Down Syndrome Screening: Detection Rates From 30% to 96%

Down syndrome screening detects about 30% of affected pregnancies when it relies on maternal age alone, and 93 to 96% when maternal age is combined with the nuchal translucency (NT) measurement, the double marker blood test and three further ultrasound markers, at a false-positive rate of 2.5%. This combined first-trimester screen is performed between 11 weeks and 13 weeks 6 days of pregnancy.

Dr. Aanchal Sablok, Senior Consultant - Fetal Medicine, Artemis Hospitals, Gurugram, India, traces how screening moved from that single demographic filter, maternal age, to the combined model. She also makes a point that matters as much for counselling as for detection: an increased NT is a reason for referral, not a diagnosis, and never on its own a reason to end a pregnancy.

Why Down syndrome is the focus of first-trimester screening

In Dr. Sablok's reasoning, trisomy 21 (Down syndrome) dominates screening because of its natural history. Many major chromosomal defects are incompatible with survival, and those pregnancies frequently end on their own. Trisomy 21 does not behave that way. Affected individuals are born and live a long lifespan, which places a sustained load on the family and on the healthcare system. A family whose baby is diagnosed with trisomy 21 therefore needs proper counselling about the problems they may face after birth, and that counselling depends on the condition being identified in pregnancy.

Humans carry 46 chromosomes. An aneuploidy is any departure from that normal number, and the presence of 47 chromosomes with an extra chromosome 21 produces Down syndrome. Screening is offered for all the common aneuploidies, including Edwards and Patau syndromes, but trisomy 21 is the one that dominates the programme.

Down syndrome was first described by John Langdon Down in 1866. The finding that affected fetuses accumulate excess fluid behind the neck, visible on ultrasound in the first trimester, was established in the early 1990s, and screening for the common chromosomal abnormalities has advanced rapidly since.

Why screening on maternal age alone is not enough

Maternal age alone detects only about 30% of Down syndrome cases, because, as Dr. Sablok notes, 70 to 80% of babies with Down syndrome are born to mothers younger than 35. Age is one factor in the risk calculation, not a screening test in itself.

The risk of trisomy 21 does rise with maternal age, and the earliest screening programmes, which started in Europe and the UK, used age as the entry criterion. Women older than 35 were offered invasive testing: a needle was passed into the uterus to draw fluid for genetic analysis. Younger women were not screened.

The guideline position she follows is universal: screening for trisomy 21 should be offered to every pregnant woman, irrespective of her age.

Down syndrome screening detection rates, from 30% to 96%

Each layer added to the screening model raises the detection rate:

• Maternal age alone: about 30%.
• Maternal age plus first-trimester biochemistry (free beta-hCG and PAPP-A) without ultrasound markers: about 60 to 70%.
• Maternal age plus nuchal translucency: about 75 to 80%.
• Maternal age, NT and maternal biochemistry (the double marker): about 85 to 95%.
• The Fetal Medicine Foundation (FMF) combined protocol, adding nasal bone, tricuspid flow and ductus venosus flow: 93 to 96%, at a false-positive rate of only 2.5%.

The biochemistry is the maternal double marker test, a blood test measuring pregnancy-associated plasma protein A (PAPP-A) and beta-hCG. The four ultrasound soft markers, findings that shift the chance of a chromosomal condition without being abnormalities in themselves, are the NT, the nasal bone, the ductus venosus flow and the tricuspid flow. Dr. Sablok's unit at Artemis Hospitals follows the FMF protocol, combining all four soft markers with the double marker to reach that 93 to 96% detection rate.

When the nuchal translucency scan is done

The fetal examination is performed when the crown-rump length (CRL), the length of the fetus from the top of the head to the bottom, is between 45 and 84 millimetres, equivalent to 11 weeks 0 days to 13 weeks 6 days. Dr. Sablok's preference is to see women at around 12 weeks. Because the first-trimester fetus is still developing, the nasal bone may not yet be visible at the smaller end of that range; at around 12 weeks the anatomy is easier to assess and an evolving nasal bone has had time to appear.

