What is the management approach for patients with suspected soft markers for Down syndrome?

Management of Soft Markers for Down Syndrome

If aneuploidy screening (serum or cfDNA) is negative and only an isolated soft marker is present, no further aneuploidy evaluation is needed—diagnostic testing is not recommended solely for isolated soft markers after negative screening. 1

Management Algorithm Based on Screening Status

For Patients WITH Negative Screening Results

The management differs significantly based on which specific soft marker is identified and the type of prior screening:

Low-Risk Markers (No Further Testing Needed)

• Echogenic intracardiac focus: No further evaluation required after negative serum or cfDNA screening—this is a normal variant with no clinical significance and no indication for echocardiography, follow-up ultrasound, or postnatal evaluation 1
• Choroid plexus cysts: No further aneuploidy evaluation needed after negative serum or cfDNA screening—this is a normal variant requiring no follow-up imaging or postnatal evaluation 1
• Echogenic bowel, urinary tract dilation, or shortened humerus/femur: No further aneuploidy evaluation required after negative serum or cfDNA screening 1

Higher-Risk Markers (Requires Nuanced Approach)

• Thickened nuchal fold or absent/hypoplastic nasal bone with negative cfDNA: No further aneuploidy evaluation 1
• Thickened nuchal fold or absent/hypoplastic nasal bone with negative serum screening only: Counsel regarding residual risk of trisomy 21 and discuss options including no further testing, cfDNA screening, or diagnostic amniocentesis based on clinical circumstances and patient preference 1

The distinction here is critical: thickened nuchal fold has a positive likelihood ratio of 11-23 for Down syndrome, making it one of the most specific markers 1. When only serum screening (not cfDNA) is negative, the residual risk may still warrant consideration of further testing given the high likelihood ratio of this marker 1.

For Patients WITHOUT Prior Screening

Counsel all patients to estimate probability of aneuploidy and offer noninvasive screening:

Standard-Risk Markers

For isolated echogenic intracardiac focus, echogenic bowel, urinary tract dilation, or shortened humerus/femur:

• Counsel to estimate probability of trisomy 21 1
• Offer cfDNA screening, or quad screen if cfDNA unavailable or cost-prohibitive 1
• Diagnostic testing is not recommended solely for these indications 1

Higher-Risk Markers

For isolated thickened nuchal fold or absent/hypoplastic nasal bone:

• Counsel to estimate probability of trisomy 21 1
• Offer cfDNA or quad screen if cfDNA unavailable 1
• Also discuss diagnostic amniocentesis as an option depending on clinical circumstances and patient preference 1

This reflects the substantially higher likelihood ratios for these markers (LR 11-23 for thickened nuchal fold) 1.

Trisomy 18 Markers

For isolated choroid plexus cysts:

• Counsel regarding probability of trisomy 18 (not trisomy 21) 1
• Offer cfDNA or quad screen if cfDNA unavailable 1

Marker-Specific Additional Management

Beyond aneuploidy evaluation, certain markers require additional workup:

Echogenic Bowel

• Evaluate for cystic fibrosis 1
• Test for fetal cytomegalovirus (CMV) infection 1
• Perform third-trimester ultrasound for reassessment and fetal growth evaluation 1

Shortened Humerus/Femur

• Evaluate for skeletal dysplasias with thorough measurement of all appendicular bones compared to gestational age nomograms 1
• Perform third-trimester ultrasound for reassessment and growth evaluation 1
• Note: Many skeletal dysplasias fall below 3rd percentile in second trimester, except achondroplasia which may not manifest until third trimester 1

Urinary Tract Dilation (UTD)

• Classify as A1 (low risk) versus A2-3 (increased risk) based on anterior-posterior renal pelvis diameter and additional features 1
• For UTD A1: Ultrasound at ≥32 weeks to determine need for postnatal pediatric urology/nephrology follow-up 1
• For UTD A2-3: Individualized follow-up ultrasound with planned postnatal follow-up 1

Single Umbilical Artery

• No additional aneuploidy evaluation regardless of screening status 1
• Third-trimester ultrasound to evaluate growth 1
• Consider weekly antenatal fetal surveillance beginning at 36 0/7 weeks gestation 1

Critical Pitfalls to Avoid

Do not perform diagnostic testing solely for isolated soft markers after negative screening 1. This is a Grade 1B recommendation and represents strong evidence that the risks of amniocentesis outweigh benefits in this scenario.

Do not order serial ultrasounds to monitor evolution of thickened nuchal fold—this is not indicated regardless of aneuploidy evaluation pursued 1.

Do not perform fetal echocardiography for isolated echogenic intracardiac focus after negative screening—this is a normal variant 1.

Recognize that likelihood ratios guide risk modification: LRs of 1.5-5 confer small increases in risk, LRs of 5-10 confer moderate increases, and LRs >10 confer substantial increases 1. This framework helps contextualize which markers warrant more aggressive evaluation.

Multiple soft markers or presence of structural abnormalities change the entire approach—the guidelines above apply only to isolated markers 1, 2. When multiple markers or cardiac defects are present, diagnostic testing should be offered rather than screening alone 2.