TEACHINGS / LECTURES / CASES

Soft markers of Down syndrome

Lou Pistorius

September 2002

Two questions for today:

• What are soft markers?

• How should they be used?

What are soft markers of Down syndrome?

Ultrasound       Clinical finding

Soft marker      Minor abnormality

Hard marker      Major abnormality

 

i.e.: a soft marker is a sonographic finding at the anatomy scan which:

• occurs in otherwise normal fetus in the general population,

• occurs more commonly in fetus with Down syndrome,

• is not the sonographic presentation of a major abnormality,

• and increases the relative risk of Down syndrome

For example:

… examples

• Nuchal fold more than 6 mm

• Echogenic bowel

• Short femur

• Echogenic focus in the heart

• Choroid plexus cysts

• Mild hydronephrosis

• and many, many more…

Where do soft markers come from?

• Ultrasound = clinical examination of unborn infant

• Soft markers = sonographic markers of clinical features of Down syndrome

Where do soft markers fit in?
Evolution of screening for Down syndrome

How to screen for Down syndrome: Maternal age

Maternal age: efficiency

• 5% false positive rate,

• 30% sensitivity

Biochemical screening:
…how does it work?

Biochemical screening:
…how does it work?

Biochemical screening:
…how does it work?

Adjusted risk =

    background risk

    x previous history

    x likelihood ratio

Maternal age & biochemical screening: efficiency

• 5% false positive rate,

• 65% sensitivity

From biochemical screening to soft markers:

• Biochemical screening:

  • Ultrasound for gestational age (therefore 15 – 18 weeks)

• Soft markers:

  • Ultrasound as clinical examination (still 15 – 18 weeks)

Soft markers

• 50% sensitivity

• 10% false positive rate

How to combine risks?

• Scoring index (Benacerraf)

• Relative risks (Nicolaides)

• Multivariant analysis (Bahado-Singh)

Relative risks:

• Nuchal fold more than 6 mm 10x

• Echogenic bowel 7x

• Short femur 4x

• Echogenic focus in the heart 3x

• Choroid plexus cysts 1.5x

• Mild hydronephrosis 1.5x

Soft markers: relative risks

• Advantage: easy to combine with prior risk

• Disadvantage: heuristics & biases

• Are the markers:

  • independent

    "the more, the merrier"

• or related

  • "making the same mistake with greater confidence"

• Regression analysis (Bahado-Singh)

  • Guess what is left?

Regression analysis

Bahado-Singh

• What is left?

  • Nuchal skin fold

  • Humerus length

   

• Relative risks:

  • Nuchal skin fold

  • Humerus length

Nuchal translucency is not a soft marker

Nuchal translucency screening

• 5% false positive rate;

• 75% sensitivity

Nicolaides (n = 100 000)

First trimester biochemistry

• Combined with NT:

• 5% false positive rate

• 80% sensitivity

Is it…

time for a total shift to first-trimester screening for Down syndrome

 

Cuckle Lancet 2001; 358:1658-9.

 

?

 

… thereafter: ignore soft markers?

(a good test cannot be improved by combining it with a bad test)