How to measure nuchal translucency correctly

Nuchal translucency is measured to strict FMF criteria, because the risk calculation is so sensitive to it. The NT is the fluid collection just behind the back of the fetal neck, and it is the single most important first-trimester soft marker for trisomy 21. Dr. Sablok stresses that her team adheres to each criterion:

1. Neutral position. The fetus must lie in a neutral position.
2. Magnification. The image is magnified so that the fetus occupies approximately 75% of the screen.
3. Sagittal section. The measurement is taken in the sagittal plane.
4. Maximum measurement. The maximum thickness of the NT is recorded.
5. Calliper placement "on to on". Calliper placement is critical, and an NT taken incorrectly produces a wrong risk assessment.

When the umbilical cord is wrapped around the fetal neck, the method changes. The NT is measured above the cord and below the cord, and the average of the two is used.

What a high nuchal translucency means

Most fetuses with an increased NT are healthy. Dr. Sablok's emphasis is on what the numbers do not mean:

• NT between the 95th and 99th centiles. About 93% of these fetuses will be entirely normal. The woman is counselled that other problems may be evolving and need to be looked for, but the most likely outcome is a healthy baby.
• NT above the 99th centile (about 3.5 to 4.4 millimetres). Even here, 70% of these fetuses will be healthy and normal.

The clinical conclusion is unequivocal in her view: a pregnancy should never be terminated on the finding of an increased NT alone. The woman should be referred to a fetal medicine specialist for a proper examination of the baby.

Why the NT is read by centile, not a fixed cut-off

A raw NT figure means little in isolation. The NT increases with gestational age, so a measurement of 2.3 millimetres at 12 weeks cannot be interpreted until it is plotted on a chart against gestation. Dr. Sablok's practice is to look at the centile on which the measurement falls rather than to apply a single fixed cut-off. The higher the centile, the greater the chance of trisomy 21. Fixed cut-offs such as 3 millimetres are sometimes used, but they ignore the change with gestation: the 95th centile of NT rises as the CRL increases, whereas the 99th centile stays at about 3.5 millimetres across the range.

Structural defects linked to an increased NT

Chromosomal abnormality is the first association of a raised NT, but not the only one. An increased NT can accompany structural abnormalities that are still evolving at 12 weeks. When the NT is raised, the fetal medicine examination screens both for chromosomal problems and for structural defects across several systems:

• facial defects
• gastrointestinal defects
• genitourinary defects
• skeletal dysplasias
• body stalk anomaly
• Noonan syndrome

An increased NT in a chromosomally normal fetus is associated with facial, pulmonary, gastrointestinal and genitourinary anomalies, skeletal dysplasias, body stalk anomaly and genetic syndromes such as Noonan syndrome; cardiac defects are a further recognised association in the literature.

This is why the referral matters. A raised NT in a chromosomally normal fetus may still point to a structural problem that a thorough anatomical survey can find. One of Dr. Sablok's own cases shows the reverse situation: in the second twin of a twin pregnancy, what first looked like an increased NT turned out, on closer inspection, to contain septations behind the head, and the diagnosis was monosomy X (Turner syndrome).

What happens after a high-risk screening result

A high-risk result for trisomy 21 leads to invasive diagnostic testing, and a low-risk result leads to the routine anomaly scan at 20 weeks. However high the detection rate, Dr. Sablok is clear that a screening test will never be 100% diagnostic. The combined screen produces a risk figure. The cut-off that defines a high-risk result varies between screening programmes; the UK national screening programme, for example, uses 1 in 150. The result determines the next step:

• High risk for trisomy 21. The next step is invasive diagnostic testing. In the first trimester this is chorionic villus sampling (CVS), in which a small sample of placental tissue is taken for genetic analysis.
• Low risk. The pregnancy continues and proceeds to the routine anomaly scan at 20 weeks.

She also noted that non-invasive prenatal testing (NIPT), a maternal blood test, is offered as an option alongside the double marker test, although her session concentrated on ultrasound rather than on NIPT.

How the combined risk is calculated

At Artemis Hospitals, findings are entered into dedicated fetal medicine software. The CRL and the NT are recorded first, followed by the ductus venosus Doppler, nasal bone and tricuspid flow, together with a structural review of the brain, head, heart, stomach, hands and spine. The software plots the NT against gestation and generates the combined risk.

Where aneuploidy screening fits in the 12-week scan

Dr. Sablok's closing caution is that the 12-week scan should no longer be thought of only as the "NT scan". Aneuploidy screening is the first of several things it does. The same visit diagnoses major structural abnormalities, as described in the complete guide to the first trimester ultrasound, and assesses the mother's risk of preeclampsia and preterm birth, covered in preeclampsia screening at 12 weeks and preterm birth risk.