioned in some of the options, plays a part in this later screening, and would be low when there is a higher chance of Down’s syndrome.

Question 24

A 41-year-old woman presents to the antenatal clinic. She is 17 weeks pregnant and she discovered her pregnancy just last week, as it was unexpected for her, following years of failed fertility treatments. She has already been pregnant six times but she had three spontaneous abortions.

The doctor offers her a quadruple test due to her late discovery of her pregnancy, which shows the following:

Alpha-fetoprotein (AFP) ↓
Unconjugated oestriol (uE3) ↓
Total human chorionic gonadotrophin (hCG) ↓
inhibin-A ↑

What is the most likely diagnosis?

Autosomal recessive polycystic kidney disease (ARPKD)
Down’s syndrome
Neural tube defects
Patau syndrome
Turner’s syndrome

Answer 24

Patau syndrome

Down’s syndrome combined screening: trisomy 18 (Edward syndrome) and 13 (Patau syndrome) give similar results but the hCG tends to be lower, whereas in Down’s it is raised

Patau syndrome is the correct answer. The quadruple test is a screening test used to find patients with a higher chance of having pregnancies where the fetus is affected by Down’s syndrome, Edwards’ syndrome, Patau’s syndrome, or neural tube defects. It is usually offered to patients who discovered their pregnancy late and are not suitable anymore for the combined test. In this case, the results indicate Patau syndrome, caused by trisomy 13. It would present with microcephalia, small eyes, cleft lip/palate, polydactyly and scalp lesions.

Autosomal recessive polycystic kidney disease (ARPKD) is a genetic Domitian condition affecting the development of the kidneys and causing cysts to form. It can be diagnosed prenatally with an ultrasound but not with a quadruple test.

Down’s syndrome also known as trisomy 21, is a genetic condition that would present with low AFP, low unconjugated oestriol, but high hCG and inhibin A.

Neural tube defects, the most common manifestations of which are spina bifida and anencephaly, would present with isolated high AFP and normal oestriol, hCG and inhibin A.

Turner’s syndrome is a genetic syndrome characterised by only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. It is not screened using the quadruple tests.