What are the chances of having a child with Trisomy 21 (Down syndrome)?

Trisomy 21 (Down Syndrome) Risk Assessment

The risk of having a child with Trisomy 21 (Down syndrome) increases significantly with advancing maternal age, with a baseline risk of approximately 1 in 356 at age 35, which can be reduced to less than 1 in 50,000 after a negative cell-free DNA screening test. 1

Age-Related Risk Factors

• Maternal Age: The primary risk factor for Down syndrome, with risk increasing exponentially after age 35 1
• Paternal Factors: In women over 35, having a father aged 20-24 years increases risk compared to fathers aged 25-29 (adjusted prevalence ratio 2.27) 2
• Previous Affected Pregnancy: Women with a previous trisomy 21 pregnancy have approximately 2.2 times higher risk in subsequent pregnancies, with risk being even higher (3.5 times) for women under 35 3

Screening Options and Detection Rates

First Trimester Options:

• Nuchal Translucency (NT) with Maternal Age: Detects approximately 80% of Down syndrome cases when using a risk cutoff of 1 in 300 4

Second Trimester Options:

• Triple Screen (MSAFP, hCG, uE3): Detects approximately 65% of Down syndrome cases 1
• Quad Screen (MSAFP, hCG, uE3, INH-A): Detects approximately 75% of cases in women under 35 and over 80% in women 35 and older 1

Most Effective Option:

• Cell-free DNA (cfDNA): Provides the highest detection rate for trisomy 21 and lowest residual risk, reducing risk by approximately 300-fold 1

Biochemical Marker Patterns in Down Syndrome

• Alpha-fetoprotein (AFP): Typically lower than normal 1, 5
• Human Chorionic Gonadotropin (hCG): Typically higher than normal 1, 5
• Unconjugated Estriol (uE3): Typically lower than normal 1
• Inhibin-A (INH-A): Typically higher than normal 1

Clinical Management Algorithm

1. Assess baseline risk based on maternal age and history of previous affected pregnancies 1, 3

2. Offer appropriate screening based on gestational age:

   • First trimester (10-14 weeks): NT measurement and/or cfDNA 1
   • Second trimester (15-20 weeks): Quad screen or cfDNA if not done earlier 1

3. Interpret screening results:

   • Negative cfDNA result: Extremely low residual risk, no further testing needed 1
   • Negative serum screen: Low residual risk, typically no further testing needed 1
   • Positive screen: Offer diagnostic testing (CVS or amniocentesis) 1

4. Consider ultrasound soft markers in context of screening results:

   • With negative cfDNA: Isolated soft markers do not significantly increase risk 1
   • With negative serum screen: May consider additional testing depending on specific marker 1
   • No previous screening: Offer screening or diagnostic testing 1

Important Considerations and Pitfalls

• Screening vs. Diagnostic Testing: All serum and ultrasound screening tests have false positives and negatives; only diagnostic testing (CVS or amniocentesis) provides definitive results 1

• Gestational Age Accuracy: Ultrasound dating improves screening accuracy; results must be reinterpreted if gestational age changes by 2 or more weeks 1, 5

• Multiple Gestations: Different cutoff values apply for twin pregnancies (e.g., 4.0-5.0 MoM for AFP in twins vs. 2.0-2.5 MoM in singletons) 1, 5

• Demographic Factors: Hispanic ethnicity is associated with higher prevalence of trisomy 21 compared to non-Hispanic white women 2

• Risk Communication: Present risk as both ratios (e.g., 1 in 356) and percentages to improve patient understanding 1

Bold recommendation: For optimal detection of Down syndrome with minimal invasive procedures, cell-free DNA screening is recommended as the primary screening method due to its superior detection rate and extremely low residual risk after a negative result. 1