What are the recommended screening and diagnostic tests for detecting Down syndrome in a fetus?

Prenatal Testing for Down Syndrome

For prenatal Down syndrome detection, offer first-trimester combined screening (nuchal translucency ultrasound plus PAPP-A and free β-hCG at 11-13 weeks) to all pregnant women, with diagnostic confirmation via chorionic villus sampling (10-13 weeks) or amniocentesis (≥15 weeks) for screen-positive results.

Screening Tests (Non-Invasive)

First-Trimester Combined Screening (Recommended Approach)

First-trimester combined screening is the preferred initial approach, combining three components performed between 10 weeks 3 days and 13 weeks 6 days of gestation 1:

• Nuchal translucency (NT) measurement via ultrasound—measures the fluid-filled space at the back of the fetal neck 1
• Pregnancy-associated plasma protein A (PAPP-A) in maternal serum 1
• Free β-subunit of human chorionic gonadotropin (free β-hCG) in maternal serum 1

Performance characteristics: At 11 weeks gestation with a 5% false-positive rate, this combination detects 87% of Down syndrome cases 2. Detection rates decrease slightly at later gestational ages (85% at 12 weeks, 82% at 13 weeks) 2. Free β-hCG performs better than intact hCG before 11 weeks and remains superior through 13 weeks when combined with other markers 1.

Second-Trimester Screening (Alternative)

Second-trimester quadruple screening is performed at 15-18 weeks and measures 2:

• Alpha-fetoprotein
• Total human chorionic gonadotropin
• Unconjugated estriol
• Inhibin A

Performance: Detects 81% of Down syndrome cases at a 5% false-positive rate 2. This is less effective than first-trimester screening at 11 weeks but comparable to first-trimester screening performed at 13 weeks 2.

Integrated Screening Approaches (Highest Detection)

Fully integrated screening combines first-trimester measurements (NT, PAPP-A, free β-hCG at 11 weeks) with second-trimester quadruple markers, providing a single risk result 2. This achieves the highest detection rate of 96% at a 5% false-positive rate 2.

Stepwise sequential screening provides risk results after each trimester's testing and detects 95% of cases at a 5% false-positive rate 2.

Diagnostic Tests (Invasive)

Chorionic Villus Sampling (CVS)

CVS is the diagnostic option for first-trimester confirmation, typically offered between 10 weeks 0 days and 12 weeks 6 days of gestation, though many physicians perform it through 13 weeks 6 days 1.

• Provides definitive karyotype analysis to confirm or exclude Down syndrome 1
• Fetal loss risk: 1.32 times higher than amniocentesis (odds ratio 1.32,95% CI 1.11-1.57) 3
• Potential concern: Some case-control studies suggest increased risk of transverse limb deficiency 3

Amniocentesis

Amniocentesis is offered beginning at 15 weeks gestation as the standard diagnostic test 1.

• Provides definitive karyotype analysis 1
• Fetal loss risk: 1.7% when performed after 16 weeks versus 0.7% in controls (difference of 1%, 95% CI 0.3%-1.5%) 3
• Lower complication rate than CVS, making it the preferred diagnostic option when timing permits 3

Clinical Algorithm

For All Pregnant Women:

1. Offer first-trimester combined screening at 11-13 weeks (optimal timing: 11 weeks) 1, 2
2. Screen-negative results: Transmit to referring physician by standard methods 1
3. Screen-positive results: Promptly notify referring physician by phone/fax within one working day 1

For Screen-Positive Results:

1. Provide genetic counseling to discuss risks, diagnostic options, and implications 1
2. Offer diagnostic testing:
   • CVS if still in first trimester (10-13 weeks) 1
   • Amniocentesis if ≥15 weeks gestation 1
3. Consider family history: Refer for genetic counseling if multiple family members have Down syndrome, suggesting possible familial translocation 1

For Women ≥35 Years at Delivery:

Offer diagnostic testing (CVS or amniocentesis) directly due to age-related increased risk, though first-trimester screening may be offered as an alternative 3.

Critical Caveats

Timing is crucial: NT measurement must be performed by appropriately trained ultrasonographers within the narrow gestational age window of 10 weeks 3 days to 13 weeks 6 days 1, 4. Performance deteriorates outside this window 2.

Enlarged NT has broader implications: An increased NT measurement indicates not only Down syndrome risk but also increased risk for spontaneous abortion and other fetal abnormalities not detectable by karyotype analysis 4. These pregnancies require first-trimester counseling and follow-up ultrasound with fetal echocardiography in the second trimester 4.

Screen-positive reclassification risks: Avoid reclassifying screen-positive women as screen-negative when gestational age is revised, as this creates risk of converting a true positive to a false negative 1. This is less problematic with first-trimester screening that includes NT and CRL measurements 1.

Modifying factors affect interpretation: Results require adjustment for maternal race, family history, twin pregnancies, maternal weight, and accurate gestational age determination 1.

Most screen-positive results are false positives: Delivery of an unaffected infant is the most common outcome associated with high Down syndrome risk estimates 1. At a 5% false-positive rate with triple-marker screening, the true-positive rate is only 0.1% while the false-positive rate is 3.7% 3.